Neil Osterweil

Further evidence for the benefit of adding immune checkpoint inhibitors to neoadjuvant chemotherapy in patients with early high-risk estrogen receptor–positive, HER2-negative (HR+/HER2–) breast cancer comes from results of two randomized trials presented at the annual meeting of the European Society for Medical Oncology.

In the KEYNOTE-756 trial, adding pembrolizumab (Keytruda) to neoadjuvant chemotherapy resulted in an 8.5% increase in pathologic complete response (pCR) rates, compared with chemotherapy alone, regardless of the patients’ programmed death ligand-1 (PD-L1) status, reported Fatima Cardoso, MD, director of the breast unit at the Champalimaud Clinical Center in Lisbon.

In the Checkmate 7FL trial, a study bedeviled by unexpected circumstances, the addition of nivolumab (Opdivo) to neoadjuvant chemotherapy resulted in a 10.5% absolute increase in pCR rates, compared with chemotherapy alone, reported Sherene Loi, MBBS, PhD, from the Peter MacCallum Cancer Centre in Melbourne.

A new paradigm?

Taken together, the trials suggest that neoadjuvant immunotherapy has the potential to be “a new paradigm,” said ESMO invited discussant Steven RD Johnston, MD, PhD, professor of breast cancer medicine at the Royal Marsden Hospital and Institute of Cancer Research in London.

“Is the management of ER-positive breast cancer going to change with immunotherapy? Can we improve pCR rates? Yes, we can. We’ve seen a significant improvement in two separate studies, albeit the rates are only at 24%, and at this point, it’s unclear if this will translate into a better event-free survival [EFS] because we have to wait and follow the data,” he said.

The data from the two studies suggest that the patients who are likely to benefit most would be those with higher-grade tumors, luminal B subtype tumors, and, possibly, those whose tumors express higher levels of PD-L1, although the definition of PD-L1 positive depends on the assay used, he said

“I think we have to make better efforts to evaluate whether genomic or immune signatures can further define those who have most to gain, and I would urge investigators in both studies to do more digging into understanding this, because you might really enrich the patients who have the most to gain from the is approach,” Dr. Johnston said.

Checkmate 7FL details

In this prospective, randomized multicenter trial patients received four cycles of neoadjuvant paclitaxel followed by four cycles of doxorubicin and cyclophosphamide (AC) and surgery with adjuvant endocrine therapy. In arm A, 257 patients received neoadjuvant and adjuvant nivolumab. In arm B 253, patients received a nivolumab placebo in both the neoadjuvant and adjuvant settings.

Eligible patients had newly diagnosed ER+/HER2– breast cancer centrally confirmed. Patients with T1c or T2 tumors who were clinically node positive on histology and those with T3 or T4 tumors of any nodal status were eligible. Patients were required to have grade 3 histology as determined by the local pathologist, or grade 2 with low ER expression.

Patients were stratified by PD-L1 status, tumor grade, axillary nodal status and frequency of AC delivery (every 2 or 3 weeks) and were then randomized into one of the two treatment arms.

Destiny takes a hand

The protocol was changed following the approval in October 2021 of adjuvant abemaciclib in patients with high-risk ER+/HER2– disease.

“This was expected to result in a high rate of withdrawals due to safety concerns when combining a CDK4/6 inhibitor with an anti-PD-1, and this put the co-primary endpoint of EFS at risk,” Dr. Loi explained.

Therefore, the investigators amended the trial protocol to establish pCR as the sole primary endpoint and ceased accrual after 521 patients were randomized.

In addition, the primary efficacy population was modified to include 510 patients across 221 sites in 31 countries after Russian sites with a total of 11 patients closed due to Russia’s war on Ukraine.

And another hurdle, trial recruitment occurred from November 2019 through April 2022, during the COVID-19 pandemic.

Checkmate 7FL results

The pCR rate in the modified intention-to-treat (ITT) population was 24.5% for patients who received nivolumab, compared with 13.8% for patients who did not, translating in an odds ratio for benefit with the ICI of 2.05 (P = .0021),

In patients with PD-L1 expression in at least 1% of cells, a secondary endpoint, the respective pCR rates were 44.3% and 20.2%, with OR of 3.11, and a confidence interval indicating statistical significance.

Residual cancer burden (RCB) rates of 0 or 1 were also higher in the nivolumab-containing arm in both the modified ITT population (30.7% vs. 21.3%), and in the PD-L1–enriched population (54.5% vs. 26.2%).

In the safety population, which included 517 patients who received at least one dose of nivolumab or placebo, rates of overall adverse events and treatment-related adverse events were similar between the two arms, with the exception of two deaths from drug toxicity in Arm A (from pneumonitis in a patient 61 days after the last neoadjuvant cycles and hepatitis in a patient 51 days after) vs. no drug toxicity deaths reported in Arm B.

Safety of the nivolumab and neoadjuvant chemotherapy combinations was consistent with known safety profiles, with no new safety signals seen, Dr. Loi said.

KEYNOTE-756 details

The KEYNOTE-756 investigators had an easier time of it than Dr. Loi and colleagues. In fact, the trial “is the first fully accrued phase 3 immunotherapy study in high-risk, early-stage ER-positive, HER2-negative breast cancer, and it met one of its primary endpoints, pCR,” Dr. Cardoso said.

She noted that in the adaptive I-SPY2 trial, the addition of pembrolizumab to neoadjuvant chemotherapy resulted in a nearly threefold improvement in estimated pCR rates in patients with ER+/HER2– tumors, indicating that the role of immunotherapy in this population warranted further exploration.

In the placebo-controlled KEYNOTE-756 trial, treatment-naive patients with locally confirmed invasive ductal breast carcinoma with stage T1c or T2 tumors 2 cm or larger with nodal status CN1 or 2, or T3 and T4 tumors with nodal status CN0-2 were enrolled.

In most centers (Eastern Europe and China being the exceptions) patients were stratified by PD-L1 status, nodal status, anthracycline regimen chosen (AC or epirubicin-cyclophosphamide [EC]) and by degree of ER-positivity. Patients, 1,278 in total, were then randomly assigned to pembrolizumab for four cycles plus paclitaxel for 12 weeks, followed by AC or EC for four cycles plus pembrolizumab, or to the same regimen without pembrolizumab.

Following surgery, patients went on to endocrine therapy for up to 10 years, with or without 6 months of additional pembrolizumab every 6 months.

KEYNOTE-756 results

For the ITT analysis, 635 patients assigned to pembrolizumab and 643 assigned to placebo were evaluable.

At the first interim assessment, conducted at a median follow-up of 33.2 months, with the longest follow-up out to 51.8 months, the co-primary endpoint of an improvement in pCR with immunotherapy was met. The pCR rate with pembrolizumab was 24.3%, compared with 15.6% with placebo, an absolute difference of 8.5% (P = .00005).

Data for the other co-primary endpoint, EFS, were not mature at the time of data cutoff, and will be reported at a future date, Dr. Cardoso said.

An analysis of pCR rates in subgroups showed that pembrolizumab benefited most patients, with the exception of those 65 years and older, patients with Eastern Cooperative Oncology Group performance status of 1 (vs. 0), patients who received their anthracycline regimen every 2 weeks rather than every 3, and node-negative patients.

The benefit was particular pronounced among patients with less than 10% ER positivity, she pointed out.

Adverse events in the neoadjuvant phase were primarily related to chemotherapy, with no major differences between the arms, although grade 3 or greater events were slightly more frequent with pembrolizumab (52.5% vs. 46.4%), and two patients in the pembrolizumab arm died (one death was from acute myocardial infarction considered related to the long QT syndrome; cause of the other patient’s death was not specified).

Adverse events leading to discontinuation were also more common with pembrolizumab (19.1% vs. 10.1%, respectively).

Immune-mediated adverse events of any grade were also higher in the immunotherapy arm, occurring in 32.8% of patients vs. 7% of patients in the placebo arm.

There were no deaths from immune-related adverse events.

Eye on safety

In his discussion, Dr. Johnston emphasized that “it’s important in a curative population that we don’t harm patients in a setting where we have a variety of other therapies available.”

Recalling the deaths of patients in the immunotherapy arm of each trial, he commented that “deaths in early breast cancer in a treatment setting are always a disaster, and we have to make sure that we manage these adverse events as we can best, and we know how to do that now.”

Checkmate 7FL was supported by Bristol Myers Squibb. Dr. Loi reported financial and nonfinancial interests with BMS and with other companies. KEYNOTE-756 was supported by Merck Sharp & Dohme. Dr. Cardoso disclosed consulting and institutional research support from Merck and others. Dr. Johnston reported consulting or advisory roles, honoraria, and research funding from several companies, not including either BMS or Merck.

Further evidence for the benefit of adding immune checkpoint inhibitors to neoadjuvant chemotherapy in patients with early high-risk estrogen receptor–positive, HER2-negative (HR+/HER2–) breast cancer comes from results of two randomized trials presented at the annual meeting of the European Society for Medical Oncology.

In the KEYNOTE-756 trial, adding pembrolizumab (Keytruda) to neoadjuvant chemotherapy resulted in an 8.5% increase in pathologic complete response (pCR) rates, compared with chemotherapy alone, regardless of the patients’ programmed death ligand-1 (PD-L1) status, reported Fatima Cardoso, MD, director of the breast unit at the Champalimaud Clinical Center in Lisbon.

In the Checkmate 7FL trial, a study bedeviled by unexpected circumstances, the addition of nivolumab (Opdivo) to neoadjuvant chemotherapy resulted in a 10.5% absolute increase in pCR rates, compared with chemotherapy alone, reported Sherene Loi, MBBS, PhD, from the Peter MacCallum Cancer Centre in Melbourne.

A new paradigm?

Taken together, the trials suggest that neoadjuvant immunotherapy has the potential to be “a new paradigm,” said ESMO invited discussant Steven RD Johnston, MD, PhD, professor of breast cancer medicine at the Royal Marsden Hospital and Institute of Cancer Research in London.

“Is the management of ER-positive breast cancer going to change with immunotherapy? Can we improve pCR rates? Yes, we can. We’ve seen a significant improvement in two separate studies, albeit the rates are only at 24%, and at this point, it’s unclear if this will translate into a better event-free survival [EFS] because we have to wait and follow the data,” he said.

The data from the two studies suggest that the patients who are likely to benefit most would be those with higher-grade tumors, luminal B subtype tumors, and, possibly, those whose tumors express higher levels of PD-L1, although the definition of PD-L1 positive depends on the assay used, he said

“I think we have to make better efforts to evaluate whether genomic or immune signatures can further define those who have most to gain, and I would urge investigators in both studies to do more digging into understanding this, because you might really enrich the patients who have the most to gain from the is approach,” Dr. Johnston said.

Checkmate 7FL details

In this prospective, randomized multicenter trial patients received four cycles of neoadjuvant paclitaxel followed by four cycles of doxorubicin and cyclophosphamide (AC) and surgery with adjuvant endocrine therapy. In arm A, 257 patients received neoadjuvant and adjuvant nivolumab. In arm B 253, patients received a nivolumab placebo in both the neoadjuvant and adjuvant settings.

Eligible patients had newly diagnosed ER+/HER2– breast cancer centrally confirmed. Patients with T1c or T2 tumors who were clinically node positive on histology and those with T3 or T4 tumors of any nodal status were eligible. Patients were required to have grade 3 histology as determined by the local pathologist, or grade 2 with low ER expression.

Patients were stratified by PD-L1 status, tumor grade, axillary nodal status and frequency of AC delivery (every 2 or 3 weeks) and were then randomized into one of the two treatment arms.

Destiny takes a hand

The protocol was changed following the approval in October 2021 of adjuvant abemaciclib in patients with high-risk ER+/HER2– disease.

“This was expected to result in a high rate of withdrawals due to safety concerns when combining a CDK4/6 inhibitor with an anti-PD-1, and this put the co-primary endpoint of EFS at risk,” Dr. Loi explained.

Therefore, the investigators amended the trial protocol to establish pCR as the sole primary endpoint and ceased accrual after 521 patients were randomized.

In addition, the primary efficacy population was modified to include 510 patients across 221 sites in 31 countries after Russian sites with a total of 11 patients closed due to Russia’s war on Ukraine.

And another hurdle, trial recruitment occurred from November 2019 through April 2022, during the COVID-19 pandemic.

Checkmate 7FL results

The pCR rate in the modified intention-to-treat (ITT) population was 24.5% for patients who received nivolumab, compared with 13.8% for patients who did not, translating in an odds ratio for benefit with the ICI of 2.05 (P = .0021),

In patients with PD-L1 expression in at least 1% of cells, a secondary endpoint, the respective pCR rates were 44.3% and 20.2%, with OR of 3.11, and a confidence interval indicating statistical significance.

Residual cancer burden (RCB) rates of 0 or 1 were also higher in the nivolumab-containing arm in both the modified ITT population (30.7% vs. 21.3%), and in the PD-L1–enriched population (54.5% vs. 26.2%).

In the safety population, which included 517 patients who received at least one dose of nivolumab or placebo, rates of overall adverse events and treatment-related adverse events were similar between the two arms, with the exception of two deaths from drug toxicity in Arm A (from pneumonitis in a patient 61 days after the last neoadjuvant cycles and hepatitis in a patient 51 days after) vs. no drug toxicity deaths reported in Arm B.

Safety of the nivolumab and neoadjuvant chemotherapy combinations was consistent with known safety profiles, with no new safety signals seen, Dr. Loi said.

KEYNOTE-756 details

The KEYNOTE-756 investigators had an easier time of it than Dr. Loi and colleagues. In fact, the trial “is the first fully accrued phase 3 immunotherapy study in high-risk, early-stage ER-positive, HER2-negative breast cancer, and it met one of its primary endpoints, pCR,” Dr. Cardoso said.

She noted that in the adaptive I-SPY2 trial, the addition of pembrolizumab to neoadjuvant chemotherapy resulted in a nearly threefold improvement in estimated pCR rates in patients with ER+/HER2– tumors, indicating that the role of immunotherapy in this population warranted further exploration.

In the placebo-controlled KEYNOTE-756 trial, treatment-naive patients with locally confirmed invasive ductal breast carcinoma with stage T1c or T2 tumors 2 cm or larger with nodal status CN1 or 2, or T3 and T4 tumors with nodal status CN0-2 were enrolled.

In most centers (Eastern Europe and China being the exceptions) patients were stratified by PD-L1 status, nodal status, anthracycline regimen chosen (AC or epirubicin-cyclophosphamide [EC]) and by degree of ER-positivity. Patients, 1,278 in total, were then randomly assigned to pembrolizumab for four cycles plus paclitaxel for 12 weeks, followed by AC or EC for four cycles plus pembrolizumab, or to the same regimen without pembrolizumab.

Following surgery, patients went on to endocrine therapy for up to 10 years, with or without 6 months of additional pembrolizumab every 6 months.

KEYNOTE-756 results

For the ITT analysis, 635 patients assigned to pembrolizumab and 643 assigned to placebo were evaluable.

At the first interim assessment, conducted at a median follow-up of 33.2 months, with the longest follow-up out to 51.8 months, the co-primary endpoint of an improvement in pCR with immunotherapy was met. The pCR rate with pembrolizumab was 24.3%, compared with 15.6% with placebo, an absolute difference of 8.5% (P = .00005).

Data for the other co-primary endpoint, EFS, were not mature at the time of data cutoff, and will be reported at a future date, Dr. Cardoso said.

An analysis of pCR rates in subgroups showed that pembrolizumab benefited most patients, with the exception of those 65 years and older, patients with Eastern Cooperative Oncology Group performance status of 1 (vs. 0), patients who received their anthracycline regimen every 2 weeks rather than every 3, and node-negative patients.

The benefit was particular pronounced among patients with less than 10% ER positivity, she pointed out.

Adverse events in the neoadjuvant phase were primarily related to chemotherapy, with no major differences between the arms, although grade 3 or greater events were slightly more frequent with pembrolizumab (52.5% vs. 46.4%), and two patients in the pembrolizumab arm died (one death was from acute myocardial infarction considered related to the long QT syndrome; cause of the other patient’s death was not specified).

Adverse events leading to discontinuation were also more common with pembrolizumab (19.1% vs. 10.1%, respectively).

Immune-mediated adverse events of any grade were also higher in the immunotherapy arm, occurring in 32.8% of patients vs. 7% of patients in the placebo arm.

There were no deaths from immune-related adverse events.

Eye on safety

In his discussion, Dr. Johnston emphasized that “it’s important in a curative population that we don’t harm patients in a setting where we have a variety of other therapies available.”

Recalling the deaths of patients in the immunotherapy arm of each trial, he commented that “deaths in early breast cancer in a treatment setting are always a disaster, and we have to make sure that we manage these adverse events as we can best, and we know how to do that now.”

Checkmate 7FL was supported by Bristol Myers Squibb. Dr. Loi reported financial and nonfinancial interests with BMS and with other companies. KEYNOTE-756 was supported by Merck Sharp & Dohme. Dr. Cardoso disclosed consulting and institutional research support from Merck and others. Dr. Johnston reported consulting or advisory roles, honoraria, and research funding from several companies, not including either BMS or Merck.

Further evidence for the benefit of adding immune checkpoint inhibitors to neoadjuvant chemotherapy in patients with early high-risk estrogen receptor–positive, HER2-negative (HR+/HER2–) breast cancer comes from results of two randomized trials presented at the annual meeting of the European Society for Medical Oncology.

In the KEYNOTE-756 trial, adding pembrolizumab (Keytruda) to neoadjuvant chemotherapy resulted in an 8.5% increase in pathologic complete response (pCR) rates, compared with chemotherapy alone, regardless of the patients’ programmed death ligand-1 (PD-L1) status, reported Fatima Cardoso, MD, director of the breast unit at the Champalimaud Clinical Center in Lisbon.

In the Checkmate 7FL trial, a study bedeviled by unexpected circumstances, the addition of nivolumab (Opdivo) to neoadjuvant chemotherapy resulted in a 10.5% absolute increase in pCR rates, compared with chemotherapy alone, reported Sherene Loi, MBBS, PhD, from the Peter MacCallum Cancer Centre in Melbourne.

A new paradigm?

Taken together, the trials suggest that neoadjuvant immunotherapy has the potential to be “a new paradigm,” said ESMO invited discussant Steven RD Johnston, MD, PhD, professor of breast cancer medicine at the Royal Marsden Hospital and Institute of Cancer Research in London.

“Is the management of ER-positive breast cancer going to change with immunotherapy? Can we improve pCR rates? Yes, we can. We’ve seen a significant improvement in two separate studies, albeit the rates are only at 24%, and at this point, it’s unclear if this will translate into a better event-free survival [EFS] because we have to wait and follow the data,” he said.

The data from the two studies suggest that the patients who are likely to benefit most would be those with higher-grade tumors, luminal B subtype tumors, and, possibly, those whose tumors express higher levels of PD-L1, although the definition of PD-L1 positive depends on the assay used, he said

“I think we have to make better efforts to evaluate whether genomic or immune signatures can further define those who have most to gain, and I would urge investigators in both studies to do more digging into understanding this, because you might really enrich the patients who have the most to gain from the is approach,” Dr. Johnston said.

Checkmate 7FL details

In this prospective, randomized multicenter trial patients received four cycles of neoadjuvant paclitaxel followed by four cycles of doxorubicin and cyclophosphamide (AC) and surgery with adjuvant endocrine therapy. In arm A, 257 patients received neoadjuvant and adjuvant nivolumab. In arm B 253, patients received a nivolumab placebo in both the neoadjuvant and adjuvant settings.

Eligible patients had newly diagnosed ER+/HER2– breast cancer centrally confirmed. Patients with T1c or T2 tumors who were clinically node positive on histology and those with T3 or T4 tumors of any nodal status were eligible. Patients were required to have grade 3 histology as determined by the local pathologist, or grade 2 with low ER expression.

Patients were stratified by PD-L1 status, tumor grade, axillary nodal status and frequency of AC delivery (every 2 or 3 weeks) and were then randomized into one of the two treatment arms.

Destiny takes a hand

The protocol was changed following the approval in October 2021 of adjuvant abemaciclib in patients with high-risk ER+/HER2– disease.

“This was expected to result in a high rate of withdrawals due to safety concerns when combining a CDK4/6 inhibitor with an anti-PD-1, and this put the co-primary endpoint of EFS at risk,” Dr. Loi explained.

Therefore, the investigators amended the trial protocol to establish pCR as the sole primary endpoint and ceased accrual after 521 patients were randomized.

In addition, the primary efficacy population was modified to include 510 patients across 221 sites in 31 countries after Russian sites with a total of 11 patients closed due to Russia’s war on Ukraine.

And another hurdle, trial recruitment occurred from November 2019 through April 2022, during the COVID-19 pandemic.

Checkmate 7FL results

The pCR rate in the modified intention-to-treat (ITT) population was 24.5% for patients who received nivolumab, compared with 13.8% for patients who did not, translating in an odds ratio for benefit with the ICI of 2.05 (P = .0021),

In patients with PD-L1 expression in at least 1% of cells, a secondary endpoint, the respective pCR rates were 44.3% and 20.2%, with OR of 3.11, and a confidence interval indicating statistical significance.

Residual cancer burden (RCB) rates of 0 or 1 were also higher in the nivolumab-containing arm in both the modified ITT population (30.7% vs. 21.3%), and in the PD-L1–enriched population (54.5% vs. 26.2%).

In the safety population, which included 517 patients who received at least one dose of nivolumab or placebo, rates of overall adverse events and treatment-related adverse events were similar between the two arms, with the exception of two deaths from drug toxicity in Arm A (from pneumonitis in a patient 61 days after the last neoadjuvant cycles and hepatitis in a patient 51 days after) vs. no drug toxicity deaths reported in Arm B.

Safety of the nivolumab and neoadjuvant chemotherapy combinations was consistent with known safety profiles, with no new safety signals seen, Dr. Loi said.

KEYNOTE-756 details

The KEYNOTE-756 investigators had an easier time of it than Dr. Loi and colleagues. In fact, the trial “is the first fully accrued phase 3 immunotherapy study in high-risk, early-stage ER-positive, HER2-negative breast cancer, and it met one of its primary endpoints, pCR,” Dr. Cardoso said.

She noted that in the adaptive I-SPY2 trial, the addition of pembrolizumab to neoadjuvant chemotherapy resulted in a nearly threefold improvement in estimated pCR rates in patients with ER+/HER2– tumors, indicating that the role of immunotherapy in this population warranted further exploration.

In the placebo-controlled KEYNOTE-756 trial, treatment-naive patients with locally confirmed invasive ductal breast carcinoma with stage T1c or T2 tumors 2 cm or larger with nodal status CN1 or 2, or T3 and T4 tumors with nodal status CN0-2 were enrolled.

In most centers (Eastern Europe and China being the exceptions) patients were stratified by PD-L1 status, nodal status, anthracycline regimen chosen (AC or epirubicin-cyclophosphamide [EC]) and by degree of ER-positivity. Patients, 1,278 in total, were then randomly assigned to pembrolizumab for four cycles plus paclitaxel for 12 weeks, followed by AC or EC for four cycles plus pembrolizumab, or to the same regimen without pembrolizumab.

Following surgery, patients went on to endocrine therapy for up to 10 years, with or without 6 months of additional pembrolizumab every 6 months.

KEYNOTE-756 results

For the ITT analysis, 635 patients assigned to pembrolizumab and 643 assigned to placebo were evaluable.

At the first interim assessment, conducted at a median follow-up of 33.2 months, with the longest follow-up out to 51.8 months, the co-primary endpoint of an improvement in pCR with immunotherapy was met. The pCR rate with pembrolizumab was 24.3%, compared with 15.6% with placebo, an absolute difference of 8.5% (P = .00005).

Data for the other co-primary endpoint, EFS, were not mature at the time of data cutoff, and will be reported at a future date, Dr. Cardoso said.

An analysis of pCR rates in subgroups showed that pembrolizumab benefited most patients, with the exception of those 65 years and older, patients with Eastern Cooperative Oncology Group performance status of 1 (vs. 0), patients who received their anthracycline regimen every 2 weeks rather than every 3, and node-negative patients.

The benefit was particular pronounced among patients with less than 10% ER positivity, she pointed out.

Adverse events in the neoadjuvant phase were primarily related to chemotherapy, with no major differences between the arms, although grade 3 or greater events were slightly more frequent with pembrolizumab (52.5% vs. 46.4%), and two patients in the pembrolizumab arm died (one death was from acute myocardial infarction considered related to the long QT syndrome; cause of the other patient’s death was not specified).

Adverse events leading to discontinuation were also more common with pembrolizumab (19.1% vs. 10.1%, respectively).

Immune-mediated adverse events of any grade were also higher in the immunotherapy arm, occurring in 32.8% of patients vs. 7% of patients in the placebo arm.

There were no deaths from immune-related adverse events.

Eye on safety

In his discussion, Dr. Johnston emphasized that “it’s important in a curative population that we don’t harm patients in a setting where we have a variety of other therapies available.”

Recalling the deaths of patients in the immunotherapy arm of each trial, he commented that “deaths in early breast cancer in a treatment setting are always a disaster, and we have to make sure that we manage these adverse events as we can best, and we know how to do that now.”

Checkmate 7FL was supported by Bristol Myers Squibb. Dr. Loi reported financial and nonfinancial interests with BMS and with other companies. KEYNOTE-756 was supported by Merck Sharp & Dohme. Dr. Cardoso disclosed consulting and institutional research support from Merck and others. Dr. Johnston reported consulting or advisory roles, honoraria, and research funding from several companies, not including either BMS or Merck.

Despite the proven benefit of adding an immune checkpoint inhibitor (ICI) to preoperative chemotherapy for patients with triple-negative breast cancer (TNBC), the NeoTRIP Michelangelo trial stumbled at the finish line, showing that adding atezolizumab (Tecentriq) to nab-paclitaxel and carboplatin followed by surgery and adjuvant anthracycline-based chemotherapy did not improve 5-year event-free survival (EFS), compared with the same regimen without atezolizumab.

Although the trial did not produce the desired result, it still provided important impetus for researchers to do better, said lead investigator Luca Gianni, MD, chair of the international breast cancer research committee at Fondazione Michelangelo in Milan.

“I strongly believe that the results of NeoTRIP, rather than being viewed as negative, should bring forth the search for dependable and widely applicable predictors of ICIs’ benefit in women with operable triple negative breast cancer,” he said in an oral abstract session at the annual meeting of the European Society for Medical Oncology.

Other neoadjuvant trials with different agents have shown benefit from the addition of an ICI to chemotherapy for patients with TNBC, Dr. Gianni noted, with pembrolizumab (Keytruda) in Keynote-522, durvalumab (Imfinzi) in GeparNuevo, and with atezolizumab in IMpassion031.

NeoTRIP results

Dr. Gianni and colleagues had previously reported that adding atezolizumab to neoadjuvant carboplatin/nab-paclitaxel did not significantly improve pathologic complete response rates (pCR) in the randomized trial, although other trials of neoadjuvant ICIs in this population had shown a pCR benefit.

“Our analysis of NeoTRIP supports that pCR may not be an appropriate surrogate endpoint for the role of ICIs in early TNBC,” they wrote in that analysis.

At ESMO 2023, the investigators presented 5-year event-free survival rates, the primary study endpoint, and results of an exploratory analysis of predictive biomarkers.

In the phase 3 trial, patients with HER2-negative, estrogen receptor–negative, and progesterone receptor–negative early high-risk or locally advanced unilateral breast cancer were randomly assigned to receive eight cycles of carboplatin plus nab-paclitaxel with or without atezolizumab, followed by surgery and four cycles of an anthracycline-based chemotherapy regimen of the investigators choice.

A total of 280 patients were included in the intention-to-treat (ITT) population, including 138 assigned to receive atezolizumab and 142 who received chemotherapy alone.

Of these groups. 119 and 120, respectively, went on to surgery and were eligible for adjuvant chemotherapy. In all, 79 patients (66%) in the atezolizumab arm and 90 (75%) in the no-atezolizumab arm completed the four planned cycles of postoperative chemotherapy.

At a median follow-up of 54 months, the EFS rate with atezolizumab was 70.6%, compared with 74.9% without atezolizumab, translating into a nonsignificant hazard ratio of 1.076­­ for disease progression while on primary therapy or disease recurrence after surgery, or death from any cause, including unknown causes.

Pathologic complete responses key

In multivariate analysis, significant predictors for better EFS included achievement of a pCR; disease stage (early high risk vs. locally advanced); programmed death ligand-1 (PD-L1) levels above 1% as assessed by the SP142 assay; and higher levels of stromal tumor-infiltrating lymphocytes, but these factors were not predictive of atezolizumab benefit, Dr. Gianni said.

Among all patients who had a pCR, regardless of regimen, the 5-year EFS rate was 90.3%, compared with 55.7% for those who did not receive a pCR, translating into a hazard ratio of 0.19 for pathologic complete responses (P < .0001).

Looking at treatment-related adverse events occurring following surgery – that is, after atezolizumab therapy had stopped – they did not detect any new safety signals. The most common grade 3 or greater toxicity in each arm was neutropenia, followed by leukopenia, and in the atezolizumab arm there was one case of a grade 3 myocarditis that occurred 2 weeks after surgery and before the patient started on an anthracycline.

The authors also conducted a mass cytometry analysis of potential predictors of response to checkpoint inhibitors in TNBC, and reported the results in Nature.

“Basically, baseline density of several activated immune cells predicted for higher probability of pCR with atezolizumab but not with chemotherapy without atezolizumab,” Dr. Gianni said.

Specifically, they saw that high density of CD8-positive, TCF1-positive and Ki-67-positive markers were associated with increased pCR and EFS rates with the addition of atezolizumab.

Why no benefit to the ICI?

Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University in Atlanta said that at least two possible explanations floated for the lack of either a pCR or EFS benefit in NeoTRIP don’t hold water.

For example, the theory that a difference in efficacy between PD-1 and PD-L1 inhibitors might explain the lack of benefit in NeoTRIP is undermined by IMpassion031, which showed pCR and EFS benefits with atezolizumab.

In addition, although NeoTRIP did not include an anthracycline in the neoadjuvant regimen, neither did the NeoPACT trial, in which patients received six cycles of neoadjuvant taxane, carboplatin, and pembrolizumab, and had a 58% pCR rate, with a high 2-year EFS rate among patients who had a pCR.

“As we know, triple-negative breast cancer is a heterogeneous disease. Could it be by chance that there are differences in tumor biology reflected across the various neoadjuvant trials, including molecular subtypes? Also in NeoTRIP, previously reported we’ve seen that there were a higher rate of TILs in the chemo-alone arm; high TILs can be associated with chemosensitivity, and maybe this influenced the results,” he said.

Predictive markers to immunotherapy in TNBC are still needed, he said, because neither PD-L1 expression, tumor mutational burden, or TILs have proven to be reliable biomarkers for this subtype.

The NeoTRIP Michelangelo trial was supported by Hoffman-La Roche and Celgene. Dr. Gianni disclosed financial interests with Roche and others including advisory board activity, consulting, and personal fees. Dr. Kalinsky reported advisory/consulting activities for various companies, including Genentech/Roche.

Despite the proven benefit of adding an immune checkpoint inhibitor (ICI) to preoperative chemotherapy for patients with triple-negative breast cancer (TNBC), the NeoTRIP Michelangelo trial stumbled at the finish line, showing that adding atezolizumab (Tecentriq) to nab-paclitaxel and carboplatin followed by surgery and adjuvant anthracycline-based chemotherapy did not improve 5-year event-free survival (EFS), compared with the same regimen without atezolizumab.

Although the trial did not produce the desired result, it still provided important impetus for researchers to do better, said lead investigator Luca Gianni, MD, chair of the international breast cancer research committee at Fondazione Michelangelo in Milan.

“I strongly believe that the results of NeoTRIP, rather than being viewed as negative, should bring forth the search for dependable and widely applicable predictors of ICIs’ benefit in women with operable triple negative breast cancer,” he said in an oral abstract session at the annual meeting of the European Society for Medical Oncology.

Other neoadjuvant trials with different agents have shown benefit from the addition of an ICI to chemotherapy for patients with TNBC, Dr. Gianni noted, with pembrolizumab (Keytruda) in Keynote-522, durvalumab (Imfinzi) in GeparNuevo, and with atezolizumab in IMpassion031.

NeoTRIP results

Dr. Gianni and colleagues had previously reported that adding atezolizumab to neoadjuvant carboplatin/nab-paclitaxel did not significantly improve pathologic complete response rates (pCR) in the randomized trial, although other trials of neoadjuvant ICIs in this population had shown a pCR benefit.

“Our analysis of NeoTRIP supports that pCR may not be an appropriate surrogate endpoint for the role of ICIs in early TNBC,” they wrote in that analysis.

At ESMO 2023, the investigators presented 5-year event-free survival rates, the primary study endpoint, and results of an exploratory analysis of predictive biomarkers.

In the phase 3 trial, patients with HER2-negative, estrogen receptor–negative, and progesterone receptor–negative early high-risk or locally advanced unilateral breast cancer were randomly assigned to receive eight cycles of carboplatin plus nab-paclitaxel with or without atezolizumab, followed by surgery and four cycles of an anthracycline-based chemotherapy regimen of the investigators choice.

A total of 280 patients were included in the intention-to-treat (ITT) population, including 138 assigned to receive atezolizumab and 142 who received chemotherapy alone.

Of these groups. 119 and 120, respectively, went on to surgery and were eligible for adjuvant chemotherapy. In all, 79 patients (66%) in the atezolizumab arm and 90 (75%) in the no-atezolizumab arm completed the four planned cycles of postoperative chemotherapy.

At a median follow-up of 54 months, the EFS rate with atezolizumab was 70.6%, compared with 74.9% without atezolizumab, translating into a nonsignificant hazard ratio of 1.076­­ for disease progression while on primary therapy or disease recurrence after surgery, or death from any cause, including unknown causes.

Pathologic complete responses key

In multivariate analysis, significant predictors for better EFS included achievement of a pCR; disease stage (early high risk vs. locally advanced); programmed death ligand-1 (PD-L1) levels above 1% as assessed by the SP142 assay; and higher levels of stromal tumor-infiltrating lymphocytes, but these factors were not predictive of atezolizumab benefit, Dr. Gianni said.

Among all patients who had a pCR, regardless of regimen, the 5-year EFS rate was 90.3%, compared with 55.7% for those who did not receive a pCR, translating into a hazard ratio of 0.19 for pathologic complete responses (P < .0001).

Looking at treatment-related adverse events occurring following surgery – that is, after atezolizumab therapy had stopped – they did not detect any new safety signals. The most common grade 3 or greater toxicity in each arm was neutropenia, followed by leukopenia, and in the atezolizumab arm there was one case of a grade 3 myocarditis that occurred 2 weeks after surgery and before the patient started on an anthracycline.

The authors also conducted a mass cytometry analysis of potential predictors of response to checkpoint inhibitors in TNBC, and reported the results in Nature.

“Basically, baseline density of several activated immune cells predicted for higher probability of pCR with atezolizumab but not with chemotherapy without atezolizumab,” Dr. Gianni said.

Specifically, they saw that high density of CD8-positive, TCF1-positive and Ki-67-positive markers were associated with increased pCR and EFS rates with the addition of atezolizumab.

Why no benefit to the ICI?

Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University in Atlanta said that at least two possible explanations floated for the lack of either a pCR or EFS benefit in NeoTRIP don’t hold water.

For example, the theory that a difference in efficacy between PD-1 and PD-L1 inhibitors might explain the lack of benefit in NeoTRIP is undermined by IMpassion031, which showed pCR and EFS benefits with atezolizumab.

In addition, although NeoTRIP did not include an anthracycline in the neoadjuvant regimen, neither did the NeoPACT trial, in which patients received six cycles of neoadjuvant taxane, carboplatin, and pembrolizumab, and had a 58% pCR rate, with a high 2-year EFS rate among patients who had a pCR.

“As we know, triple-negative breast cancer is a heterogeneous disease. Could it be by chance that there are differences in tumor biology reflected across the various neoadjuvant trials, including molecular subtypes? Also in NeoTRIP, previously reported we’ve seen that there were a higher rate of TILs in the chemo-alone arm; high TILs can be associated with chemosensitivity, and maybe this influenced the results,” he said.

Predictive markers to immunotherapy in TNBC are still needed, he said, because neither PD-L1 expression, tumor mutational burden, or TILs have proven to be reliable biomarkers for this subtype.

The NeoTRIP Michelangelo trial was supported by Hoffman-La Roche and Celgene. Dr. Gianni disclosed financial interests with Roche and others including advisory board activity, consulting, and personal fees. Dr. Kalinsky reported advisory/consulting activities for various companies, including Genentech/Roche.

Despite the proven benefit of adding an immune checkpoint inhibitor (ICI) to preoperative chemotherapy for patients with triple-negative breast cancer (TNBC), the NeoTRIP Michelangelo trial stumbled at the finish line, showing that adding atezolizumab (Tecentriq) to nab-paclitaxel and carboplatin followed by surgery and adjuvant anthracycline-based chemotherapy did not improve 5-year event-free survival (EFS), compared with the same regimen without atezolizumab.

Although the trial did not produce the desired result, it still provided important impetus for researchers to do better, said lead investigator Luca Gianni, MD, chair of the international breast cancer research committee at Fondazione Michelangelo in Milan.

“I strongly believe that the results of NeoTRIP, rather than being viewed as negative, should bring forth the search for dependable and widely applicable predictors of ICIs’ benefit in women with operable triple negative breast cancer,” he said in an oral abstract session at the annual meeting of the European Society for Medical Oncology.

Other neoadjuvant trials with different agents have shown benefit from the addition of an ICI to chemotherapy for patients with TNBC, Dr. Gianni noted, with pembrolizumab (Keytruda) in Keynote-522, durvalumab (Imfinzi) in GeparNuevo, and with atezolizumab in IMpassion031.

NeoTRIP results

Dr. Gianni and colleagues had previously reported that adding atezolizumab to neoadjuvant carboplatin/nab-paclitaxel did not significantly improve pathologic complete response rates (pCR) in the randomized trial, although other trials of neoadjuvant ICIs in this population had shown a pCR benefit.

“Our analysis of NeoTRIP supports that pCR may not be an appropriate surrogate endpoint for the role of ICIs in early TNBC,” they wrote in that analysis.

At ESMO 2023, the investigators presented 5-year event-free survival rates, the primary study endpoint, and results of an exploratory analysis of predictive biomarkers.

In the phase 3 trial, patients with HER2-negative, estrogen receptor–negative, and progesterone receptor–negative early high-risk or locally advanced unilateral breast cancer were randomly assigned to receive eight cycles of carboplatin plus nab-paclitaxel with or without atezolizumab, followed by surgery and four cycles of an anthracycline-based chemotherapy regimen of the investigators choice.

A total of 280 patients were included in the intention-to-treat (ITT) population, including 138 assigned to receive atezolizumab and 142 who received chemotherapy alone.

Of these groups. 119 and 120, respectively, went on to surgery and were eligible for adjuvant chemotherapy. In all, 79 patients (66%) in the atezolizumab arm and 90 (75%) in the no-atezolizumab arm completed the four planned cycles of postoperative chemotherapy.

At a median follow-up of 54 months, the EFS rate with atezolizumab was 70.6%, compared with 74.9% without atezolizumab, translating into a nonsignificant hazard ratio of 1.076­­ for disease progression while on primary therapy or disease recurrence after surgery, or death from any cause, including unknown causes.

Pathologic complete responses key

In multivariate analysis, significant predictors for better EFS included achievement of a pCR; disease stage (early high risk vs. locally advanced); programmed death ligand-1 (PD-L1) levels above 1% as assessed by the SP142 assay; and higher levels of stromal tumor-infiltrating lymphocytes, but these factors were not predictive of atezolizumab benefit, Dr. Gianni said.

Among all patients who had a pCR, regardless of regimen, the 5-year EFS rate was 90.3%, compared with 55.7% for those who did not receive a pCR, translating into a hazard ratio of 0.19 for pathologic complete responses (P < .0001).

Looking at treatment-related adverse events occurring following surgery – that is, after atezolizumab therapy had stopped – they did not detect any new safety signals. The most common grade 3 or greater toxicity in each arm was neutropenia, followed by leukopenia, and in the atezolizumab arm there was one case of a grade 3 myocarditis that occurred 2 weeks after surgery and before the patient started on an anthracycline.

The authors also conducted a mass cytometry analysis of potential predictors of response to checkpoint inhibitors in TNBC, and reported the results in Nature.

“Basically, baseline density of several activated immune cells predicted for higher probability of pCR with atezolizumab but not with chemotherapy without atezolizumab,” Dr. Gianni said.

Specifically, they saw that high density of CD8-positive, TCF1-positive and Ki-67-positive markers were associated with increased pCR and EFS rates with the addition of atezolizumab.

Why no benefit to the ICI?

Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University in Atlanta said that at least two possible explanations floated for the lack of either a pCR or EFS benefit in NeoTRIP don’t hold water.

For example, the theory that a difference in efficacy between PD-1 and PD-L1 inhibitors might explain the lack of benefit in NeoTRIP is undermined by IMpassion031, which showed pCR and EFS benefits with atezolizumab.

In addition, although NeoTRIP did not include an anthracycline in the neoadjuvant regimen, neither did the NeoPACT trial, in which patients received six cycles of neoadjuvant taxane, carboplatin, and pembrolizumab, and had a 58% pCR rate, with a high 2-year EFS rate among patients who had a pCR.

“As we know, triple-negative breast cancer is a heterogeneous disease. Could it be by chance that there are differences in tumor biology reflected across the various neoadjuvant trials, including molecular subtypes? Also in NeoTRIP, previously reported we’ve seen that there were a higher rate of TILs in the chemo-alone arm; high TILs can be associated with chemosensitivity, and maybe this influenced the results,” he said.

Predictive markers to immunotherapy in TNBC are still needed, he said, because neither PD-L1 expression, tumor mutational burden, or TILs have proven to be reliable biomarkers for this subtype.

The NeoTRIP Michelangelo trial was supported by Hoffman-La Roche and Celgene. Dr. Gianni disclosed financial interests with Roche and others including advisory board activity, consulting, and personal fees. Dr. Kalinsky reported advisory/consulting activities for various companies, including Genentech/Roche.

MADRID – Five years on, the addition of the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy for women with high-risk hormone receptor–positive, HER2-negative (HR+/HER2–) early breast cancer continues to show modest but clinically significant benefits, compared with endocrine therapy alone.

Results of a planned 5-year efficacy analysis of the monarchE trial showed that at a median follow-up of 4.5 years, the abemaciclib/endocrine therapy combination was associated with a 7.6% absolute improvement in invasive disease–free survival (IDFS) and 6.7% edge in distant relapse–free survival (DRFS), compared with endocrine therapy alone, reported Nadia Harbeck, MD, from the Breast Center at Ludwig Maximilians University Hospital in Munich.

“The data are consistent with a carryover effect and further support the addition of adjuvant abemaciclib to endocrine therapy for patients with hormone receptor–positive, HER2-negative, node-positive high-risk early breast cancer,” she said at the 2023 European Society for Medical Oncology Congress.
 

High recurrence risk

Although HR+/HER2– breast cancer, the most common subtype of breast cancer, is generally associated with better outcomes than other subtypes, patients with node-positive early disease are at high risk for early recurrence and need treatment intensification, Dr. Harbeck said.

The monarchE trial included two cohorts: a primary cohort consisting of patients deemed at high risk based on clinical pathological features such as the number of involved axillary nodes, grade 3 disease, and tumors 5 cm or larger, and a second cohort of patients with lower disease grade and smaller tumors but with high levels of the proliferation marker Ki-67.

A total of 5,637 patients were randomized to receive either 2 years of abemaciclib 150 mg twice daily plus endocrine therapy, or endocrine therapy alone, followed by 3-8 years of additional endocrine as clinically indicated in each study arm.

An earlier preplanned interim analysis of the phase 3 trial of more than 5,600 patients was presented at the ESMO Virtual Congress 2020, and simultaneously published in the Journal of Clinical Oncology.

As that analysis showed, at a median follow-up of 15.5 months abemaciclib plus endocrine therapy was associated with a 25% relative risk reduction in the primary endpoint of IDFS vs. endocrine therapy alone.

At the time, the findings were hailed as practice-changing and, once approved for high-risk HR+/HER2-negative early breast cancer, as the new standard of care.

In the current analysis, Dr. Harbeck and colleagues looked at 5-year outcomes from a prespecified analysis, with a data cutoff of July 3, 2023.

All patients originally assigned to abemaciclib are now off the drug, and more than 80% have been followed for a minimum of 2 year since completing therapy with the CDK4/6 inhibitor.
 

Results

At 5 years there were cumulative totals of 407 IDFS events in the combination arm, compared with 585 in the endocrine therapy alone arm, a difference that translated into a hazard ratio of 0.68 favoring abemaciclib (P < .001).

The IDFS benefit with the combination was consistent across most subgroups, including older patients, perimenopausal and postmenopausal patients, those who had received prior neoadjuvant or adjuvant chemotherapy, all tumor sizes, number of positive lymph nodes, less favorable tumor stage or grade, and order of endocrine therapy (tamoxifen or aromatase inhibitor as first drug).

As noted before, DRFS, a secondary endpoint, also favored abemaciclib, with 345 events occurring over 5 years in the combination arm, compared with 501 in the endocrine therapy arm alone. This translated into a HR with the combination of 0.68 (P < .001).

There were fewer deaths in the abemaciclib arm (208 vs. 234), but this difference was not statistically significant.

The proportions of patients with treatment-emergent adverse events and serious adverse events (SAEs) were higher in the combination arm than in the endocrine therapy alone arm in all previous analyses of the trial data.

In the current analysis, “I would say it’s reassuring to see that the SAEs reported in the follow-up period, after the study treatment had been completed, are quite similar between the endocrine therapy alone arm and the abemaciclib plus endocrine therapy arm,” Dr. Harbeck said.
 

Changing road map

Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University, Atlanta, commented that CDK4/6 inhibitors “have changed the road map for treating hormone receptor–positive, HER2-negative disease.”

To put the monarchE results in context, he compared them with those of the NATALEE trial, in which patients were randomized to endocrine therapy with or without the CDK4/6 inhibitor ribociclib (Kisqali). That combination was previously shown to provide a significant survival advantage for women with metastatic breast cancer.

In NATALEE, which included both high-risk and intermediate-risk patients with early breast cancer, the absolute difference in 3-year IDFS rates between the combination group and endocrine monotherapy groups was 3.3%.

To determine the ultimate value of combining a CDK4/6 inhibitor with endocrine therapy in early breast cancer, longer follow-up of both trials will be necessary, Dr. Kalinsky said.

“The reason that follow-up is critical for both of these studies is that for this subtype of breast cancer, based upon data including from the Early Breast Cancer Trialists Group, we can see approximately 50% of recurrences after the first 5 years, and we think of cytotoxic chemotherapy as benefiting patients within those first 5 years. And while we think of CDK4/6 inhibitors as being cytostatic drugs, we are seeing a carryover effect in which 2 years of abemaciclib is improving outcome at the 5-year landmark,” he said.

Questions that still need to be answered include the optimal duration of CDK4/6 inhibitor therapy, whether adjuvant therapy should be resumed when there are signs of renewed proliferation, and whether there would be a benefit to restarting CDK4/6 inhibitors when metastasis occurs.

The monarchE trial was sponsored by Eli Lilly and Co. Dr. Harbeck disclosed research funding and speaker’s bureau activity for Lilly and others, and a consulting or advisory role with Gilead, Roche, Sanofi, Sandoz, and Seagen. Dr. Kalinsky disclosed a consulting or advisory role with multiple companies, not including Lilly.

MADRID – Five years on, the addition of the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy for women with high-risk hormone receptor–positive, HER2-negative (HR+/HER2–) early breast cancer continues to show modest but clinically significant benefits, compared with endocrine therapy alone.

Results of a planned 5-year efficacy analysis of the monarchE trial showed that at a median follow-up of 4.5 years, the abemaciclib/endocrine therapy combination was associated with a 7.6% absolute improvement in invasive disease–free survival (IDFS) and 6.7% edge in distant relapse–free survival (DRFS), compared with endocrine therapy alone, reported Nadia Harbeck, MD, from the Breast Center at Ludwig Maximilians University Hospital in Munich.

“The data are consistent with a carryover effect and further support the addition of adjuvant abemaciclib to endocrine therapy for patients with hormone receptor–positive, HER2-negative, node-positive high-risk early breast cancer,” she said at the 2023 European Society for Medical Oncology Congress.
 

High recurrence risk

Although HR+/HER2– breast cancer, the most common subtype of breast cancer, is generally associated with better outcomes than other subtypes, patients with node-positive early disease are at high risk for early recurrence and need treatment intensification, Dr. Harbeck said.

The monarchE trial included two cohorts: a primary cohort consisting of patients deemed at high risk based on clinical pathological features such as the number of involved axillary nodes, grade 3 disease, and tumors 5 cm or larger, and a second cohort of patients with lower disease grade and smaller tumors but with high levels of the proliferation marker Ki-67.

A total of 5,637 patients were randomized to receive either 2 years of abemaciclib 150 mg twice daily plus endocrine therapy, or endocrine therapy alone, followed by 3-8 years of additional endocrine as clinically indicated in each study arm.

An earlier preplanned interim analysis of the phase 3 trial of more than 5,600 patients was presented at the ESMO Virtual Congress 2020, and simultaneously published in the Journal of Clinical Oncology.

As that analysis showed, at a median follow-up of 15.5 months abemaciclib plus endocrine therapy was associated with a 25% relative risk reduction in the primary endpoint of IDFS vs. endocrine therapy alone.

At the time, the findings were hailed as practice-changing and, once approved for high-risk HR+/HER2-negative early breast cancer, as the new standard of care.

In the current analysis, Dr. Harbeck and colleagues looked at 5-year outcomes from a prespecified analysis, with a data cutoff of July 3, 2023.

All patients originally assigned to abemaciclib are now off the drug, and more than 80% have been followed for a minimum of 2 year since completing therapy with the CDK4/6 inhibitor.
 

Results

At 5 years there were cumulative totals of 407 IDFS events in the combination arm, compared with 585 in the endocrine therapy alone arm, a difference that translated into a hazard ratio of 0.68 favoring abemaciclib (P < .001).

The IDFS benefit with the combination was consistent across most subgroups, including older patients, perimenopausal and postmenopausal patients, those who had received prior neoadjuvant or adjuvant chemotherapy, all tumor sizes, number of positive lymph nodes, less favorable tumor stage or grade, and order of endocrine therapy (tamoxifen or aromatase inhibitor as first drug).

As noted before, DRFS, a secondary endpoint, also favored abemaciclib, with 345 events occurring over 5 years in the combination arm, compared with 501 in the endocrine therapy arm alone. This translated into a HR with the combination of 0.68 (P < .001).

There were fewer deaths in the abemaciclib arm (208 vs. 234), but this difference was not statistically significant.

The proportions of patients with treatment-emergent adverse events and serious adverse events (SAEs) were higher in the combination arm than in the endocrine therapy alone arm in all previous analyses of the trial data.

In the current analysis, “I would say it’s reassuring to see that the SAEs reported in the follow-up period, after the study treatment had been completed, are quite similar between the endocrine therapy alone arm and the abemaciclib plus endocrine therapy arm,” Dr. Harbeck said.
 

Changing road map

Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University, Atlanta, commented that CDK4/6 inhibitors “have changed the road map for treating hormone receptor–positive, HER2-negative disease.”

To put the monarchE results in context, he compared them with those of the NATALEE trial, in which patients were randomized to endocrine therapy with or without the CDK4/6 inhibitor ribociclib (Kisqali). That combination was previously shown to provide a significant survival advantage for women with metastatic breast cancer.

In NATALEE, which included both high-risk and intermediate-risk patients with early breast cancer, the absolute difference in 3-year IDFS rates between the combination group and endocrine monotherapy groups was 3.3%.

To determine the ultimate value of combining a CDK4/6 inhibitor with endocrine therapy in early breast cancer, longer follow-up of both trials will be necessary, Dr. Kalinsky said.

“The reason that follow-up is critical for both of these studies is that for this subtype of breast cancer, based upon data including from the Early Breast Cancer Trialists Group, we can see approximately 50% of recurrences after the first 5 years, and we think of cytotoxic chemotherapy as benefiting patients within those first 5 years. And while we think of CDK4/6 inhibitors as being cytostatic drugs, we are seeing a carryover effect in which 2 years of abemaciclib is improving outcome at the 5-year landmark,” he said.

Questions that still need to be answered include the optimal duration of CDK4/6 inhibitor therapy, whether adjuvant therapy should be resumed when there are signs of renewed proliferation, and whether there would be a benefit to restarting CDK4/6 inhibitors when metastasis occurs.

The monarchE trial was sponsored by Eli Lilly and Co. Dr. Harbeck disclosed research funding and speaker’s bureau activity for Lilly and others, and a consulting or advisory role with Gilead, Roche, Sanofi, Sandoz, and Seagen. Dr. Kalinsky disclosed a consulting or advisory role with multiple companies, not including Lilly.

MADRID – Five years on, the addition of the CDK4/6 inhibitor abemaciclib (Verzenio) to endocrine therapy for women with high-risk hormone receptor–positive, HER2-negative (HR+/HER2–) early breast cancer continues to show modest but clinically significant benefits, compared with endocrine therapy alone.

Results of a planned 5-year efficacy analysis of the monarchE trial showed that at a median follow-up of 4.5 years, the abemaciclib/endocrine therapy combination was associated with a 7.6% absolute improvement in invasive disease–free survival (IDFS) and 6.7% edge in distant relapse–free survival (DRFS), compared with endocrine therapy alone, reported Nadia Harbeck, MD, from the Breast Center at Ludwig Maximilians University Hospital in Munich.

“The data are consistent with a carryover effect and further support the addition of adjuvant abemaciclib to endocrine therapy for patients with hormone receptor–positive, HER2-negative, node-positive high-risk early breast cancer,” she said at the 2023 European Society for Medical Oncology Congress.
 

High recurrence risk

Although HR+/HER2– breast cancer, the most common subtype of breast cancer, is generally associated with better outcomes than other subtypes, patients with node-positive early disease are at high risk for early recurrence and need treatment intensification, Dr. Harbeck said.

The monarchE trial included two cohorts: a primary cohort consisting of patients deemed at high risk based on clinical pathological features such as the number of involved axillary nodes, grade 3 disease, and tumors 5 cm or larger, and a second cohort of patients with lower disease grade and smaller tumors but with high levels of the proliferation marker Ki-67.

A total of 5,637 patients were randomized to receive either 2 years of abemaciclib 150 mg twice daily plus endocrine therapy, or endocrine therapy alone, followed by 3-8 years of additional endocrine as clinically indicated in each study arm.

An earlier preplanned interim analysis of the phase 3 trial of more than 5,600 patients was presented at the ESMO Virtual Congress 2020, and simultaneously published in the Journal of Clinical Oncology.

As that analysis showed, at a median follow-up of 15.5 months abemaciclib plus endocrine therapy was associated with a 25% relative risk reduction in the primary endpoint of IDFS vs. endocrine therapy alone.

At the time, the findings were hailed as practice-changing and, once approved for high-risk HR+/HER2-negative early breast cancer, as the new standard of care.

In the current analysis, Dr. Harbeck and colleagues looked at 5-year outcomes from a prespecified analysis, with a data cutoff of July 3, 2023.

All patients originally assigned to abemaciclib are now off the drug, and more than 80% have been followed for a minimum of 2 year since completing therapy with the CDK4/6 inhibitor.
 

Results

At 5 years there were cumulative totals of 407 IDFS events in the combination arm, compared with 585 in the endocrine therapy alone arm, a difference that translated into a hazard ratio of 0.68 favoring abemaciclib (P < .001).

The IDFS benefit with the combination was consistent across most subgroups, including older patients, perimenopausal and postmenopausal patients, those who had received prior neoadjuvant or adjuvant chemotherapy, all tumor sizes, number of positive lymph nodes, less favorable tumor stage or grade, and order of endocrine therapy (tamoxifen or aromatase inhibitor as first drug).

As noted before, DRFS, a secondary endpoint, also favored abemaciclib, with 345 events occurring over 5 years in the combination arm, compared with 501 in the endocrine therapy arm alone. This translated into a HR with the combination of 0.68 (P < .001).

There were fewer deaths in the abemaciclib arm (208 vs. 234), but this difference was not statistically significant.

The proportions of patients with treatment-emergent adverse events and serious adverse events (SAEs) were higher in the combination arm than in the endocrine therapy alone arm in all previous analyses of the trial data.

In the current analysis, “I would say it’s reassuring to see that the SAEs reported in the follow-up period, after the study treatment had been completed, are quite similar between the endocrine therapy alone arm and the abemaciclib plus endocrine therapy arm,” Dr. Harbeck said.
 

Changing road map

Invited discussant Kevin Kalinsky, MD, MS, from the Winship Cancer Institute at Emory University, Atlanta, commented that CDK4/6 inhibitors “have changed the road map for treating hormone receptor–positive, HER2-negative disease.”

To put the monarchE results in context, he compared them with those of the NATALEE trial, in which patients were randomized to endocrine therapy with or without the CDK4/6 inhibitor ribociclib (Kisqali). That combination was previously shown to provide a significant survival advantage for women with metastatic breast cancer.

In NATALEE, which included both high-risk and intermediate-risk patients with early breast cancer, the absolute difference in 3-year IDFS rates between the combination group and endocrine monotherapy groups was 3.3%.

To determine the ultimate value of combining a CDK4/6 inhibitor with endocrine therapy in early breast cancer, longer follow-up of both trials will be necessary, Dr. Kalinsky said.

“The reason that follow-up is critical for both of these studies is that for this subtype of breast cancer, based upon data including from the Early Breast Cancer Trialists Group, we can see approximately 50% of recurrences after the first 5 years, and we think of cytotoxic chemotherapy as benefiting patients within those first 5 years. And while we think of CDK4/6 inhibitors as being cytostatic drugs, we are seeing a carryover effect in which 2 years of abemaciclib is improving outcome at the 5-year landmark,” he said.

Questions that still need to be answered include the optimal duration of CDK4/6 inhibitor therapy, whether adjuvant therapy should be resumed when there are signs of renewed proliferation, and whether there would be a benefit to restarting CDK4/6 inhibitors when metastasis occurs.

The monarchE trial was sponsored by Eli Lilly and Co. Dr. Harbeck disclosed research funding and speaker’s bureau activity for Lilly and others, and a consulting or advisory role with Gilead, Roche, Sanofi, Sandoz, and Seagen. Dr. Kalinsky disclosed a consulting or advisory role with multiple companies, not including Lilly.

HONOLULU – Sexual and gender minority (SGM) people are at increased risk for asthma severity, compared with non-SGM people, and asthma is especially exacerbated in SGM persons who use e-cigarettes compared with heterosexuals.

These findings come from a study of asthma severity among SGM people, with a special focus on the contribution of tobacco, reported Tugba Kaplan, MD, a resident in internal medicine at Luminis Health Anne Arundel Medical Center, Annapolis, Md.

“To the best of our knowledge, this is the first study assessing asthma severity among SGM people in a nationally representative longitudinal cohort study,” she said in an oral abstract session at the annual meeting of the American College of Chest Physicians (CHEST).

There has been only limited research on the health status and health needs of SGM people, and most of the studies conducted have focused on issues such as HIV/AIDS, sexual health, and substance use, not respiratory health, she said.
 

Following the PATH

Dr. Kaplan and colleagues drew on data from the Population Assessment of Tobacco and Health (PATH) Study, a nationally representative longitudinal cohort study with data on approximately 46,000 adults and adolescents in the United States.

The study uses self-reported data on tobacco use patterns; perceptions of risk and attitudes toward tobacco products; tobacco initiation, cessation, and relapse; and associated health outcomes.

The investigators combined data from three waves of the PATH Study, conducted from 2015 to 2019 on nonpregnant participants aged 18 years and older, and used mixed-effect logistic regression models to look for potential associations between sexual orientation and asthma severity.

They used standard definitions of asthma severity, based on lung function impairment measured by forced expiratory volume in 1 second and forced vital capacity, nighttime awakenings, use of a short-acting beta2-agonist for symptoms, interference with normal activity, and exacerbations requiring oral systemic corticosteroids.

The study also includes a sexual orientation question, asking participants, “do you consider yourself to be ...” with the options “straight, lesbian or gay, bisexual, something else, don’t know, or refused.”

Based on these responses, Dr. Kaplan and colleagues studied a total sample of 1,815 people who identify as SGM and 12,879 who identify as non-SGM.
 

Risks increased

In an analysis adjusted for age, sex, race/ethnicity, tobacco use, body mass index, physical activity, and asthma medication use, the authors found that, compared with non-SGM people, SGM respondents were significantly more likely to have had asthma attacks requiring steroid use in the past years (odds ratio, 1.47; 95% confidence interval, 1.01-2.15), asthma interfering with daily activities in the past month (OR, 1.33; CI, 1.10-1.61), and shortness of breath in any week over the 30 days (OR, 1.82; CI, 1.32-2.51). There was no significant difference between the groups in inhaler use over the past month, however.

They also found two interactions in the logistic regression models, one between urgent care visits and respondents who reported using both regular tobacco and e-cigarettes (dual users), and between exclusive e-cigarette use and waking up at night.

Among dual users, SGM respondents had a nearly fourfold greater risk for asthma attacks requiring urgent care visits, compared with non-SGM respondents (OR, 3.89; CI, 1.99-7.63). In contrast, among those who never used tobacco, there were no significant differences between the sexual orientation groups in regard to asthma attacks requiring urgent care visits.

Among those who reported using e-cigarettes exclusively, SGM respondents were nearly eight times more likely to report night awakening, compared with non-SGM users (OR, 7.81; CI, 2.93-20.8).

Among never users, in contrast, there was no significant difference in nighttime disturbances.
 

Possible confounders

The data suggest that “in the context of chronic illnesses like asthma, it is crucial to offer patients the knowledge and tools required to proficiently handle their conditions,” Dr. Kaplan said, adding that the differences seen between SGM and non-SGM respondents may be caused by health care disparities among SGM people that result in nonadherence to regular follow-ups.

In an interview, Jean Bourbeau, MD, MSc, who was a moderator for the session but was not involved in the study, commented that “we have to be very careful before making any conclusions, because this population could be at high risk for different reasons, and especially, do they get the same attention in terms of the care that is provided to the general population, and do they get access to the same medication?”

Nonetheless, Dr. Bourbeau continued, “I think this study is very important, because it shows us how much awareness we need to determine differences in populations, and [sexual orientation] is probably one thing that nobody had considered before, and for the first time we are now considering these potential differences in our population.”

The authors did not report a study funding source. Dr. Kaplan and Dr. Bourbeau reported having no relevant financial relationships.

A version of this article first appeared on Medscape.com.

HONOLULU – Sexual and gender minority (SGM) people are at increased risk for asthma severity, compared with non-SGM people, and asthma is especially exacerbated in SGM persons who use e-cigarettes compared with heterosexuals.

These findings come from a study of asthma severity among SGM people, with a special focus on the contribution of tobacco, reported Tugba Kaplan, MD, a resident in internal medicine at Luminis Health Anne Arundel Medical Center, Annapolis, Md.

“To the best of our knowledge, this is the first study assessing asthma severity among SGM people in a nationally representative longitudinal cohort study,” she said in an oral abstract session at the annual meeting of the American College of Chest Physicians (CHEST).

There has been only limited research on the health status and health needs of SGM people, and most of the studies conducted have focused on issues such as HIV/AIDS, sexual health, and substance use, not respiratory health, she said.
 

Following the PATH

Dr. Kaplan and colleagues drew on data from the Population Assessment of Tobacco and Health (PATH) Study, a nationally representative longitudinal cohort study with data on approximately 46,000 adults and adolescents in the United States.

The study uses self-reported data on tobacco use patterns; perceptions of risk and attitudes toward tobacco products; tobacco initiation, cessation, and relapse; and associated health outcomes.

The investigators combined data from three waves of the PATH Study, conducted from 2015 to 2019 on nonpregnant participants aged 18 years and older, and used mixed-effect logistic regression models to look for potential associations between sexual orientation and asthma severity.

They used standard definitions of asthma severity, based on lung function impairment measured by forced expiratory volume in 1 second and forced vital capacity, nighttime awakenings, use of a short-acting beta2-agonist for symptoms, interference with normal activity, and exacerbations requiring oral systemic corticosteroids.

The study also includes a sexual orientation question, asking participants, “do you consider yourself to be ...” with the options “straight, lesbian or gay, bisexual, something else, don’t know, or refused.”

Based on these responses, Dr. Kaplan and colleagues studied a total sample of 1,815 people who identify as SGM and 12,879 who identify as non-SGM.
 

Risks increased

In an analysis adjusted for age, sex, race/ethnicity, tobacco use, body mass index, physical activity, and asthma medication use, the authors found that, compared with non-SGM people, SGM respondents were significantly more likely to have had asthma attacks requiring steroid use in the past years (odds ratio, 1.47; 95% confidence interval, 1.01-2.15), asthma interfering with daily activities in the past month (OR, 1.33; CI, 1.10-1.61), and shortness of breath in any week over the 30 days (OR, 1.82; CI, 1.32-2.51). There was no significant difference between the groups in inhaler use over the past month, however.

They also found two interactions in the logistic regression models, one between urgent care visits and respondents who reported using both regular tobacco and e-cigarettes (dual users), and between exclusive e-cigarette use and waking up at night.

Among dual users, SGM respondents had a nearly fourfold greater risk for asthma attacks requiring urgent care visits, compared with non-SGM respondents (OR, 3.89; CI, 1.99-7.63). In contrast, among those who never used tobacco, there were no significant differences between the sexual orientation groups in regard to asthma attacks requiring urgent care visits.

Among those who reported using e-cigarettes exclusively, SGM respondents were nearly eight times more likely to report night awakening, compared with non-SGM users (OR, 7.81; CI, 2.93-20.8).

Among never users, in contrast, there was no significant difference in nighttime disturbances.
 

Possible confounders

The data suggest that “in the context of chronic illnesses like asthma, it is crucial to offer patients the knowledge and tools required to proficiently handle their conditions,” Dr. Kaplan said, adding that the differences seen between SGM and non-SGM respondents may be caused by health care disparities among SGM people that result in nonadherence to regular follow-ups.

In an interview, Jean Bourbeau, MD, MSc, who was a moderator for the session but was not involved in the study, commented that “we have to be very careful before making any conclusions, because this population could be at high risk for different reasons, and especially, do they get the same attention in terms of the care that is provided to the general population, and do they get access to the same medication?”

Nonetheless, Dr. Bourbeau continued, “I think this study is very important, because it shows us how much awareness we need to determine differences in populations, and [sexual orientation] is probably one thing that nobody had considered before, and for the first time we are now considering these potential differences in our population.”

The authors did not report a study funding source. Dr. Kaplan and Dr. Bourbeau reported having no relevant financial relationships.

A version of this article first appeared on Medscape.com.

HONOLULU – Sexual and gender minority (SGM) people are at increased risk for asthma severity, compared with non-SGM people, and asthma is especially exacerbated in SGM persons who use e-cigarettes compared with heterosexuals.

These findings come from a study of asthma severity among SGM people, with a special focus on the contribution of tobacco, reported Tugba Kaplan, MD, a resident in internal medicine at Luminis Health Anne Arundel Medical Center, Annapolis, Md.

“To the best of our knowledge, this is the first study assessing asthma severity among SGM people in a nationally representative longitudinal cohort study,” she said in an oral abstract session at the annual meeting of the American College of Chest Physicians (CHEST).

There has been only limited research on the health status and health needs of SGM people, and most of the studies conducted have focused on issues such as HIV/AIDS, sexual health, and substance use, not respiratory health, she said.
 

Following the PATH

Dr. Kaplan and colleagues drew on data from the Population Assessment of Tobacco and Health (PATH) Study, a nationally representative longitudinal cohort study with data on approximately 46,000 adults and adolescents in the United States.

The study uses self-reported data on tobacco use patterns; perceptions of risk and attitudes toward tobacco products; tobacco initiation, cessation, and relapse; and associated health outcomes.

The investigators combined data from three waves of the PATH Study, conducted from 2015 to 2019 on nonpregnant participants aged 18 years and older, and used mixed-effect logistic regression models to look for potential associations between sexual orientation and asthma severity.

They used standard definitions of asthma severity, based on lung function impairment measured by forced expiratory volume in 1 second and forced vital capacity, nighttime awakenings, use of a short-acting beta2-agonist for symptoms, interference with normal activity, and exacerbations requiring oral systemic corticosteroids.

The study also includes a sexual orientation question, asking participants, “do you consider yourself to be ...” with the options “straight, lesbian or gay, bisexual, something else, don’t know, or refused.”

Based on these responses, Dr. Kaplan and colleagues studied a total sample of 1,815 people who identify as SGM and 12,879 who identify as non-SGM.
 

Risks increased

In an analysis adjusted for age, sex, race/ethnicity, tobacco use, body mass index, physical activity, and asthma medication use, the authors found that, compared with non-SGM people, SGM respondents were significantly more likely to have had asthma attacks requiring steroid use in the past years (odds ratio, 1.47; 95% confidence interval, 1.01-2.15), asthma interfering with daily activities in the past month (OR, 1.33; CI, 1.10-1.61), and shortness of breath in any week over the 30 days (OR, 1.82; CI, 1.32-2.51). There was no significant difference between the groups in inhaler use over the past month, however.

They also found two interactions in the logistic regression models, one between urgent care visits and respondents who reported using both regular tobacco and e-cigarettes (dual users), and between exclusive e-cigarette use and waking up at night.

Among dual users, SGM respondents had a nearly fourfold greater risk for asthma attacks requiring urgent care visits, compared with non-SGM respondents (OR, 3.89; CI, 1.99-7.63). In contrast, among those who never used tobacco, there were no significant differences between the sexual orientation groups in regard to asthma attacks requiring urgent care visits.

Among those who reported using e-cigarettes exclusively, SGM respondents were nearly eight times more likely to report night awakening, compared with non-SGM users (OR, 7.81; CI, 2.93-20.8).

Among never users, in contrast, there was no significant difference in nighttime disturbances.
 

Possible confounders

The data suggest that “in the context of chronic illnesses like asthma, it is crucial to offer patients the knowledge and tools required to proficiently handle their conditions,” Dr. Kaplan said, adding that the differences seen between SGM and non-SGM respondents may be caused by health care disparities among SGM people that result in nonadherence to regular follow-ups.

In an interview, Jean Bourbeau, MD, MSc, who was a moderator for the session but was not involved in the study, commented that “we have to be very careful before making any conclusions, because this population could be at high risk for different reasons, and especially, do they get the same attention in terms of the care that is provided to the general population, and do they get access to the same medication?”

Nonetheless, Dr. Bourbeau continued, “I think this study is very important, because it shows us how much awareness we need to determine differences in populations, and [sexual orientation] is probably one thing that nobody had considered before, and for the first time we are now considering these potential differences in our population.”

The authors did not report a study funding source. Dr. Kaplan and Dr. Bourbeau reported having no relevant financial relationships.

A version of this article first appeared on Medscape.com.

HONOLULU – Patients with acute respiratory distress syndrome (ARDS) and coexisting pulmonary hypertension (PH) are significantly more likely to have longer and more costly hospital stays and to die in-hospital than patients with ARDS without PH, results of a retrospective study suggest.

Among more than 156,000 hospitalized patients with ARDS, 16.8% of whom also had a diagnosis of PH, the presence of PH was associated with about a 50% higher risk for in-hospital mortality and a 37% higher risk for longer hospital stays. In addition, the presence of PH was associated with nearly $20,000 of higher hospital expenditures, reported Kaushik Kumar, MBBS, at the annual meeting of the American College of Chest Physicians (CHEST).

“Clinicians should be vigilant in identifying and managing pulmonary hypertension in ARDS patients,” Dr. Kumar, a resident in internal medicine at Medstar Health, Baltimore, said in an oral abstract presentation.

He added that PH has the potential to serve as an indicator of disease severity for patients with ARDS.
 

National database

PH is a frequent complication of ARDS, likely related to a combination of pulmonary vasoconstriction, thromboembolism, and interstitial edema, he said.

To test their hypothesis that the presence of PH in patients with ARDS is associated with worse outcomes, Dr. Kumar and colleagues drew on the National Inpatient Sample database for information on adults aged 18 years and older who had been diagnosed with ARDS with or without PH.

They identified a total of 156,687 patients of whom 26,324 (16.8%) also had been diagnosed with PH. Among the cohort with PH, there were higher proportions of older patients, women, and patients with multiple comorbidities.

The in-hospital mortality rate was 36.8% among patients with PH, compared with 24.6% among those without. The mean length of stay was also longer among patients with PH, at 12 days versus 10 days.

In an unadjusted analysis, mean total hospital charges for patients with ARDS and PH were $210,165, versus $160,683 for patients with ARDS who did not have PH.

In an analysis in which the investigators controlled for age, sex, index admission length of stay, insurance status, and comorbidities, in-hospital mortality for patients with PH remained significantly higher, with an odds ratio of 1.52 (P < .001). PH was also significantly associated with longer length of stay (odds ratio, 1.37; P < .001) and higher total hospital costs, with a mean difference of $19,406.

Dr. Kumar said that the findings underscore the importance of a tailored approach to managing patients with ARDS, especially in the presence of PH.

The investigators plan further studies to assess the role of PH-targeted therapies, to examine the role of sepsis and right ventricular failure and to explore the long-term impact of PH among ARDS survivors, including effects with respect to pulmonary function, quality of life, and long-term morbidity.
 

Potential to inform practice

A pulmonologist who was not involved in the study said in an interview that the findings of the trial suggest that PH may have a greater influence on mortality than is currently understood and that further investigations into this association could change practice in the future.

“I think it would be very important for us to understand if that is going to change our outlook on how ARDS is managed. It’s possible that some of the interventions that we give people who don’t have pulmonary hypertension, for example, increasing the airway pressure in order to minimize oxygenation, may have a detrimental effect on the pulmonary vasculature,” said Timothy Morris, MD, medical director of the pulmonary and exercise lab and professor of medicine at the University of California, San Diego.

“I think it’s a little bit premature to say that this should guide management now, but it’s certainly an interesting question that may end up changing practice in the future,” said Dr. Morris, who was moderator of the session in which Dr. Kumar presented the data.

The study was supported by the Agency for Healthcare Research and Quality and Medstar Health Research Institute. Dr. Kumar and Dr. Morris have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

HONOLULU – Patients with acute respiratory distress syndrome (ARDS) and coexisting pulmonary hypertension (PH) are significantly more likely to have longer and more costly hospital stays and to die in-hospital than patients with ARDS without PH, results of a retrospective study suggest.

Among more than 156,000 hospitalized patients with ARDS, 16.8% of whom also had a diagnosis of PH, the presence of PH was associated with about a 50% higher risk for in-hospital mortality and a 37% higher risk for longer hospital stays. In addition, the presence of PH was associated with nearly $20,000 of higher hospital expenditures, reported Kaushik Kumar, MBBS, at the annual meeting of the American College of Chest Physicians (CHEST).

“Clinicians should be vigilant in identifying and managing pulmonary hypertension in ARDS patients,” Dr. Kumar, a resident in internal medicine at Medstar Health, Baltimore, said in an oral abstract presentation.

He added that PH has the potential to serve as an indicator of disease severity for patients with ARDS.
 

National database

PH is a frequent complication of ARDS, likely related to a combination of pulmonary vasoconstriction, thromboembolism, and interstitial edema, he said.

To test their hypothesis that the presence of PH in patients with ARDS is associated with worse outcomes, Dr. Kumar and colleagues drew on the National Inpatient Sample database for information on adults aged 18 years and older who had been diagnosed with ARDS with or without PH.

They identified a total of 156,687 patients of whom 26,324 (16.8%) also had been diagnosed with PH. Among the cohort with PH, there were higher proportions of older patients, women, and patients with multiple comorbidities.

The in-hospital mortality rate was 36.8% among patients with PH, compared with 24.6% among those without. The mean length of stay was also longer among patients with PH, at 12 days versus 10 days.

In an unadjusted analysis, mean total hospital charges for patients with ARDS and PH were $210,165, versus $160,683 for patients with ARDS who did not have PH.

In an analysis in which the investigators controlled for age, sex, index admission length of stay, insurance status, and comorbidities, in-hospital mortality for patients with PH remained significantly higher, with an odds ratio of 1.52 (P < .001). PH was also significantly associated with longer length of stay (odds ratio, 1.37; P < .001) and higher total hospital costs, with a mean difference of $19,406.

Dr. Kumar said that the findings underscore the importance of a tailored approach to managing patients with ARDS, especially in the presence of PH.

The investigators plan further studies to assess the role of PH-targeted therapies, to examine the role of sepsis and right ventricular failure and to explore the long-term impact of PH among ARDS survivors, including effects with respect to pulmonary function, quality of life, and long-term morbidity.
 

Potential to inform practice

A pulmonologist who was not involved in the study said in an interview that the findings of the trial suggest that PH may have a greater influence on mortality than is currently understood and that further investigations into this association could change practice in the future.

“I think it would be very important for us to understand if that is going to change our outlook on how ARDS is managed. It’s possible that some of the interventions that we give people who don’t have pulmonary hypertension, for example, increasing the airway pressure in order to minimize oxygenation, may have a detrimental effect on the pulmonary vasculature,” said Timothy Morris, MD, medical director of the pulmonary and exercise lab and professor of medicine at the University of California, San Diego.

“I think it’s a little bit premature to say that this should guide management now, but it’s certainly an interesting question that may end up changing practice in the future,” said Dr. Morris, who was moderator of the session in which Dr. Kumar presented the data.

The study was supported by the Agency for Healthcare Research and Quality and Medstar Health Research Institute. Dr. Kumar and Dr. Morris have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

HONOLULU – Patients with acute respiratory distress syndrome (ARDS) and coexisting pulmonary hypertension (PH) are significantly more likely to have longer and more costly hospital stays and to die in-hospital than patients with ARDS without PH, results of a retrospective study suggest.

Among more than 156,000 hospitalized patients with ARDS, 16.8% of whom also had a diagnosis of PH, the presence of PH was associated with about a 50% higher risk for in-hospital mortality and a 37% higher risk for longer hospital stays. In addition, the presence of PH was associated with nearly $20,000 of higher hospital expenditures, reported Kaushik Kumar, MBBS, at the annual meeting of the American College of Chest Physicians (CHEST).

“Clinicians should be vigilant in identifying and managing pulmonary hypertension in ARDS patients,” Dr. Kumar, a resident in internal medicine at Medstar Health, Baltimore, said in an oral abstract presentation.

He added that PH has the potential to serve as an indicator of disease severity for patients with ARDS.
 

National database

PH is a frequent complication of ARDS, likely related to a combination of pulmonary vasoconstriction, thromboembolism, and interstitial edema, he said.

To test their hypothesis that the presence of PH in patients with ARDS is associated with worse outcomes, Dr. Kumar and colleagues drew on the National Inpatient Sample database for information on adults aged 18 years and older who had been diagnosed with ARDS with or without PH.

They identified a total of 156,687 patients of whom 26,324 (16.8%) also had been diagnosed with PH. Among the cohort with PH, there were higher proportions of older patients, women, and patients with multiple comorbidities.

The in-hospital mortality rate was 36.8% among patients with PH, compared with 24.6% among those without. The mean length of stay was also longer among patients with PH, at 12 days versus 10 days.

In an unadjusted analysis, mean total hospital charges for patients with ARDS and PH were $210,165, versus $160,683 for patients with ARDS who did not have PH.

In an analysis in which the investigators controlled for age, sex, index admission length of stay, insurance status, and comorbidities, in-hospital mortality for patients with PH remained significantly higher, with an odds ratio of 1.52 (P < .001). PH was also significantly associated with longer length of stay (odds ratio, 1.37; P < .001) and higher total hospital costs, with a mean difference of $19,406.

Dr. Kumar said that the findings underscore the importance of a tailored approach to managing patients with ARDS, especially in the presence of PH.

The investigators plan further studies to assess the role of PH-targeted therapies, to examine the role of sepsis and right ventricular failure and to explore the long-term impact of PH among ARDS survivors, including effects with respect to pulmonary function, quality of life, and long-term morbidity.
 

Potential to inform practice

A pulmonologist who was not involved in the study said in an interview that the findings of the trial suggest that PH may have a greater influence on mortality than is currently understood and that further investigations into this association could change practice in the future.

“I think it would be very important for us to understand if that is going to change our outlook on how ARDS is managed. It’s possible that some of the interventions that we give people who don’t have pulmonary hypertension, for example, increasing the airway pressure in order to minimize oxygenation, may have a detrimental effect on the pulmonary vasculature,” said Timothy Morris, MD, medical director of the pulmonary and exercise lab and professor of medicine at the University of California, San Diego.

“I think it’s a little bit premature to say that this should guide management now, but it’s certainly an interesting question that may end up changing practice in the future,” said Dr. Morris, who was moderator of the session in which Dr. Kumar presented the data.

The study was supported by the Agency for Healthcare Research and Quality and Medstar Health Research Institute. Dr. Kumar and Dr. Morris have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

It took 160 years but, in February 2023, the Food and Drug Administration approved the first drug specifically designed to treat the rare neuromuscular disease Friedreich ataxia (FA). The disease, first described in 1863 by German physician Nikolaus Friedreich, has an estimated incidence of 1 in 50,000 worldwide. It is the most common form of hereditary ataxia, accounting for approximately 50% of all cases of ataxia and approximately 75% of cases among patients younger than 25 years in the United States.¹

FA typically presents in childhood or early adolescence; in some patients, symptoms manifest in the middle of the third decade of life. Patients exhibit symptoms such as ataxia that becomes worse over time, gait ataxia, impaired sensation in the extremities that can spread centrally, loss of normal reflexes, especially in the knees, speech disorders (dysarthria), muscle spasticity, scoliosis, and dysphagia.

Severity of disease ranges from relatively mild to completely disabling. Symptoms are progressive; patients almost inevitably require ambulatory support or a wheelchair. They might develop diabetes mellitus and can lose hearing and vision as the disease progresses. Hypertrophic cardiomyopathy is the most common cause of death among FA patients. Some patients who have less severe features might live into their 60s – even beyond that age.²There is no cure for FA. Until recently, no therapy was available other than supportive care to address associated neuromuscular, cardiovascular, and metabolic complications.

Making the diagnosis

Genetic testing can provide a definitive diagnosis of FA. (The genetic etiology of the disease is described later in this article.)

In addition to genetic screening, the workup includes a thorough medical history and physical examination that focuses on problems with balance, proprioception, absence of reflexes, and neurological signs. Tests include electromyography, nerve-conduction studies, electrocardiography, a metabolic profile, and MRI of the brain and spinal cord.

MRI utility in FA. In a paper published in July 2023 in Brain Communications, investigators from the University of Minnesota, Minneapolis, reported that various MRI techniques can be combined to detect early-stage alterations and disease progression in patients with FA.³ The researchers compared images taken at baseline and at 1, 2, and 3 years in 28 FA patients and 20 age- and gender-matched controls.

They observed that, compared with controls, patients with FA had lower cerebellar white matter volume but not lower cerebellar gray matter volume; larger cerebellar peduncle, thalamus, and brain stem structures; and a higher volume of the fourth ventricle. Using diffusion-tensor imaging and fixel-based analysis of diffusion MRI metrics, they also detected microstructural differences in several brain regions – especially in the cerebellum and corticospinal tract.

“Over time, many of these macrostructural and microstructural alterations progressed, especially cerebellar gray- and white-matter volume and microstructures of the superior cerebellar peduncle, the posterior limb of the internal capsule, and the superior corona radiata,” the investigators reported. In addition, “linear regressions showed significant associations between many of those imaging metrics and clinical scales.”

Pathophysiological basis of FA

The underlying genetic pathology of FA was first described in 1996 by investigators from the University of Valencia (Spain). They reported that FA is caused by a mutation in FXN (formerly X25), a gene that encodes for the protein frataxin, which is important for producing mitochondrial adenosine triphosphate and managing iron stores.⁴

The mutation results in multiple guanine-adenine-adenine repeats in FXN, or, in a few cases, a point mutation or deletion in 1 allele of FXN, with multiple GAA repeats in the other allele. A hallmark of FA is impairment of cellular antioxidative defense mechanisms – a major cause of disease progression.

Treatment options have been limited

Omaveloxolone. Dr. Lynch is principal investigator for the MOXIe trial of the safety, pharmacodynamics, and efficacy of omaveloxolone (marketed as Skyclarys [Reata Pharmaceuticals]),⁵ which received FDA orphan drug, fast track, priority review, and rare pediatric disease designations for the treatment of FA and, in February 2023, formal FDA approval.⁶ Development of this drug, which activates Nrf2 and induces antioxidant target genes, arose from basic science investigation into mechanisms by which cells respond to stresses.

“Omaveloxolone works on the Nrf2 pathway, which is, paradoxically, deficient in FA,” Dr. Lynch said. “This pathway should be active all the time. You would expect that, in cells from Friedreich ataxia in a person or an animal model of the disease, you’d see that Nrf2 would be very active but, in fact, what you find is the opposite,” Dr. Lynch explained. “It’s relatively inefficient, it’s localized in the cell, and the antioxidant response element genes – the things we all use to protect ourselves from mitochondrial damage – are all relatively turned off.”

In the first phase of MOXIe, 103 patients with FA were randomly assigned to receive either omaveloxolone, 15 mg orally (51 patients), or placebo (52 patients) for 48 weeks.

The primary endpoint was change in the modified Friedreich’s Ataxia Rating Scale (mFARS) score at 48 weeks. The scale is a clinically validated neurological instrument that evaluates upper- and lower-limb coordination, upright stability, and bulbar function.

Patients assigned to placebo had worsening of function at 48 weeks (mean increase in mFARS score, 0.85). In contrast, patients assigned to omaveloxolone had a mean decrease in the mFARS score of –1.56, indicating improvement. The between-group difference of –2.41 points was statistically significant in favor of omaveloxolone (P = .038).

In a 3-year, post hoc, propensity-matched analysis, patients assigned to omaveloxolone had lower mFARS scores than a matched set of untreated patients in a study of the natural history of FA.⁷Dimethyl fumarate (marketed as Tecfidera [Biogen]), approved in the United States and other countries for the treatment of patients with relapsing forms of multiple sclerosis, also has Nrf2 as a therapeutic target, although its precise mechanism of action is unclear. Clinical trials of this agent for the treatment of FA are under consideration in Europe, Dr. Lynch said.

Apart from these agents, treatment of patients with FA largely centers on management of metabolic and cardiac complications; physical and occupational therapy; devices such as orthopedic shoes, canes, and wheelchairs; and, when indicated, surgery to correct skeletal problems or for implantation of a cardiac-assist device.
 

The FA therapeutic pipeline

According to the Friedreich’s Ataxia Research Alliance, other approaches to improving mitochondrial function and reducing oxidative stress in FA are under investigation or awaiting approval, including elamipretide, for which FDA approval is pending for Barth syndrome (a rare, X-linked disorder) and for primary mitochondrial myopathy; nicotinamide adenine dinucleotide (NAD+, a coenzyme for redox reactions) plus exercise; and MIB-626, a crystalline form of nicotinamide mononucleotide, a precursor of NAD+.

Vatiquinone, an investigational inhibitor of 15-lipoxygenase, a regulator of energetic and oxidative stress pathways, failed to meet its primary endpoint of significant improvement on the mFARS score at 72 weeks of follow-up in the MOVE-FA trial, according to the manufacturer, PTC Therapeutics.⁸Another therapeutic approach under investigation is modulation of frataxin-controlled metabolic pathways with leriglitazone, an orally available selective peroxisome proliferator-activated receptor gamma agonist,⁹ or with the prodrug precursor of monomethyl fumarate plus dimethyl fumarate.

CTI-1601, a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA, is in phase 1 trials. This compound has been granted rare pediatric disease designation, fast track designation, and orphan drug status by the FDA, according to the manufacturer, Larimar Therapeutics.¹⁰Etravirine, a nonnucleoside reverse transcriptase inhibitor approved for treating HIV infection, has been demonstrated to increase the frataxin protein in cells derived from FA patients and in the heart and skeletal muscle of frataxin-deficient YG8 mice. This agent recently completed a phase 2 trial in patients with FA.¹¹

Gene therapy: Promising

Given the genetic etiology of FA, gene therapy strategies aimed at either increasing FA gene expression or editing the genome to replace defective FXN are under active investigation.

Increasing FA gene expression. DT-216 (Design Therapeutics) is a novel, gene-targeted chimera small molecule designed to target the GAA repeat expansion mutation and restore FXN expression. This agent completed phase 1 dosing studies in 2022.

Oligonucleotides, which are nucleic acid polymers primarily used for gene silencing, are also being explored for increasing the expression of FXN, in research at the University of Texas Southwestern Medical Center, Dallas, and the University of Massachusetts, Worcester.

Gene replacement strategies under investigation to treat FA include LX2006 (Lexeo Therapeutics), a gene replacement therapy using an adeno-associated viral vector to deliver FXN intravenously, with the goal of getting the gene into myocardial cells and increasing the frataxin level in mitochondria.

Future directions

Dr. Koeppen, Dr. Lynch, and colleagues Ian H. Harding, PhD, from Monash University, Melbourne, and Massimo Pandolfo, MD, McGill University, Montreal, conducted an extensive review of FA with a focus on challenges that researchers and drug developers face crafting therapies for this complex disorder.¹³

They noted that FA is “characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate.”

The authors took a deep dive into the evidence, old and new, to evaluate the effects of FA on the central and peripheral nervous systems and to look at the course of neuropathologic changes associated with the disease. They propose a comprehensive approach to identify nervous system locations that are likely to be most successfully targeted at different disease time points.

“The proprioceptive system, usually considered a major target for frataxin-restoring treatments, shows substantial evidence of hypoplasia and/or early developmental loss, with minimal evidence of progression over time,” they wrote. “It seems likely that this system is not an ideal target for therapies given after early childhood. Targeting the [dentate nucleus] of the cerebellum is likely to be most effective early in the course of the disease, when it is functionally affected, but still shows limited atrophy. The corticospinal tract degenerates over time contributing to disease progression throughout its late stages and may be considered a target.”

David Lynch, MD, PhD, and Arnulf Koeppen, MD, disclose support from the Friedreich’s Ataxia Research Alliance. Dr. Lynch also discloses support from the National Institutes of Health, U.S. Food and Drug Administration, Muscular Dystrophy Association, Reata Pharmaceuticals, and Retrotope.

References

1. Williams CT and De Jesus O. Friedreich ataxia. StatPearls. 2023 Jun 27. https://www.ncbi.nlm.nih.gov/books/NBK563199/.

2. National Institute of Neurological Disorders and Stroke. Friedreich ataxia. 2023 Sep 2. https://www.ninds.nih.gov/health-information/disorders/friedreich-ataxia.

3. Adanyeguh IM et al. Brain Commun. 2023;5(4):fcad196. doi: 10.1093/braincomms/fcad196.

4. Camapuzano V et al. Science. 1996;271(5254):1423-7. doi: 10.1126/science.271.5254.1423.

5. RTA 408 capsules in patients with Friedreich’s ataxia–MOXIe. ClinicalTrials. gov Identifier: NCT02255435. 2022 Dec 6. https://clinicaltrials.gov/study/NCT02255435.

6. Food and Drug Administration. FDA approves first treatment for Friedreich’s ataxia. 2023 Feb 28. www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-friedreichs-ataxia#.

7. Lynch DR et al. Ann Clin Transl Neurol. 2023 Sep 10. doi: 10.1002/acn3.51897

8. PTC Therapeutics. PTC Therapeutics announces topline results from vatiquinone MOVE-FA registration-directed trial. 2023 May 23. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-topline-results-vatiquinone-move-fa.

9. Minoryx Therapeutics. The FRAMES Clinical Study in FRDA. https://www.minoryx.com/clinical-studies/clinical-study-frames/.

10. Larimar Therapeutics. CTI-1601 for Friedreich’s ataxia. https://larimartx.com/our-programs/cti-1601/.

11. Safety and efficacy of etravirine in Friedreich ataxia patients (FAEST1). ClinicalTrials.gov Identifier: NCT04273165. 2023 Mar 20. https://clinicaltrials.gov/study/NCT04273165.

12. Phase IA study of AAVrh.10hFXN gene therapy for the cardiomyopathy of Friedreich’s ataxia. ClinicalTrials.gov Identifier: NCT05302271. https://clinicaltrials.gov/study/NCT05302271.

13. Harding IH et al. Hum Gene Ther. 2020;31(23-24):1226-36. doi: 10.1089/hum.2020.264

It took 160 years but, in February 2023, the Food and Drug Administration approved the first drug specifically designed to treat the rare neuromuscular disease Friedreich ataxia (FA). The disease, first described in 1863 by German physician Nikolaus Friedreich, has an estimated incidence of 1 in 50,000 worldwide. It is the most common form of hereditary ataxia, accounting for approximately 50% of all cases of ataxia and approximately 75% of cases among patients younger than 25 years in the United States.¹

FA typically presents in childhood or early adolescence; in some patients, symptoms manifest in the middle of the third decade of life. Patients exhibit symptoms such as ataxia that becomes worse over time, gait ataxia, impaired sensation in the extremities that can spread centrally, loss of normal reflexes, especially in the knees, speech disorders (dysarthria), muscle spasticity, scoliosis, and dysphagia.

Severity of disease ranges from relatively mild to completely disabling. Symptoms are progressive; patients almost inevitably require ambulatory support or a wheelchair. They might develop diabetes mellitus and can lose hearing and vision as the disease progresses. Hypertrophic cardiomyopathy is the most common cause of death among FA patients. Some patients who have less severe features might live into their 60s – even beyond that age.²There is no cure for FA. Until recently, no therapy was available other than supportive care to address associated neuromuscular, cardiovascular, and metabolic complications.

Making the diagnosis

Genetic testing can provide a definitive diagnosis of FA. (The genetic etiology of the disease is described later in this article.)

In addition to genetic screening, the workup includes a thorough medical history and physical examination that focuses on problems with balance, proprioception, absence of reflexes, and neurological signs. Tests include electromyography, nerve-conduction studies, electrocardiography, a metabolic profile, and MRI of the brain and spinal cord.

MRI utility in FA. In a paper published in July 2023 in Brain Communications, investigators from the University of Minnesota, Minneapolis, reported that various MRI techniques can be combined to detect early-stage alterations and disease progression in patients with FA.³ The researchers compared images taken at baseline and at 1, 2, and 3 years in 28 FA patients and 20 age- and gender-matched controls.

They observed that, compared with controls, patients with FA had lower cerebellar white matter volume but not lower cerebellar gray matter volume; larger cerebellar peduncle, thalamus, and brain stem structures; and a higher volume of the fourth ventricle. Using diffusion-tensor imaging and fixel-based analysis of diffusion MRI metrics, they also detected microstructural differences in several brain regions – especially in the cerebellum and corticospinal tract.

“Over time, many of these macrostructural and microstructural alterations progressed, especially cerebellar gray- and white-matter volume and microstructures of the superior cerebellar peduncle, the posterior limb of the internal capsule, and the superior corona radiata,” the investigators reported. In addition, “linear regressions showed significant associations between many of those imaging metrics and clinical scales.”

Pathophysiological basis of FA

The underlying genetic pathology of FA was first described in 1996 by investigators from the University of Valencia (Spain). They reported that FA is caused by a mutation in FXN (formerly X25), a gene that encodes for the protein frataxin, which is important for producing mitochondrial adenosine triphosphate and managing iron stores.⁴

The mutation results in multiple guanine-adenine-adenine repeats in FXN, or, in a few cases, a point mutation or deletion in 1 allele of FXN, with multiple GAA repeats in the other allele. A hallmark of FA is impairment of cellular antioxidative defense mechanisms – a major cause of disease progression.

Treatment options have been limited

Omaveloxolone. Dr. Lynch is principal investigator for the MOXIe trial of the safety, pharmacodynamics, and efficacy of omaveloxolone (marketed as Skyclarys [Reata Pharmaceuticals]),⁵ which received FDA orphan drug, fast track, priority review, and rare pediatric disease designations for the treatment of FA and, in February 2023, formal FDA approval.⁶ Development of this drug, which activates Nrf2 and induces antioxidant target genes, arose from basic science investigation into mechanisms by which cells respond to stresses.

“Omaveloxolone works on the Nrf2 pathway, which is, paradoxically, deficient in FA,” Dr. Lynch said. “This pathway should be active all the time. You would expect that, in cells from Friedreich ataxia in a person or an animal model of the disease, you’d see that Nrf2 would be very active but, in fact, what you find is the opposite,” Dr. Lynch explained. “It’s relatively inefficient, it’s localized in the cell, and the antioxidant response element genes – the things we all use to protect ourselves from mitochondrial damage – are all relatively turned off.”

In the first phase of MOXIe, 103 patients with FA were randomly assigned to receive either omaveloxolone, 15 mg orally (51 patients), or placebo (52 patients) for 48 weeks.

The primary endpoint was change in the modified Friedreich’s Ataxia Rating Scale (mFARS) score at 48 weeks. The scale is a clinically validated neurological instrument that evaluates upper- and lower-limb coordination, upright stability, and bulbar function.

Patients assigned to placebo had worsening of function at 48 weeks (mean increase in mFARS score, 0.85). In contrast, patients assigned to omaveloxolone had a mean decrease in the mFARS score of –1.56, indicating improvement. The between-group difference of –2.41 points was statistically significant in favor of omaveloxolone (P = .038).

In a 3-year, post hoc, propensity-matched analysis, patients assigned to omaveloxolone had lower mFARS scores than a matched set of untreated patients in a study of the natural history of FA.⁷Dimethyl fumarate (marketed as Tecfidera [Biogen]), approved in the United States and other countries for the treatment of patients with relapsing forms of multiple sclerosis, also has Nrf2 as a therapeutic target, although its precise mechanism of action is unclear. Clinical trials of this agent for the treatment of FA are under consideration in Europe, Dr. Lynch said.

Apart from these agents, treatment of patients with FA largely centers on management of metabolic and cardiac complications; physical and occupational therapy; devices such as orthopedic shoes, canes, and wheelchairs; and, when indicated, surgery to correct skeletal problems or for implantation of a cardiac-assist device.
 

The FA therapeutic pipeline

According to the Friedreich’s Ataxia Research Alliance, other approaches to improving mitochondrial function and reducing oxidative stress in FA are under investigation or awaiting approval, including elamipretide, for which FDA approval is pending for Barth syndrome (a rare, X-linked disorder) and for primary mitochondrial myopathy; nicotinamide adenine dinucleotide (NAD+, a coenzyme for redox reactions) plus exercise; and MIB-626, a crystalline form of nicotinamide mononucleotide, a precursor of NAD+.

Vatiquinone, an investigational inhibitor of 15-lipoxygenase, a regulator of energetic and oxidative stress pathways, failed to meet its primary endpoint of significant improvement on the mFARS score at 72 weeks of follow-up in the MOVE-FA trial, according to the manufacturer, PTC Therapeutics.⁸Another therapeutic approach under investigation is modulation of frataxin-controlled metabolic pathways with leriglitazone, an orally available selective peroxisome proliferator-activated receptor gamma agonist,⁹ or with the prodrug precursor of monomethyl fumarate plus dimethyl fumarate.

CTI-1601, a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA, is in phase 1 trials. This compound has been granted rare pediatric disease designation, fast track designation, and orphan drug status by the FDA, according to the manufacturer, Larimar Therapeutics.¹⁰Etravirine, a nonnucleoside reverse transcriptase inhibitor approved for treating HIV infection, has been demonstrated to increase the frataxin protein in cells derived from FA patients and in the heart and skeletal muscle of frataxin-deficient YG8 mice. This agent recently completed a phase 2 trial in patients with FA.¹¹

Gene therapy: Promising

Given the genetic etiology of FA, gene therapy strategies aimed at either increasing FA gene expression or editing the genome to replace defective FXN are under active investigation.

Increasing FA gene expression. DT-216 (Design Therapeutics) is a novel, gene-targeted chimera small molecule designed to target the GAA repeat expansion mutation and restore FXN expression. This agent completed phase 1 dosing studies in 2022.

Oligonucleotides, which are nucleic acid polymers primarily used for gene silencing, are also being explored for increasing the expression of FXN, in research at the University of Texas Southwestern Medical Center, Dallas, and the University of Massachusetts, Worcester.

Gene replacement strategies under investigation to treat FA include LX2006 (Lexeo Therapeutics), a gene replacement therapy using an adeno-associated viral vector to deliver FXN intravenously, with the goal of getting the gene into myocardial cells and increasing the frataxin level in mitochondria.

Future directions

Dr. Koeppen, Dr. Lynch, and colleagues Ian H. Harding, PhD, from Monash University, Melbourne, and Massimo Pandolfo, MD, McGill University, Montreal, conducted an extensive review of FA with a focus on challenges that researchers and drug developers face crafting therapies for this complex disorder.¹³

They noted that FA is “characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate.”

The authors took a deep dive into the evidence, old and new, to evaluate the effects of FA on the central and peripheral nervous systems and to look at the course of neuropathologic changes associated with the disease. They propose a comprehensive approach to identify nervous system locations that are likely to be most successfully targeted at different disease time points.

“The proprioceptive system, usually considered a major target for frataxin-restoring treatments, shows substantial evidence of hypoplasia and/or early developmental loss, with minimal evidence of progression over time,” they wrote. “It seems likely that this system is not an ideal target for therapies given after early childhood. Targeting the [dentate nucleus] of the cerebellum is likely to be most effective early in the course of the disease, when it is functionally affected, but still shows limited atrophy. The corticospinal tract degenerates over time contributing to disease progression throughout its late stages and may be considered a target.”

David Lynch, MD, PhD, and Arnulf Koeppen, MD, disclose support from the Friedreich’s Ataxia Research Alliance. Dr. Lynch also discloses support from the National Institutes of Health, U.S. Food and Drug Administration, Muscular Dystrophy Association, Reata Pharmaceuticals, and Retrotope.

References

1. Williams CT and De Jesus O. Friedreich ataxia. StatPearls. 2023 Jun 27. https://www.ncbi.nlm.nih.gov/books/NBK563199/.

2. National Institute of Neurological Disorders and Stroke. Friedreich ataxia. 2023 Sep 2. https://www.ninds.nih.gov/health-information/disorders/friedreich-ataxia.

3. Adanyeguh IM et al. Brain Commun. 2023;5(4):fcad196. doi: 10.1093/braincomms/fcad196.

4. Camapuzano V et al. Science. 1996;271(5254):1423-7. doi: 10.1126/science.271.5254.1423.

5. RTA 408 capsules in patients with Friedreich’s ataxia–MOXIe. ClinicalTrials. gov Identifier: NCT02255435. 2022 Dec 6. https://clinicaltrials.gov/study/NCT02255435.

6. Food and Drug Administration. FDA approves first treatment for Friedreich’s ataxia. 2023 Feb 28. www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-friedreichs-ataxia#.

7. Lynch DR et al. Ann Clin Transl Neurol. 2023 Sep 10. doi: 10.1002/acn3.51897

8. PTC Therapeutics. PTC Therapeutics announces topline results from vatiquinone MOVE-FA registration-directed trial. 2023 May 23. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-topline-results-vatiquinone-move-fa.

9. Minoryx Therapeutics. The FRAMES Clinical Study in FRDA. https://www.minoryx.com/clinical-studies/clinical-study-frames/.

10. Larimar Therapeutics. CTI-1601 for Friedreich’s ataxia. https://larimartx.com/our-programs/cti-1601/.

11. Safety and efficacy of etravirine in Friedreich ataxia patients (FAEST1). ClinicalTrials.gov Identifier: NCT04273165. 2023 Mar 20. https://clinicaltrials.gov/study/NCT04273165.

12. Phase IA study of AAVrh.10hFXN gene therapy for the cardiomyopathy of Friedreich’s ataxia. ClinicalTrials.gov Identifier: NCT05302271. https://clinicaltrials.gov/study/NCT05302271.

13. Harding IH et al. Hum Gene Ther. 2020;31(23-24):1226-36. doi: 10.1089/hum.2020.264

It took 160 years but, in February 2023, the Food and Drug Administration approved the first drug specifically designed to treat the rare neuromuscular disease Friedreich ataxia (FA). The disease, first described in 1863 by German physician Nikolaus Friedreich, has an estimated incidence of 1 in 50,000 worldwide. It is the most common form of hereditary ataxia, accounting for approximately 50% of all cases of ataxia and approximately 75% of cases among patients younger than 25 years in the United States.¹

FA typically presents in childhood or early adolescence; in some patients, symptoms manifest in the middle of the third decade of life. Patients exhibit symptoms such as ataxia that becomes worse over time, gait ataxia, impaired sensation in the extremities that can spread centrally, loss of normal reflexes, especially in the knees, speech disorders (dysarthria), muscle spasticity, scoliosis, and dysphagia.

Severity of disease ranges from relatively mild to completely disabling. Symptoms are progressive; patients almost inevitably require ambulatory support or a wheelchair. They might develop diabetes mellitus and can lose hearing and vision as the disease progresses. Hypertrophic cardiomyopathy is the most common cause of death among FA patients. Some patients who have less severe features might live into their 60s – even beyond that age.²There is no cure for FA. Until recently, no therapy was available other than supportive care to address associated neuromuscular, cardiovascular, and metabolic complications.

Making the diagnosis

Genetic testing can provide a definitive diagnosis of FA. (The genetic etiology of the disease is described later in this article.)

In addition to genetic screening, the workup includes a thorough medical history and physical examination that focuses on problems with balance, proprioception, absence of reflexes, and neurological signs. Tests include electromyography, nerve-conduction studies, electrocardiography, a metabolic profile, and MRI of the brain and spinal cord.

MRI utility in FA. In a paper published in July 2023 in Brain Communications, investigators from the University of Minnesota, Minneapolis, reported that various MRI techniques can be combined to detect early-stage alterations and disease progression in patients with FA.³ The researchers compared images taken at baseline and at 1, 2, and 3 years in 28 FA patients and 20 age- and gender-matched controls.

They observed that, compared with controls, patients with FA had lower cerebellar white matter volume but not lower cerebellar gray matter volume; larger cerebellar peduncle, thalamus, and brain stem structures; and a higher volume of the fourth ventricle. Using diffusion-tensor imaging and fixel-based analysis of diffusion MRI metrics, they also detected microstructural differences in several brain regions – especially in the cerebellum and corticospinal tract.

“Over time, many of these macrostructural and microstructural alterations progressed, especially cerebellar gray- and white-matter volume and microstructures of the superior cerebellar peduncle, the posterior limb of the internal capsule, and the superior corona radiata,” the investigators reported. In addition, “linear regressions showed significant associations between many of those imaging metrics and clinical scales.”

Pathophysiological basis of FA

The underlying genetic pathology of FA was first described in 1996 by investigators from the University of Valencia (Spain). They reported that FA is caused by a mutation in FXN (formerly X25), a gene that encodes for the protein frataxin, which is important for producing mitochondrial adenosine triphosphate and managing iron stores.⁴

The mutation results in multiple guanine-adenine-adenine repeats in FXN, or, in a few cases, a point mutation or deletion in 1 allele of FXN, with multiple GAA repeats in the other allele. A hallmark of FA is impairment of cellular antioxidative defense mechanisms – a major cause of disease progression.

Treatment options have been limited

Omaveloxolone. Dr. Lynch is principal investigator for the MOXIe trial of the safety, pharmacodynamics, and efficacy of omaveloxolone (marketed as Skyclarys [Reata Pharmaceuticals]),⁵ which received FDA orphan drug, fast track, priority review, and rare pediatric disease designations for the treatment of FA and, in February 2023, formal FDA approval.⁶ Development of this drug, which activates Nrf2 and induces antioxidant target genes, arose from basic science investigation into mechanisms by which cells respond to stresses.

“Omaveloxolone works on the Nrf2 pathway, which is, paradoxically, deficient in FA,” Dr. Lynch said. “This pathway should be active all the time. You would expect that, in cells from Friedreich ataxia in a person or an animal model of the disease, you’d see that Nrf2 would be very active but, in fact, what you find is the opposite,” Dr. Lynch explained. “It’s relatively inefficient, it’s localized in the cell, and the antioxidant response element genes – the things we all use to protect ourselves from mitochondrial damage – are all relatively turned off.”

In the first phase of MOXIe, 103 patients with FA were randomly assigned to receive either omaveloxolone, 15 mg orally (51 patients), or placebo (52 patients) for 48 weeks.

The primary endpoint was change in the modified Friedreich’s Ataxia Rating Scale (mFARS) score at 48 weeks. The scale is a clinically validated neurological instrument that evaluates upper- and lower-limb coordination, upright stability, and bulbar function.

Patients assigned to placebo had worsening of function at 48 weeks (mean increase in mFARS score, 0.85). In contrast, patients assigned to omaveloxolone had a mean decrease in the mFARS score of –1.56, indicating improvement. The between-group difference of –2.41 points was statistically significant in favor of omaveloxolone (P = .038).

In a 3-year, post hoc, propensity-matched analysis, patients assigned to omaveloxolone had lower mFARS scores than a matched set of untreated patients in a study of the natural history of FA.⁷Dimethyl fumarate (marketed as Tecfidera [Biogen]), approved in the United States and other countries for the treatment of patients with relapsing forms of multiple sclerosis, also has Nrf2 as a therapeutic target, although its precise mechanism of action is unclear. Clinical trials of this agent for the treatment of FA are under consideration in Europe, Dr. Lynch said.

Apart from these agents, treatment of patients with FA largely centers on management of metabolic and cardiac complications; physical and occupational therapy; devices such as orthopedic shoes, canes, and wheelchairs; and, when indicated, surgery to correct skeletal problems or for implantation of a cardiac-assist device.
 

The FA therapeutic pipeline

According to the Friedreich’s Ataxia Research Alliance, other approaches to improving mitochondrial function and reducing oxidative stress in FA are under investigation or awaiting approval, including elamipretide, for which FDA approval is pending for Barth syndrome (a rare, X-linked disorder) and for primary mitochondrial myopathy; nicotinamide adenine dinucleotide (NAD+, a coenzyme for redox reactions) plus exercise; and MIB-626, a crystalline form of nicotinamide mononucleotide, a precursor of NAD+.

Vatiquinone, an investigational inhibitor of 15-lipoxygenase, a regulator of energetic and oxidative stress pathways, failed to meet its primary endpoint of significant improvement on the mFARS score at 72 weeks of follow-up in the MOVE-FA trial, according to the manufacturer, PTC Therapeutics.⁸Another therapeutic approach under investigation is modulation of frataxin-controlled metabolic pathways with leriglitazone, an orally available selective peroxisome proliferator-activated receptor gamma agonist,⁹ or with the prodrug precursor of monomethyl fumarate plus dimethyl fumarate.

CTI-1601, a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA, is in phase 1 trials. This compound has been granted rare pediatric disease designation, fast track designation, and orphan drug status by the FDA, according to the manufacturer, Larimar Therapeutics.¹⁰Etravirine, a nonnucleoside reverse transcriptase inhibitor approved for treating HIV infection, has been demonstrated to increase the frataxin protein in cells derived from FA patients and in the heart and skeletal muscle of frataxin-deficient YG8 mice. This agent recently completed a phase 2 trial in patients with FA.¹¹

Gene therapy: Promising

Given the genetic etiology of FA, gene therapy strategies aimed at either increasing FA gene expression or editing the genome to replace defective FXN are under active investigation.

Increasing FA gene expression. DT-216 (Design Therapeutics) is a novel, gene-targeted chimera small molecule designed to target the GAA repeat expansion mutation and restore FXN expression. This agent completed phase 1 dosing studies in 2022.

Oligonucleotides, which are nucleic acid polymers primarily used for gene silencing, are also being explored for increasing the expression of FXN, in research at the University of Texas Southwestern Medical Center, Dallas, and the University of Massachusetts, Worcester.

Gene replacement strategies under investigation to treat FA include LX2006 (Lexeo Therapeutics), a gene replacement therapy using an adeno-associated viral vector to deliver FXN intravenously, with the goal of getting the gene into myocardial cells and increasing the frataxin level in mitochondria.

Future directions

Dr. Koeppen, Dr. Lynch, and colleagues Ian H. Harding, PhD, from Monash University, Melbourne, and Massimo Pandolfo, MD, McGill University, Montreal, conducted an extensive review of FA with a focus on challenges that researchers and drug developers face crafting therapies for this complex disorder.¹³

They noted that FA is “characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate.”

The authors took a deep dive into the evidence, old and new, to evaluate the effects of FA on the central and peripheral nervous systems and to look at the course of neuropathologic changes associated with the disease. They propose a comprehensive approach to identify nervous system locations that are likely to be most successfully targeted at different disease time points.

“The proprioceptive system, usually considered a major target for frataxin-restoring treatments, shows substantial evidence of hypoplasia and/or early developmental loss, with minimal evidence of progression over time,” they wrote. “It seems likely that this system is not an ideal target for therapies given after early childhood. Targeting the [dentate nucleus] of the cerebellum is likely to be most effective early in the course of the disease, when it is functionally affected, but still shows limited atrophy. The corticospinal tract degenerates over time contributing to disease progression throughout its late stages and may be considered a target.”

David Lynch, MD, PhD, and Arnulf Koeppen, MD, disclose support from the Friedreich’s Ataxia Research Alliance. Dr. Lynch also discloses support from the National Institutes of Health, U.S. Food and Drug Administration, Muscular Dystrophy Association, Reata Pharmaceuticals, and Retrotope.

References

1. Williams CT and De Jesus O. Friedreich ataxia. StatPearls. 2023 Jun 27. https://www.ncbi.nlm.nih.gov/books/NBK563199/.

2. National Institute of Neurological Disorders and Stroke. Friedreich ataxia. 2023 Sep 2. https://www.ninds.nih.gov/health-information/disorders/friedreich-ataxia.

3. Adanyeguh IM et al. Brain Commun. 2023;5(4):fcad196. doi: 10.1093/braincomms/fcad196.

4. Camapuzano V et al. Science. 1996;271(5254):1423-7. doi: 10.1126/science.271.5254.1423.

5. RTA 408 capsules in patients with Friedreich’s ataxia–MOXIe. ClinicalTrials. gov Identifier: NCT02255435. 2022 Dec 6. https://clinicaltrials.gov/study/NCT02255435.

6. Food and Drug Administration. FDA approves first treatment for Friedreich’s ataxia. 2023 Feb 28. www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-friedreichs-ataxia#.

7. Lynch DR et al. Ann Clin Transl Neurol. 2023 Sep 10. doi: 10.1002/acn3.51897

8. PTC Therapeutics. PTC Therapeutics announces topline results from vatiquinone MOVE-FA registration-directed trial. 2023 May 23. https://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-announces-topline-results-vatiquinone-move-fa.

9. Minoryx Therapeutics. The FRAMES Clinical Study in FRDA. https://www.minoryx.com/clinical-studies/clinical-study-frames/.

10. Larimar Therapeutics. CTI-1601 for Friedreich’s ataxia. https://larimartx.com/our-programs/cti-1601/.

11. Safety and efficacy of etravirine in Friedreich ataxia patients (FAEST1). ClinicalTrials.gov Identifier: NCT04273165. 2023 Mar 20. https://clinicaltrials.gov/study/NCT04273165.

12. Phase IA study of AAVrh.10hFXN gene therapy for the cardiomyopathy of Friedreich’s ataxia. ClinicalTrials.gov Identifier: NCT05302271. https://clinicaltrials.gov/study/NCT05302271.

13. Harding IH et al. Hum Gene Ther. 2020;31(23-24):1226-36. doi: 10.1089/hum.2020.264

HONOLULU – There’s new evidence to support a practice that many pulmonologists have been doing empirically anyway: namely, reducing the dose of the antifibrotic medication nintedanib (Ofev) for patients with idiopathic pulmonary fibrosis (IPF) who can’t tolerate the full 150-mg twice-daily dose.

An analysis of data from a large administrative claims database showed that there were no significant differences in either all-cause mortality or hospitalization rates between patients with IPF treated at the full 150-mg twice-daily dose and those treated with a reduced twice-daily dose of 100 mg nintedanib.

Although the results need to be confirmed by additional prospective and registry studies, they suggest that patients with IPF can still fare just as well with a reduced-dose nintedanib regimen, ideally with fewer gastrointestinal side effects such as diarrhea, reported Andrew Limper, MD, of the Mayo Clinic in Rochester, Minn.

“At least on this preliminary data you could ... rest assured,” Dr. Limper told his colleagues in an oral abstract session at the American College of Chest Physicians (CHEST) 2023 annual meeting.

“This is not definitive proof, I’m not making more out of this than it is, but we all put people on 100 mg twice daily because their guts don’t tolerate it; they live in the bathroom and they don’t want to live that way,” Dr. Limper said.
 

Hard to take

Nintedanib is approved in the United States for the treatment of IPF, chronic fibrosing interstitial lung diseases (ILD) with a progressive phenotype, and systemic sclerosis-associated ILD. For IPF, the standard dose established in randomized clinical trials is 150 mg twice daily.

However, nintedanib is associated with a number of side effects, including hepatic and other gastrointestinal toxicities, arterial thromboembolic events, and proteinuria within the nephrotic range. As a result, clinicians often reduce the dose to 100 mg twice daily, but there is a lack of data to indicate whether it’s safe to do so or if efficacy will be compromised.

To see whether dose reductions might result in poorer outcomes for patients with IPF, Dr. Limper and colleagues analyzed data from the OptumLabs Data Warehouse, a large administrative claims database, to compare outcomes for patients treated with IPF at either the 150-mg or 100-mg twice-daily doses.

They used propensity-score matching to account for differences among individuals according to age, sex, race/ethnicity, residence, insurance type, additional medication use, oxygen use, smoking status, health care use, and comorbidities. The final cohort included 346 patients in each dosing group.

There was no difference between the dosing groups for the primary outcome of all-cause mortality at 18 months, with a nonsignificant hazard ratio of 0.65 (P = .313), and no significant difference over 24 months in risk of hospitalization, with a hazard ratio of 0.98 (P = .899).

“This is not randomized controlled data; I doubt that [nintedanib maker Boehringer Ingelheim] is ever going to do a 150 vs. 100 milligram head-to-head trial, but it does give us some ground to start to look at this,” Dr. Limper said.
 

Not so sure

Session comoderator Misbah Baqir, MBBS, also from the Mayo Clinic, told this news organization that she would need to see more data from prospective studies using endpoints other than mortality before she could be convinced that nintedanib dose reductions do not adversely affect efficacy. She was not involved in the study.

“I feel that the endpoint should be different, either it should be forced vital capacity change, quality of life, or something else. The problem with a database study is that you don’t have everything in it. You have to play with what you have, and you don’t have forced vital capacity. You have to go into the charts to get it,” she said.

It would be more helpful to objectively compare, for example, diarrhea episodes or other adverse events to see whether they were significantly reduced with the 100-mg dose, she added.

In an interview, Dr. Limper said that he and his colleagues plan to gather additional observational data including the newly available Medicare fee-for-service data set, registry data, and other sources.

“If we get all of that, and it really still looks compelling – and that’s an if – then I think that would be the foothold to go back to the manufacturer and say, ‘Hey, maybe you ought to think about doing a prospective trial to prove it with lung function and other endpoints such as 6-minute walks,’ ” he said.

The study was supported by a grant from Three Lakes Foundation. Dr. Limper and Dr. Baqir have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

HONOLULU – There’s new evidence to support a practice that many pulmonologists have been doing empirically anyway: namely, reducing the dose of the antifibrotic medication nintedanib (Ofev) for patients with idiopathic pulmonary fibrosis (IPF) who can’t tolerate the full 150-mg twice-daily dose.

An analysis of data from a large administrative claims database showed that there were no significant differences in either all-cause mortality or hospitalization rates between patients with IPF treated at the full 150-mg twice-daily dose and those treated with a reduced twice-daily dose of 100 mg nintedanib.

Although the results need to be confirmed by additional prospective and registry studies, they suggest that patients with IPF can still fare just as well with a reduced-dose nintedanib regimen, ideally with fewer gastrointestinal side effects such as diarrhea, reported Andrew Limper, MD, of the Mayo Clinic in Rochester, Minn.

“At least on this preliminary data you could ... rest assured,” Dr. Limper told his colleagues in an oral abstract session at the American College of Chest Physicians (CHEST) 2023 annual meeting.

“This is not definitive proof, I’m not making more out of this than it is, but we all put people on 100 mg twice daily because their guts don’t tolerate it; they live in the bathroom and they don’t want to live that way,” Dr. Limper said.
 

Hard to take

Nintedanib is approved in the United States for the treatment of IPF, chronic fibrosing interstitial lung diseases (ILD) with a progressive phenotype, and systemic sclerosis-associated ILD. For IPF, the standard dose established in randomized clinical trials is 150 mg twice daily.

However, nintedanib is associated with a number of side effects, including hepatic and other gastrointestinal toxicities, arterial thromboembolic events, and proteinuria within the nephrotic range. As a result, clinicians often reduce the dose to 100 mg twice daily, but there is a lack of data to indicate whether it’s safe to do so or if efficacy will be compromised.

To see whether dose reductions might result in poorer outcomes for patients with IPF, Dr. Limper and colleagues analyzed data from the OptumLabs Data Warehouse, a large administrative claims database, to compare outcomes for patients treated with IPF at either the 150-mg or 100-mg twice-daily doses.

They used propensity-score matching to account for differences among individuals according to age, sex, race/ethnicity, residence, insurance type, additional medication use, oxygen use, smoking status, health care use, and comorbidities. The final cohort included 346 patients in each dosing group.

There was no difference between the dosing groups for the primary outcome of all-cause mortality at 18 months, with a nonsignificant hazard ratio of 0.65 (P = .313), and no significant difference over 24 months in risk of hospitalization, with a hazard ratio of 0.98 (P = .899).

“This is not randomized controlled data; I doubt that [nintedanib maker Boehringer Ingelheim] is ever going to do a 150 vs. 100 milligram head-to-head trial, but it does give us some ground to start to look at this,” Dr. Limper said.
 

Not so sure

Session comoderator Misbah Baqir, MBBS, also from the Mayo Clinic, told this news organization that she would need to see more data from prospective studies using endpoints other than mortality before she could be convinced that nintedanib dose reductions do not adversely affect efficacy. She was not involved in the study.

“I feel that the endpoint should be different, either it should be forced vital capacity change, quality of life, or something else. The problem with a database study is that you don’t have everything in it. You have to play with what you have, and you don’t have forced vital capacity. You have to go into the charts to get it,” she said.

It would be more helpful to objectively compare, for example, diarrhea episodes or other adverse events to see whether they were significantly reduced with the 100-mg dose, she added.

In an interview, Dr. Limper said that he and his colleagues plan to gather additional observational data including the newly available Medicare fee-for-service data set, registry data, and other sources.

“If we get all of that, and it really still looks compelling – and that’s an if – then I think that would be the foothold to go back to the manufacturer and say, ‘Hey, maybe you ought to think about doing a prospective trial to prove it with lung function and other endpoints such as 6-minute walks,’ ” he said.

The study was supported by a grant from Three Lakes Foundation. Dr. Limper and Dr. Baqir have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

HONOLULU – There’s new evidence to support a practice that many pulmonologists have been doing empirically anyway: namely, reducing the dose of the antifibrotic medication nintedanib (Ofev) for patients with idiopathic pulmonary fibrosis (IPF) who can’t tolerate the full 150-mg twice-daily dose.

An analysis of data from a large administrative claims database showed that there were no significant differences in either all-cause mortality or hospitalization rates between patients with IPF treated at the full 150-mg twice-daily dose and those treated with a reduced twice-daily dose of 100 mg nintedanib.

Although the results need to be confirmed by additional prospective and registry studies, they suggest that patients with IPF can still fare just as well with a reduced-dose nintedanib regimen, ideally with fewer gastrointestinal side effects such as diarrhea, reported Andrew Limper, MD, of the Mayo Clinic in Rochester, Minn.

“At least on this preliminary data you could ... rest assured,” Dr. Limper told his colleagues in an oral abstract session at the American College of Chest Physicians (CHEST) 2023 annual meeting.

“This is not definitive proof, I’m not making more out of this than it is, but we all put people on 100 mg twice daily because their guts don’t tolerate it; they live in the bathroom and they don’t want to live that way,” Dr. Limper said.
 

Hard to take

Nintedanib is approved in the United States for the treatment of IPF, chronic fibrosing interstitial lung diseases (ILD) with a progressive phenotype, and systemic sclerosis-associated ILD. For IPF, the standard dose established in randomized clinical trials is 150 mg twice daily.

However, nintedanib is associated with a number of side effects, including hepatic and other gastrointestinal toxicities, arterial thromboembolic events, and proteinuria within the nephrotic range. As a result, clinicians often reduce the dose to 100 mg twice daily, but there is a lack of data to indicate whether it’s safe to do so or if efficacy will be compromised.

To see whether dose reductions might result in poorer outcomes for patients with IPF, Dr. Limper and colleagues analyzed data from the OptumLabs Data Warehouse, a large administrative claims database, to compare outcomes for patients treated with IPF at either the 150-mg or 100-mg twice-daily doses.

They used propensity-score matching to account for differences among individuals according to age, sex, race/ethnicity, residence, insurance type, additional medication use, oxygen use, smoking status, health care use, and comorbidities. The final cohort included 346 patients in each dosing group.

There was no difference between the dosing groups for the primary outcome of all-cause mortality at 18 months, with a nonsignificant hazard ratio of 0.65 (P = .313), and no significant difference over 24 months in risk of hospitalization, with a hazard ratio of 0.98 (P = .899).

“This is not randomized controlled data; I doubt that [nintedanib maker Boehringer Ingelheim] is ever going to do a 150 vs. 100 milligram head-to-head trial, but it does give us some ground to start to look at this,” Dr. Limper said.
 

Not so sure

Session comoderator Misbah Baqir, MBBS, also from the Mayo Clinic, told this news organization that she would need to see more data from prospective studies using endpoints other than mortality before she could be convinced that nintedanib dose reductions do not adversely affect efficacy. She was not involved in the study.

“I feel that the endpoint should be different, either it should be forced vital capacity change, quality of life, or something else. The problem with a database study is that you don’t have everything in it. You have to play with what you have, and you don’t have forced vital capacity. You have to go into the charts to get it,” she said.

It would be more helpful to objectively compare, for example, diarrhea episodes or other adverse events to see whether they were significantly reduced with the 100-mg dose, she added.

In an interview, Dr. Limper said that he and his colleagues plan to gather additional observational data including the newly available Medicare fee-for-service data set, registry data, and other sources.

“If we get all of that, and it really still looks compelling – and that’s an if – then I think that would be the foothold to go back to the manufacturer and say, ‘Hey, maybe you ought to think about doing a prospective trial to prove it with lung function and other endpoints such as 6-minute walks,’ ” he said.

The study was supported by a grant from Three Lakes Foundation. Dr. Limper and Dr. Baqir have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

HONOLULU – What we eat and what’s in the gut may influence lung health for better or worse, suggest new data from an ongoing study of lung function in New York City firefighters who were at the World Trade Center site on Sept. 11, 2001, and the days immediately following the 9/11 attacks.

Among NYC firefighters enrolled in the randomized FIREHOUSE (Food Intake Restriction for Health Outcome Support and Education) study who took part in a microbiome substudy, those who followed a low-calorie, Mediterranean-style diet had higher levels in stools samples at 6 months of Bacteroides ovatus, a bacterial species associated with protection against bowel inflammation.

In contrast, participants who followed a usual-care diet had elevated 6-month levels of a species associated with high-fat diets and inflammation, reported Rachel Lam, a predoctoral fellow in the Nolan Lab at NYU Langone Medical Center, at the annual meeting of the American College of Chest Physicians (CHEST).

“Overall, we found that in our validation cohort, Bacteroides ovatus was increased in the LoCalMed arm after 6 months, and this bacterial species is associated with fewer negative health effects,” she said.

Ms. Lam noted that in a murine model of high-fat diets, mice gavaged with Bacteroides ovatus had reductions in body mass index and decreased serum LDL cholesterol and triglyceride levels.
 

FIREHOUSE cohort

Senior author Anna Nolan, MD, whose lab members study predictors of lung function loss in a cohort of firefighters who were exposed to the particulate matter clouding the air of lower Manhattan on 9/11 and the ensuing days, told this news organization that the findings, while preliminary, support previous research findings on potential links between intestinal microbiota and lung function.

“It’s interesting that we saw this done in other models, like mouse models and such, where certain bacteria were viewed as healthy for the system, and if they were able to bring that bacteria out in larger amounts they saw anti-inflammatory effects, so we’re hoping to mirror that and also do a mouse model,” she said.

Dr. Nolan’s group has previously shown that markers for the metabolic syndrome, inflammation, and vascular injury detected in serum samples taken within 6 months of 9/11 were predictive for later abnormal lung function. In addition, their group has found that elevated serum levels of an LDL metabolite after intense World Trade Center dust exposure is a risk factor for future impaired lung function as measured by forced expiratory volume in 1 second (FEV₁).

In the FIREHOUSE trial, 89 patients were randomly assigned either to a technology-supported educational and behavioral intervention targeting calorie restriction for weight loss while following a low-calorie Mediterranean diet, or to usual care. The usual-care arm included participants who were informed about their weight, BMI, and other standard measures at annual visits and were given general advice about healthy eating, but were not assigned to a specific diet.

Participants in the LoCalMed group had significant decreases in BMI and increases in FEV₁, compared with those in the usual-care group. In addition, the LoCalMed group had improved vascular health, better dietary habits, decreases in fats and calories from sweets, and decreases in inflammation as measured by a lower white blood cell count.
 

Microbiome substudy

At CHEST 2023, Ms. Lam reported on microbiome pilot and validation substudies of FIREHOUSE.

The pilot study included five patients in each arm. The validation sample included 15 participants in the Mediterranean diet group and 16 in the usual-care diet group.

Each participant’s microbiome was assessed with genomic sequencing with sequences aligned to a bacterial database.  The number and diversity of bacterial species in each sample were determined with the Chao1 Index and Shannon Index, respectively.

There were no significant differences among the study groups in mean age, exposure at the World Trade Center site, or years of service.

Although bacterial diversity did not differ between the study arms either at baseline or at 6 months, in both groups it significantly decreased over time (P = .02 in the pilot, P < .0001 in the validation arm).

In the pilot study, there was an increase over 6 months in the usual care arm only of Bilophila wadsworthia, a species associated with high-fat diets and inflammation.

In the validation study, patients in the LoCalMed arm had significant reductions in Ruminococcaceae (P = .015) and increases in both Bacteroides ovatus (P = .03) and Alistipes shahii (P = .038), a recently identified species with uncertain protective or pathogenic potential.

In contrast, there were no significant increases in species in the usual-care group, but there were significant declines in several other bacterial species; Ms.Lam, however, did not say whether these changes had clinical significance. “Future studies will assess microbial association with clinical outcomes,” Ms. Lam said.
 

Confounding factors

Samuel Evans, MD, a pulmonologist at Straub Medical Center in Honolulu who moderated the oral abstract session where the data were presented, commented that the data are interesting but added that associations are difficult to determine given the heterogeneity of exposures that firefighters encounter.

“I think it’s interesting that clearly diet is influencing the type of bacteria in the biome in the gut, and perhaps some are favorable, and some are not favorable,” he told this news organization “We already know that the Mediterranean diet is associated with better health outcomes, so it makes sense, but can we tease out in the microbiome which bacteria are harmful and which are helpful.”

He noted that there are a lot of confounding factors and that “it’s hard to find the right signal when you have so many variables.”

The FIREHOUSE study is supported by the Centers for Disease Control and Prevention’s National Institute of Occupational Safety & Health and the National Heart, Lung, and Blood Institute. Ms. Lam, Dr. Nolan, and Dr. Evans report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

HONOLULU – What we eat and what’s in the gut may influence lung health for better or worse, suggest new data from an ongoing study of lung function in New York City firefighters who were at the World Trade Center site on Sept. 11, 2001, and the days immediately following the 9/11 attacks.

Among NYC firefighters enrolled in the randomized FIREHOUSE (Food Intake Restriction for Health Outcome Support and Education) study who took part in a microbiome substudy, those who followed a low-calorie, Mediterranean-style diet had higher levels in stools samples at 6 months of Bacteroides ovatus, a bacterial species associated with protection against bowel inflammation.

In contrast, participants who followed a usual-care diet had elevated 6-month levels of a species associated with high-fat diets and inflammation, reported Rachel Lam, a predoctoral fellow in the Nolan Lab at NYU Langone Medical Center, at the annual meeting of the American College of Chest Physicians (CHEST).

“Overall, we found that in our validation cohort, Bacteroides ovatus was increased in the LoCalMed arm after 6 months, and this bacterial species is associated with fewer negative health effects,” she said.

Ms. Lam noted that in a murine model of high-fat diets, mice gavaged with Bacteroides ovatus had reductions in body mass index and decreased serum LDL cholesterol and triglyceride levels.
 

FIREHOUSE cohort

Senior author Anna Nolan, MD, whose lab members study predictors of lung function loss in a cohort of firefighters who were exposed to the particulate matter clouding the air of lower Manhattan on 9/11 and the ensuing days, told this news organization that the findings, while preliminary, support previous research findings on potential links between intestinal microbiota and lung function.

“It’s interesting that we saw this done in other models, like mouse models and such, where certain bacteria were viewed as healthy for the system, and if they were able to bring that bacteria out in larger amounts they saw anti-inflammatory effects, so we’re hoping to mirror that and also do a mouse model,” she said.

Dr. Nolan’s group has previously shown that markers for the metabolic syndrome, inflammation, and vascular injury detected in serum samples taken within 6 months of 9/11 were predictive for later abnormal lung function. In addition, their group has found that elevated serum levels of an LDL metabolite after intense World Trade Center dust exposure is a risk factor for future impaired lung function as measured by forced expiratory volume in 1 second (FEV₁).

In the FIREHOUSE trial, 89 patients were randomly assigned either to a technology-supported educational and behavioral intervention targeting calorie restriction for weight loss while following a low-calorie Mediterranean diet, or to usual care. The usual-care arm included participants who were informed about their weight, BMI, and other standard measures at annual visits and were given general advice about healthy eating, but were not assigned to a specific diet.

Participants in the LoCalMed group had significant decreases in BMI and increases in FEV₁, compared with those in the usual-care group. In addition, the LoCalMed group had improved vascular health, better dietary habits, decreases in fats and calories from sweets, and decreases in inflammation as measured by a lower white blood cell count.
 

Microbiome substudy

At CHEST 2023, Ms. Lam reported on microbiome pilot and validation substudies of FIREHOUSE.

The pilot study included five patients in each arm. The validation sample included 15 participants in the Mediterranean diet group and 16 in the usual-care diet group.

Each participant’s microbiome was assessed with genomic sequencing with sequences aligned to a bacterial database.  The number and diversity of bacterial species in each sample were determined with the Chao1 Index and Shannon Index, respectively.

There were no significant differences among the study groups in mean age, exposure at the World Trade Center site, or years of service.

Although bacterial diversity did not differ between the study arms either at baseline or at 6 months, in both groups it significantly decreased over time (P = .02 in the pilot, P < .0001 in the validation arm).

In the pilot study, there was an increase over 6 months in the usual care arm only of Bilophila wadsworthia, a species associated with high-fat diets and inflammation.

In the validation study, patients in the LoCalMed arm had significant reductions in Ruminococcaceae (P = .015) and increases in both Bacteroides ovatus (P = .03) and Alistipes shahii (P = .038), a recently identified species with uncertain protective or pathogenic potential.

In contrast, there were no significant increases in species in the usual-care group, but there were significant declines in several other bacterial species; Ms.Lam, however, did not say whether these changes had clinical significance. “Future studies will assess microbial association with clinical outcomes,” Ms. Lam said.
 

Confounding factors

Samuel Evans, MD, a pulmonologist at Straub Medical Center in Honolulu who moderated the oral abstract session where the data were presented, commented that the data are interesting but added that associations are difficult to determine given the heterogeneity of exposures that firefighters encounter.

“I think it’s interesting that clearly diet is influencing the type of bacteria in the biome in the gut, and perhaps some are favorable, and some are not favorable,” he told this news organization “We already know that the Mediterranean diet is associated with better health outcomes, so it makes sense, but can we tease out in the microbiome which bacteria are harmful and which are helpful.”

He noted that there are a lot of confounding factors and that “it’s hard to find the right signal when you have so many variables.”

The FIREHOUSE study is supported by the Centers for Disease Control and Prevention’s National Institute of Occupational Safety & Health and the National Heart, Lung, and Blood Institute. Ms. Lam, Dr. Nolan, and Dr. Evans report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

HONOLULU – What we eat and what’s in the gut may influence lung health for better or worse, suggest new data from an ongoing study of lung function in New York City firefighters who were at the World Trade Center site on Sept. 11, 2001, and the days immediately following the 9/11 attacks.

Among NYC firefighters enrolled in the randomized FIREHOUSE (Food Intake Restriction for Health Outcome Support and Education) study who took part in a microbiome substudy, those who followed a low-calorie, Mediterranean-style diet had higher levels in stools samples at 6 months of Bacteroides ovatus, a bacterial species associated with protection against bowel inflammation.

In contrast, participants who followed a usual-care diet had elevated 6-month levels of a species associated with high-fat diets and inflammation, reported Rachel Lam, a predoctoral fellow in the Nolan Lab at NYU Langone Medical Center, at the annual meeting of the American College of Chest Physicians (CHEST).

“Overall, we found that in our validation cohort, Bacteroides ovatus was increased in the LoCalMed arm after 6 months, and this bacterial species is associated with fewer negative health effects,” she said.

Ms. Lam noted that in a murine model of high-fat diets, mice gavaged with Bacteroides ovatus had reductions in body mass index and decreased serum LDL cholesterol and triglyceride levels.
 

FIREHOUSE cohort

Senior author Anna Nolan, MD, whose lab members study predictors of lung function loss in a cohort of firefighters who were exposed to the particulate matter clouding the air of lower Manhattan on 9/11 and the ensuing days, told this news organization that the findings, while preliminary, support previous research findings on potential links between intestinal microbiota and lung function.

“It’s interesting that we saw this done in other models, like mouse models and such, where certain bacteria were viewed as healthy for the system, and if they were able to bring that bacteria out in larger amounts they saw anti-inflammatory effects, so we’re hoping to mirror that and also do a mouse model,” she said.

Dr. Nolan’s group has previously shown that markers for the metabolic syndrome, inflammation, and vascular injury detected in serum samples taken within 6 months of 9/11 were predictive for later abnormal lung function. In addition, their group has found that elevated serum levels of an LDL metabolite after intense World Trade Center dust exposure is a risk factor for future impaired lung function as measured by forced expiratory volume in 1 second (FEV₁).

In the FIREHOUSE trial, 89 patients were randomly assigned either to a technology-supported educational and behavioral intervention targeting calorie restriction for weight loss while following a low-calorie Mediterranean diet, or to usual care. The usual-care arm included participants who were informed about their weight, BMI, and other standard measures at annual visits and were given general advice about healthy eating, but were not assigned to a specific diet.

Participants in the LoCalMed group had significant decreases in BMI and increases in FEV₁, compared with those in the usual-care group. In addition, the LoCalMed group had improved vascular health, better dietary habits, decreases in fats and calories from sweets, and decreases in inflammation as measured by a lower white blood cell count.
 

Microbiome substudy

At CHEST 2023, Ms. Lam reported on microbiome pilot and validation substudies of FIREHOUSE.

The pilot study included five patients in each arm. The validation sample included 15 participants in the Mediterranean diet group and 16 in the usual-care diet group.

Each participant’s microbiome was assessed with genomic sequencing with sequences aligned to a bacterial database.  The number and diversity of bacterial species in each sample were determined with the Chao1 Index and Shannon Index, respectively.

There were no significant differences among the study groups in mean age, exposure at the World Trade Center site, or years of service.

Although bacterial diversity did not differ between the study arms either at baseline or at 6 months, in both groups it significantly decreased over time (P = .02 in the pilot, P < .0001 in the validation arm).

In the pilot study, there was an increase over 6 months in the usual care arm only of Bilophila wadsworthia, a species associated with high-fat diets and inflammation.

In the validation study, patients in the LoCalMed arm had significant reductions in Ruminococcaceae (P = .015) and increases in both Bacteroides ovatus (P = .03) and Alistipes shahii (P = .038), a recently identified species with uncertain protective or pathogenic potential.

In contrast, there were no significant increases in species in the usual-care group, but there were significant declines in several other bacterial species; Ms.Lam, however, did not say whether these changes had clinical significance. “Future studies will assess microbial association with clinical outcomes,” Ms. Lam said.
 

Confounding factors

Samuel Evans, MD, a pulmonologist at Straub Medical Center in Honolulu who moderated the oral abstract session where the data were presented, commented that the data are interesting but added that associations are difficult to determine given the heterogeneity of exposures that firefighters encounter.

“I think it’s interesting that clearly diet is influencing the type of bacteria in the biome in the gut, and perhaps some are favorable, and some are not favorable,” he told this news organization “We already know that the Mediterranean diet is associated with better health outcomes, so it makes sense, but can we tease out in the microbiome which bacteria are harmful and which are helpful.”

He noted that there are a lot of confounding factors and that “it’s hard to find the right signal when you have so many variables.”

The FIREHOUSE study is supported by the Centers for Disease Control and Prevention’s National Institute of Occupational Safety & Health and the National Heart, Lung, and Blood Institute. Ms. Lam, Dr. Nolan, and Dr. Evans report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

SAN DIEGO – In low- and middle-income countries with high incidence and mortality from head and neck cancer, resources remain limited. Patients often can’t travel far for treatment or afford to stay near a treatment center for the length of time required for conventionally fractionated radiotherapy.

A hypofractionated radiotherapy regimen with or without weekly cisplatin may be a viable alternative for patients with locally advanced head and neck cancer in these settings.

The phase 3 randomized HYPNO trial, conducted in 10 low- and middle-income countries, revealed that the hypofractionated regimen shortened total treatment time by a median of 11.5 days and was noninferior to conventional fractionation for tumor control and safety.

The primary trial results were presented by Søren Bentzen, PhD, DMSc, at the annual meeting of the American Society for Radiation Oncology.

“It was Usain Bolt who said, ‘I train for 4 years to run 9 seconds,’ and that was the feeling that I had when we did the noninferiority test,” said Dr. Bentzen, from the University of Maryland School of Medicine in Baltimore. “We had not looked at the data while the data were being accumulated, and guess what? It actually turned out that we had noninferiority with respect to both locoregional control and the late effects.”

In the HYPNO trial, Dr. Bentzen and colleagues wanted to determine whether a streamlined approach to the treatment of patients in low- and middle-income countries could improve access to care and still achieve strong outcomes.

The investigators used mathematical modeling to devise a strategy to reduce the number of fractions and put this hypothesis to the test in a pragmatic trial.

Patients from Uruguay, Brazil, Argentina, Cuba, South Africa, India, Pakistan, Thailand, Indonesia, and the Philippines were enrolled. After stratification by performance status, tumor subsite, institution, and previous treatment with chemotherapy, the 792 patients in the trial were randomly assigned in a 1:1 ratio to receive either 66 Gy in 33 fractions 6 days each week over 5.5 weeks, or 55 Gy in 20 fractions 5 days per week over 4 weeks. In both groups, weekly cisplatin was optional.

Compliance with the regimens was high in both arms, with 95% of patients assigned to conventional fractionation and 99% assigned to hypofractionation receiving the total planned doses.

At 3 years’ follow-up, the rates of locoregional control were 50.7% in the hypofractionation arm and 51.2% in the conventional fractionation arm (P = .40). No significant differences between the groups have emerged over 5 years, Dr. Bentzen said.

Rates of late toxicities of grade 3 or greater at 3 years’ follow-up were similar between the groups, at 18.8% in the hypofractionation arm and 20.2% in the conventional fractionation arm (P = .68).

Three-year overall survival rates also did not differ between the groups – 54.1% in the hypofractionation arm vs. 55.5% in the conventional arm (P = .62) – nor did rates of progression-free survival – 44.0% vs. 45.3%.

“Head and neck cancer caused by factors other than the human papillomavirus (HPV) remains a significant burden especially in lower- and middle-income countries,” Dr. Bentzen said in a press release. “This is a trial that directly informs how you can effectively deliver radiation therapy to patients in a resource-scarce environment.”

Beth Beadle, MD, PhD, the invited discussant at a media briefing where Dr. Bentzen summarized the findings, said, “I think this trial is going to change practice in low- and middle-income countries and will improve access to care.”

Although the approach used in the HYPNO trial will likely allow more patients to receive treatment and will save lives in countries with limited resources, the strategy likely won’t apply to U.S. practice, noted Dr. Beadle, a professor of radiation oncology at Stanford University, California.

“The one thing I do caution, and that Dr. Bentzen brought up, is that this is a very different population than the one that we see in the United States now,” Dr. Beadle said. “In fact, it’s very challenging to find a similar patient population to even serve as a comparison in the modern era and modern techniques.”

The HYPNO trial was sponsored by the International Atomic Energy Agency. Dr. Bentzen and Dr. Beadle have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

SAN DIEGO – In low- and middle-income countries with high incidence and mortality from head and neck cancer, resources remain limited. Patients often can’t travel far for treatment or afford to stay near a treatment center for the length of time required for conventionally fractionated radiotherapy.

A hypofractionated radiotherapy regimen with or without weekly cisplatin may be a viable alternative for patients with locally advanced head and neck cancer in these settings.

The phase 3 randomized HYPNO trial, conducted in 10 low- and middle-income countries, revealed that the hypofractionated regimen shortened total treatment time by a median of 11.5 days and was noninferior to conventional fractionation for tumor control and safety.

The primary trial results were presented by Søren Bentzen, PhD, DMSc, at the annual meeting of the American Society for Radiation Oncology.

“It was Usain Bolt who said, ‘I train for 4 years to run 9 seconds,’ and that was the feeling that I had when we did the noninferiority test,” said Dr. Bentzen, from the University of Maryland School of Medicine in Baltimore. “We had not looked at the data while the data were being accumulated, and guess what? It actually turned out that we had noninferiority with respect to both locoregional control and the late effects.”

In the HYPNO trial, Dr. Bentzen and colleagues wanted to determine whether a streamlined approach to the treatment of patients in low- and middle-income countries could improve access to care and still achieve strong outcomes.

The investigators used mathematical modeling to devise a strategy to reduce the number of fractions and put this hypothesis to the test in a pragmatic trial.

Patients from Uruguay, Brazil, Argentina, Cuba, South Africa, India, Pakistan, Thailand, Indonesia, and the Philippines were enrolled. After stratification by performance status, tumor subsite, institution, and previous treatment with chemotherapy, the 792 patients in the trial were randomly assigned in a 1:1 ratio to receive either 66 Gy in 33 fractions 6 days each week over 5.5 weeks, or 55 Gy in 20 fractions 5 days per week over 4 weeks. In both groups, weekly cisplatin was optional.

Compliance with the regimens was high in both arms, with 95% of patients assigned to conventional fractionation and 99% assigned to hypofractionation receiving the total planned doses.

At 3 years’ follow-up, the rates of locoregional control were 50.7% in the hypofractionation arm and 51.2% in the conventional fractionation arm (P = .40). No significant differences between the groups have emerged over 5 years, Dr. Bentzen said.

Rates of late toxicities of grade 3 or greater at 3 years’ follow-up were similar between the groups, at 18.8% in the hypofractionation arm and 20.2% in the conventional fractionation arm (P = .68).

Three-year overall survival rates also did not differ between the groups – 54.1% in the hypofractionation arm vs. 55.5% in the conventional arm (P = .62) – nor did rates of progression-free survival – 44.0% vs. 45.3%.

“Head and neck cancer caused by factors other than the human papillomavirus (HPV) remains a significant burden especially in lower- and middle-income countries,” Dr. Bentzen said in a press release. “This is a trial that directly informs how you can effectively deliver radiation therapy to patients in a resource-scarce environment.”

Beth Beadle, MD, PhD, the invited discussant at a media briefing where Dr. Bentzen summarized the findings, said, “I think this trial is going to change practice in low- and middle-income countries and will improve access to care.”

Although the approach used in the HYPNO trial will likely allow more patients to receive treatment and will save lives in countries with limited resources, the strategy likely won’t apply to U.S. practice, noted Dr. Beadle, a professor of radiation oncology at Stanford University, California.

“The one thing I do caution, and that Dr. Bentzen brought up, is that this is a very different population than the one that we see in the United States now,” Dr. Beadle said. “In fact, it’s very challenging to find a similar patient population to even serve as a comparison in the modern era and modern techniques.”

The HYPNO trial was sponsored by the International Atomic Energy Agency. Dr. Bentzen and Dr. Beadle have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

SAN DIEGO – In low- and middle-income countries with high incidence and mortality from head and neck cancer, resources remain limited. Patients often can’t travel far for treatment or afford to stay near a treatment center for the length of time required for conventionally fractionated radiotherapy.

A hypofractionated radiotherapy regimen with or without weekly cisplatin may be a viable alternative for patients with locally advanced head and neck cancer in these settings.

The phase 3 randomized HYPNO trial, conducted in 10 low- and middle-income countries, revealed that the hypofractionated regimen shortened total treatment time by a median of 11.5 days and was noninferior to conventional fractionation for tumor control and safety.

The primary trial results were presented by Søren Bentzen, PhD, DMSc, at the annual meeting of the American Society for Radiation Oncology.

“It was Usain Bolt who said, ‘I train for 4 years to run 9 seconds,’ and that was the feeling that I had when we did the noninferiority test,” said Dr. Bentzen, from the University of Maryland School of Medicine in Baltimore. “We had not looked at the data while the data were being accumulated, and guess what? It actually turned out that we had noninferiority with respect to both locoregional control and the late effects.”

In the HYPNO trial, Dr. Bentzen and colleagues wanted to determine whether a streamlined approach to the treatment of patients in low- and middle-income countries could improve access to care and still achieve strong outcomes.

The investigators used mathematical modeling to devise a strategy to reduce the number of fractions and put this hypothesis to the test in a pragmatic trial.

Patients from Uruguay, Brazil, Argentina, Cuba, South Africa, India, Pakistan, Thailand, Indonesia, and the Philippines were enrolled. After stratification by performance status, tumor subsite, institution, and previous treatment with chemotherapy, the 792 patients in the trial were randomly assigned in a 1:1 ratio to receive either 66 Gy in 33 fractions 6 days each week over 5.5 weeks, or 55 Gy in 20 fractions 5 days per week over 4 weeks. In both groups, weekly cisplatin was optional.

Compliance with the regimens was high in both arms, with 95% of patients assigned to conventional fractionation and 99% assigned to hypofractionation receiving the total planned doses.

At 3 years’ follow-up, the rates of locoregional control were 50.7% in the hypofractionation arm and 51.2% in the conventional fractionation arm (P = .40). No significant differences between the groups have emerged over 5 years, Dr. Bentzen said.

Rates of late toxicities of grade 3 or greater at 3 years’ follow-up were similar between the groups, at 18.8% in the hypofractionation arm and 20.2% in the conventional fractionation arm (P = .68).

Three-year overall survival rates also did not differ between the groups – 54.1% in the hypofractionation arm vs. 55.5% in the conventional arm (P = .62) – nor did rates of progression-free survival – 44.0% vs. 45.3%.

“Head and neck cancer caused by factors other than the human papillomavirus (HPV) remains a significant burden especially in lower- and middle-income countries,” Dr. Bentzen said in a press release. “This is a trial that directly informs how you can effectively deliver radiation therapy to patients in a resource-scarce environment.”

Beth Beadle, MD, PhD, the invited discussant at a media briefing where Dr. Bentzen summarized the findings, said, “I think this trial is going to change practice in low- and middle-income countries and will improve access to care.”

Although the approach used in the HYPNO trial will likely allow more patients to receive treatment and will save lives in countries with limited resources, the strategy likely won’t apply to U.S. practice, noted Dr. Beadle, a professor of radiation oncology at Stanford University, California.

“The one thing I do caution, and that Dr. Bentzen brought up, is that this is a very different population than the one that we see in the United States now,” Dr. Beadle said. “In fact, it’s very challenging to find a similar patient population to even serve as a comparison in the modern era and modern techniques.”

The HYPNO trial was sponsored by the International Atomic Energy Agency. Dr. Bentzen and Dr. Beadle have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

For patients with up to 10 brain metastases from small cell lung cancer (SCLC), stereotactic radiosurgery was associated with less cognitive impairment than whole-brain radiation therapy (WBRT) without compromising overall survival, results of the randomized ENCEPHALON (ARO 2018-9) trial suggest.

Among 56 patients with one to 10 SCLC brain metastases, 24% of those who received WBRT demonstrated significant declines in memory function 3 months after treatment, compared with 7% of patients whose metastases were treated with stereotactic radiosurgery alone. Preliminary data showed no significant differences in overall survival between the treatment groups at 6 months of follow-up, Denise Bernhardt, MD, from the Technical University of Munich, reported at the American Society of Radiation Oncology (ASTRO) annual meeting.

“We propose stereotactic radiosurgery should be an option for patients with up to 10 brain metastases in small cell lung cancer,” Dr. Bernhardt said during her presentation.

Vinai Gondi, MD, who was not involved in the study, said that the primary results from the trial – while limited by the study’s small size and missing data – are notable.

Patients with brain metastases from most cancer types typically receive stereotactic radiosurgery but WBRT has remained the standard of care to control brain metastases among patients with SCLC.

“This is the first prospective trial of radiosurgery versus whole-brain radiotherapy for small cell lung cancer brain metastases, and it’s important to recognize how important this is,” said Dr. Gondi, director of Radiation Oncology and codirector of the Brain Tumor Center at Northwestern Medicine Cancer Center, Warrenville, Ill.

Prior trials that have asked the same question did not include SCLC because many of those patients received prophylactic cranial irradiation, Dr. Gondi explained. Prophylactic cranial irradiation, however, has been on the decline among patients with brain metastases from SCLC, following a study from Japan showing no difference in survival among those who received the therapy and those followed with observation as well as evidence demonstrating significant toxicities associated with the technique.

Now “with the declining use of prophylactic cranial irradiation, the emergence of brain metastases is increasing significantly in volume in the small cell lung cancer population,” said Dr. Gondi, who is principal investigator on a phase 3 trial exploring stereotactic radiosurgery versus WBRT in a similar patient population.

In a previous retrospective trial), Dr. Bernhardt and colleagues found that first-line stereotactic radiosurgery did not compromise survival, compared with WBRT, but patients receiving stereotactic radiosurgery did have a higher risk for intracranial failure.

In the current study, the investigators compared the neurocognitive responses in patients with brain metastases from SCLC treated with stereotactic radiosurgery or WBRT.

Enrolled patients had histologically confirmed extensive disease with up to 10 metastatic brain lesions and had not previously received either therapeutic or prophylactic brain irradiation. After stratifying patients by synchronous versus metachronous disease, 56 patients were randomly assigned to either WBRT, at a total dose of 30 Gy delivered in 10 fractions, or to stereotactic radiosurgery with 20 Gy, 18 Gy, or fractionated stereotactic radiosurgery with 30 Gy in 5 Gy fractions for lesions larger than 3 cm.

The primary endpoint was neurocognition after radiation therapy as defined by a decline from baseline of at least five points on the Hopkins Verbal Learning Test-Revised (HVLT-R) total recall subscale at 3 months. Secondary endpoints included survival outcomes, additional neurocognitive assessments of motor skills, executive function, attention, memory, and processing as well as quality-of-life measures.

The investigators expected a high rate of study dropout and planned their statistical analysis accordingly, using a method for estimating the likely values of missing data based on observed data.

Among 26 patients who eventually underwent stereotactic radiosurgery, 18 did not meet the primary endpoint and 2 (7%) demonstrated declines on the HVLT-R subscale of 5 or more points. Data for the remaining 6 patients were missing.

Among the 25 who underwent WBRT, 13 did not meet the primary endpoint and 6 (24%) demonstrated declines of at least 5 points. Data for 6 of the remaining patients were missing.

Although more patients in the WBRT arm had significant declines in neurocognitive function, the difference between the groups was not significant, due to the high proportion of study dropouts – approximately one-fourth of patients in each arm. But the analysis suggested that the neuroprotective effect of stereotactic radiosurgery was notable, Dr. Bernhardt said.

At 6 months, the team also found no significant difference in the survival probability between the treatment groups (P = .36). The median time to death was 124 days among patients who received stereotactic radiosurgery and 131 days among patients who received WBRT. 

Dr. Gondi said the data from ENCEPHALON, while promising, need to be carefully scrutinized because of the small sample sizes and the possibility for unintended bias.

ARO 2018-9 is an investigator-initiated trial funded by Accuray. Dr. Bernhardt disclosed consulting actives, fees, travel expenses, and research funding from Accuray and others. Dr. Gondi disclosed honoraria from UpToDate.

A version of this article appeared on Medscape.com.

For patients with up to 10 brain metastases from small cell lung cancer (SCLC), stereotactic radiosurgery was associated with less cognitive impairment than whole-brain radiation therapy (WBRT) without compromising overall survival, results of the randomized ENCEPHALON (ARO 2018-9) trial suggest.

Among 56 patients with one to 10 SCLC brain metastases, 24% of those who received WBRT demonstrated significant declines in memory function 3 months after treatment, compared with 7% of patients whose metastases were treated with stereotactic radiosurgery alone. Preliminary data showed no significant differences in overall survival between the treatment groups at 6 months of follow-up, Denise Bernhardt, MD, from the Technical University of Munich, reported at the American Society of Radiation Oncology (ASTRO) annual meeting.

“We propose stereotactic radiosurgery should be an option for patients with up to 10 brain metastases in small cell lung cancer,” Dr. Bernhardt said during her presentation.

Vinai Gondi, MD, who was not involved in the study, said that the primary results from the trial – while limited by the study’s small size and missing data – are notable.

Patients with brain metastases from most cancer types typically receive stereotactic radiosurgery but WBRT has remained the standard of care to control brain metastases among patients with SCLC.

“This is the first prospective trial of radiosurgery versus whole-brain radiotherapy for small cell lung cancer brain metastases, and it’s important to recognize how important this is,” said Dr. Gondi, director of Radiation Oncology and codirector of the Brain Tumor Center at Northwestern Medicine Cancer Center, Warrenville, Ill.

Prior trials that have asked the same question did not include SCLC because many of those patients received prophylactic cranial irradiation, Dr. Gondi explained. Prophylactic cranial irradiation, however, has been on the decline among patients with brain metastases from SCLC, following a study from Japan showing no difference in survival among those who received the therapy and those followed with observation as well as evidence demonstrating significant toxicities associated with the technique.

Now “with the declining use of prophylactic cranial irradiation, the emergence of brain metastases is increasing significantly in volume in the small cell lung cancer population,” said Dr. Gondi, who is principal investigator on a phase 3 trial exploring stereotactic radiosurgery versus WBRT in a similar patient population.

In a previous retrospective trial), Dr. Bernhardt and colleagues found that first-line stereotactic radiosurgery did not compromise survival, compared with WBRT, but patients receiving stereotactic radiosurgery did have a higher risk for intracranial failure.

In the current study, the investigators compared the neurocognitive responses in patients with brain metastases from SCLC treated with stereotactic radiosurgery or WBRT.

Enrolled patients had histologically confirmed extensive disease with up to 10 metastatic brain lesions and had not previously received either therapeutic or prophylactic brain irradiation. After stratifying patients by synchronous versus metachronous disease, 56 patients were randomly assigned to either WBRT, at a total dose of 30 Gy delivered in 10 fractions, or to stereotactic radiosurgery with 20 Gy, 18 Gy, or fractionated stereotactic radiosurgery with 30 Gy in 5 Gy fractions for lesions larger than 3 cm.

The primary endpoint was neurocognition after radiation therapy as defined by a decline from baseline of at least five points on the Hopkins Verbal Learning Test-Revised (HVLT-R) total recall subscale at 3 months. Secondary endpoints included survival outcomes, additional neurocognitive assessments of motor skills, executive function, attention, memory, and processing as well as quality-of-life measures.

The investigators expected a high rate of study dropout and planned their statistical analysis accordingly, using a method for estimating the likely values of missing data based on observed data.

Among 26 patients who eventually underwent stereotactic radiosurgery, 18 did not meet the primary endpoint and 2 (7%) demonstrated declines on the HVLT-R subscale of 5 or more points. Data for the remaining 6 patients were missing.

Among the 25 who underwent WBRT, 13 did not meet the primary endpoint and 6 (24%) demonstrated declines of at least 5 points. Data for 6 of the remaining patients were missing.

Although more patients in the WBRT arm had significant declines in neurocognitive function, the difference between the groups was not significant, due to the high proportion of study dropouts – approximately one-fourth of patients in each arm. But the analysis suggested that the neuroprotective effect of stereotactic radiosurgery was notable, Dr. Bernhardt said.

At 6 months, the team also found no significant difference in the survival probability between the treatment groups (P = .36). The median time to death was 124 days among patients who received stereotactic radiosurgery and 131 days among patients who received WBRT. 

Dr. Gondi said the data from ENCEPHALON, while promising, need to be carefully scrutinized because of the small sample sizes and the possibility for unintended bias.

ARO 2018-9 is an investigator-initiated trial funded by Accuray. Dr. Bernhardt disclosed consulting actives, fees, travel expenses, and research funding from Accuray and others. Dr. Gondi disclosed honoraria from UpToDate.

A version of this article appeared on Medscape.com.

For patients with up to 10 brain metastases from small cell lung cancer (SCLC), stereotactic radiosurgery was associated with less cognitive impairment than whole-brain radiation therapy (WBRT) without compromising overall survival, results of the randomized ENCEPHALON (ARO 2018-9) trial suggest.

Among 56 patients with one to 10 SCLC brain metastases, 24% of those who received WBRT demonstrated significant declines in memory function 3 months after treatment, compared with 7% of patients whose metastases were treated with stereotactic radiosurgery alone. Preliminary data showed no significant differences in overall survival between the treatment groups at 6 months of follow-up, Denise Bernhardt, MD, from the Technical University of Munich, reported at the American Society of Radiation Oncology (ASTRO) annual meeting.

“We propose stereotactic radiosurgery should be an option for patients with up to 10 brain metastases in small cell lung cancer,” Dr. Bernhardt said during her presentation.

Vinai Gondi, MD, who was not involved in the study, said that the primary results from the trial – while limited by the study’s small size and missing data – are notable.

Patients with brain metastases from most cancer types typically receive stereotactic radiosurgery but WBRT has remained the standard of care to control brain metastases among patients with SCLC.

“This is the first prospective trial of radiosurgery versus whole-brain radiotherapy for small cell lung cancer brain metastases, and it’s important to recognize how important this is,” said Dr. Gondi, director of Radiation Oncology and codirector of the Brain Tumor Center at Northwestern Medicine Cancer Center, Warrenville, Ill.

Prior trials that have asked the same question did not include SCLC because many of those patients received prophylactic cranial irradiation, Dr. Gondi explained. Prophylactic cranial irradiation, however, has been on the decline among patients with brain metastases from SCLC, following a study from Japan showing no difference in survival among those who received the therapy and those followed with observation as well as evidence demonstrating significant toxicities associated with the technique.

Now “with the declining use of prophylactic cranial irradiation, the emergence of brain metastases is increasing significantly in volume in the small cell lung cancer population,” said Dr. Gondi, who is principal investigator on a phase 3 trial exploring stereotactic radiosurgery versus WBRT in a similar patient population.

In a previous retrospective trial), Dr. Bernhardt and colleagues found that first-line stereotactic radiosurgery did not compromise survival, compared with WBRT, but patients receiving stereotactic radiosurgery did have a higher risk for intracranial failure.

In the current study, the investigators compared the neurocognitive responses in patients with brain metastases from SCLC treated with stereotactic radiosurgery or WBRT.

Enrolled patients had histologically confirmed extensive disease with up to 10 metastatic brain lesions and had not previously received either therapeutic or prophylactic brain irradiation. After stratifying patients by synchronous versus metachronous disease, 56 patients were randomly assigned to either WBRT, at a total dose of 30 Gy delivered in 10 fractions, or to stereotactic radiosurgery with 20 Gy, 18 Gy, or fractionated stereotactic radiosurgery with 30 Gy in 5 Gy fractions for lesions larger than 3 cm.

The primary endpoint was neurocognition after radiation therapy as defined by a decline from baseline of at least five points on the Hopkins Verbal Learning Test-Revised (HVLT-R) total recall subscale at 3 months. Secondary endpoints included survival outcomes, additional neurocognitive assessments of motor skills, executive function, attention, memory, and processing as well as quality-of-life measures.

The investigators expected a high rate of study dropout and planned their statistical analysis accordingly, using a method for estimating the likely values of missing data based on observed data.

Among 26 patients who eventually underwent stereotactic radiosurgery, 18 did not meet the primary endpoint and 2 (7%) demonstrated declines on the HVLT-R subscale of 5 or more points. Data for the remaining 6 patients were missing.

Among the 25 who underwent WBRT, 13 did not meet the primary endpoint and 6 (24%) demonstrated declines of at least 5 points. Data for 6 of the remaining patients were missing.

Although more patients in the WBRT arm had significant declines in neurocognitive function, the difference between the groups was not significant, due to the high proportion of study dropouts – approximately one-fourth of patients in each arm. But the analysis suggested that the neuroprotective effect of stereotactic radiosurgery was notable, Dr. Bernhardt said.

At 6 months, the team also found no significant difference in the survival probability between the treatment groups (P = .36). The median time to death was 124 days among patients who received stereotactic radiosurgery and 131 days among patients who received WBRT. 

Dr. Gondi said the data from ENCEPHALON, while promising, need to be carefully scrutinized because of the small sample sizes and the possibility for unintended bias.

ARO 2018-9 is an investigator-initiated trial funded by Accuray. Dr. Bernhardt disclosed consulting actives, fees, travel expenses, and research funding from Accuray and others. Dr. Gondi disclosed honoraria from UpToDate.

A version of this article appeared on Medscape.com.