Conference Coverage

Adagrasib, an investigational drug that acts as a KRASG12C inhibitor, has shown durable clinical benefit in patients with previously treated, advanced non-small cell lung cancer (NSCLC) with tumors with KRAS G12C mutations.

“KRAS G12C mutations occur in over 10% of patients with NSCL [and] remain difficult to target, and outcomes for this patient population have remained poor,” co-investigator Joshua Sabari, MD, assistant professor of medicine, Perlmutter Cancer Center at NYU Langone, said in a statement.

“Our patients benefited clinically from this agent, and it appears to have improved overall survival (OS), compared with historical outcomes with docetaxel, a standard-of-care chemotherapy regimen, in the second-line setting,” he added.

New data on adagrasib were presented at the annual meeting of the American Society for Clinical Oncology and simultaneously published in the New England Journal of Medicine.

Adagrasib (developed by Mirati) is currently awaiting approval from the U.S. Food and Drug Administration as a treatment for patients with NSCLC harboring the KRAS G12C mutation who have received at least one prior systemic therapy. This would be an accelerated approval based on overall response data from the KRYSTAL-1 study detailed below. The company has an ongoing confirmatory Phase 3 trial, KRYSTAL-12, evaluating adagrasib versus docetaxel in patients previously treated for metastatic NSCLC with a KRAS G12C mutation.

If approved, adagrasib would be the second in this class of agents. The first KRASG12C inhibitor for use in lung cancer was sotorasib (Lumakras), approved by the U.S. Food and Drug Administration in May 2021.  

Dr. Sabari noted that there are several differences between the two drugs. Adagrasib has CNS penetration and is the first KRASG12C inhibitor to demonstrate clinical activity in patients with KRAS G12C-mutated NSCLC with untreated active CNS metastases.
 

Published clinical data

The results published in the New England Journal of Medicine are from the company-funded KRYSTAL-1 clinical trial, which had the primary endpoint of objective response rate.

It was conducted in patients with KRAS G12C-mutated NSCLC who had previously received treatment with at least one platinum-containing chemotherapy regimen and checkpoint inhibitor therapy either sequentially or concurrently.

Patients were treated with oral adagrasib 600 mg twice a day until disease progression, unacceptable toxicity, or death.

On Oct. 15, 2021, the data cutoff date, a total of 116 patients had received at least one dose of adagrasib. At a median follow-up of 12.9 months, the confirmed objective response rate was 42.9% among 112 patients with measurable disease at baseline. One patient achieved a complete response: 42% achieved a partial response, and disease stabilized for a minimum of 6 weeks in over 36% of the group.

Only 5.4% of patients had progressive disease as their best overall response, investigators note. Among those patients who responded to twice-daily KRASG12C inhibition, the median time to response was 1.4 months and the median duration of response was 8.5 months. As of the data cutoff date, one-third of the group were still receiving treatment, the authors note.

Median progression-free survival (PFS) was 6.5 months and median OS was 11.7 months. With a longer median follow-up of 15.6 months, median OS was 12.6 months, and the estimated OS at 1 year was close to 51%.

“The majority of treatment-related adverse events were low-grade, started early in treatment, and quickly resolved after occurrence,” Dr. Sabari noted.

Grade 1-2 treatment-related adverse events occurred in 53% of patients while 45% had grade 3-4 treatment-related adverse events, and there were two fatal grade 5 treatment-related adverse events. The same events led to a dose reduction in 52% of the group overall and dose interruption in 61%, while in 7% of patients, treatment-related adverse events led to discontinuation of the drug.
 

CNS metastases

At baseline, some 42 patients had evidence of central nervous system (CNS) metastases. At a median follow-up of 15.4 months, an intracranial-confirmed objective response was achieved in one-third of this subgroup overall while median duration of the intracranial response was 11.2 months. Again, within the same subgroup, the median PFS was 5.4 months.

As Dr. Sabari noted, CNS metastases from KRAS mutant NSCLC are common. “Adagrasib demonstrated encouraging and durable CNS-specific activity in patients with KRAS G12C-mutant NSCLC and active, untreated CNS metastases,” he said.

The study was funded by Mirati Therapeutics.

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

Adagrasib, an investigational drug that acts as a KRASG12C inhibitor, has shown durable clinical benefit in patients with previously treated, advanced non-small cell lung cancer (NSCLC) with tumors with KRAS G12C mutations.

“KRAS G12C mutations occur in over 10% of patients with NSCL [and] remain difficult to target, and outcomes for this patient population have remained poor,” co-investigator Joshua Sabari, MD, assistant professor of medicine, Perlmutter Cancer Center at NYU Langone, said in a statement.

“Our patients benefited clinically from this agent, and it appears to have improved overall survival (OS), compared with historical outcomes with docetaxel, a standard-of-care chemotherapy regimen, in the second-line setting,” he added.

New data on adagrasib were presented at the annual meeting of the American Society for Clinical Oncology and simultaneously published in the New England Journal of Medicine.

Adagrasib (developed by Mirati) is currently awaiting approval from the U.S. Food and Drug Administration as a treatment for patients with NSCLC harboring the KRAS G12C mutation who have received at least one prior systemic therapy. This would be an accelerated approval based on overall response data from the KRYSTAL-1 study detailed below. The company has an ongoing confirmatory Phase 3 trial, KRYSTAL-12, evaluating adagrasib versus docetaxel in patients previously treated for metastatic NSCLC with a KRAS G12C mutation.

If approved, adagrasib would be the second in this class of agents. The first KRASG12C inhibitor for use in lung cancer was sotorasib (Lumakras), approved by the U.S. Food and Drug Administration in May 2021.  

Dr. Sabari noted that there are several differences between the two drugs. Adagrasib has CNS penetration and is the first KRASG12C inhibitor to demonstrate clinical activity in patients with KRAS G12C-mutated NSCLC with untreated active CNS metastases.
 

Published clinical data

The results published in the New England Journal of Medicine are from the company-funded KRYSTAL-1 clinical trial, which had the primary endpoint of objective response rate.

It was conducted in patients with KRAS G12C-mutated NSCLC who had previously received treatment with at least one platinum-containing chemotherapy regimen and checkpoint inhibitor therapy either sequentially or concurrently.

Patients were treated with oral adagrasib 600 mg twice a day until disease progression, unacceptable toxicity, or death.

On Oct. 15, 2021, the data cutoff date, a total of 116 patients had received at least one dose of adagrasib. At a median follow-up of 12.9 months, the confirmed objective response rate was 42.9% among 112 patients with measurable disease at baseline. One patient achieved a complete response: 42% achieved a partial response, and disease stabilized for a minimum of 6 weeks in over 36% of the group.

Only 5.4% of patients had progressive disease as their best overall response, investigators note. Among those patients who responded to twice-daily KRASG12C inhibition, the median time to response was 1.4 months and the median duration of response was 8.5 months. As of the data cutoff date, one-third of the group were still receiving treatment, the authors note.

Median progression-free survival (PFS) was 6.5 months and median OS was 11.7 months. With a longer median follow-up of 15.6 months, median OS was 12.6 months, and the estimated OS at 1 year was close to 51%.

“The majority of treatment-related adverse events were low-grade, started early in treatment, and quickly resolved after occurrence,” Dr. Sabari noted.

Grade 1-2 treatment-related adverse events occurred in 53% of patients while 45% had grade 3-4 treatment-related adverse events, and there were two fatal grade 5 treatment-related adverse events. The same events led to a dose reduction in 52% of the group overall and dose interruption in 61%, while in 7% of patients, treatment-related adverse events led to discontinuation of the drug.
 

CNS metastases

At baseline, some 42 patients had evidence of central nervous system (CNS) metastases. At a median follow-up of 15.4 months, an intracranial-confirmed objective response was achieved in one-third of this subgroup overall while median duration of the intracranial response was 11.2 months. Again, within the same subgroup, the median PFS was 5.4 months.

As Dr. Sabari noted, CNS metastases from KRAS mutant NSCLC are common. “Adagrasib demonstrated encouraging and durable CNS-specific activity in patients with KRAS G12C-mutant NSCLC and active, untreated CNS metastases,” he said.

The study was funded by Mirati Therapeutics.

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

Adagrasib, an investigational drug that acts as a KRASG12C inhibitor, has shown durable clinical benefit in patients with previously treated, advanced non-small cell lung cancer (NSCLC) with tumors with KRAS G12C mutations.

“KRAS G12C mutations occur in over 10% of patients with NSCL [and] remain difficult to target, and outcomes for this patient population have remained poor,” co-investigator Joshua Sabari, MD, assistant professor of medicine, Perlmutter Cancer Center at NYU Langone, said in a statement.

“Our patients benefited clinically from this agent, and it appears to have improved overall survival (OS), compared with historical outcomes with docetaxel, a standard-of-care chemotherapy regimen, in the second-line setting,” he added.

New data on adagrasib were presented at the annual meeting of the American Society for Clinical Oncology and simultaneously published in the New England Journal of Medicine.

Adagrasib (developed by Mirati) is currently awaiting approval from the U.S. Food and Drug Administration as a treatment for patients with NSCLC harboring the KRAS G12C mutation who have received at least one prior systemic therapy. This would be an accelerated approval based on overall response data from the KRYSTAL-1 study detailed below. The company has an ongoing confirmatory Phase 3 trial, KRYSTAL-12, evaluating adagrasib versus docetaxel in patients previously treated for metastatic NSCLC with a KRAS G12C mutation.

If approved, adagrasib would be the second in this class of agents. The first KRASG12C inhibitor for use in lung cancer was sotorasib (Lumakras), approved by the U.S. Food and Drug Administration in May 2021.  

Dr. Sabari noted that there are several differences between the two drugs. Adagrasib has CNS penetration and is the first KRASG12C inhibitor to demonstrate clinical activity in patients with KRAS G12C-mutated NSCLC with untreated active CNS metastases.
 

Published clinical data

The results published in the New England Journal of Medicine are from the company-funded KRYSTAL-1 clinical trial, which had the primary endpoint of objective response rate.

It was conducted in patients with KRAS G12C-mutated NSCLC who had previously received treatment with at least one platinum-containing chemotherapy regimen and checkpoint inhibitor therapy either sequentially or concurrently.

Patients were treated with oral adagrasib 600 mg twice a day until disease progression, unacceptable toxicity, or death.

On Oct. 15, 2021, the data cutoff date, a total of 116 patients had received at least one dose of adagrasib. At a median follow-up of 12.9 months, the confirmed objective response rate was 42.9% among 112 patients with measurable disease at baseline. One patient achieved a complete response: 42% achieved a partial response, and disease stabilized for a minimum of 6 weeks in over 36% of the group.

Only 5.4% of patients had progressive disease as their best overall response, investigators note. Among those patients who responded to twice-daily KRASG12C inhibition, the median time to response was 1.4 months and the median duration of response was 8.5 months. As of the data cutoff date, one-third of the group were still receiving treatment, the authors note.

Median progression-free survival (PFS) was 6.5 months and median OS was 11.7 months. With a longer median follow-up of 15.6 months, median OS was 12.6 months, and the estimated OS at 1 year was close to 51%.

“The majority of treatment-related adverse events were low-grade, started early in treatment, and quickly resolved after occurrence,” Dr. Sabari noted.

Grade 1-2 treatment-related adverse events occurred in 53% of patients while 45% had grade 3-4 treatment-related adverse events, and there were two fatal grade 5 treatment-related adverse events. The same events led to a dose reduction in 52% of the group overall and dose interruption in 61%, while in 7% of patients, treatment-related adverse events led to discontinuation of the drug.
 

CNS metastases

At baseline, some 42 patients had evidence of central nervous system (CNS) metastases. At a median follow-up of 15.4 months, an intracranial-confirmed objective response was achieved in one-third of this subgroup overall while median duration of the intracranial response was 11.2 months. Again, within the same subgroup, the median PFS was 5.4 months.

As Dr. Sabari noted, CNS metastases from KRAS mutant NSCLC are common. “Adagrasib demonstrated encouraging and durable CNS-specific activity in patients with KRAS G12C-mutant NSCLC and active, untreated CNS metastases,” he said.

The study was funded by Mirati Therapeutics.

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

CHICAGO -- A “liquid biopsy” that detects circulating tumor DNA (ctDNA) after surgery for stage 2 colon cancer helps identify patients most likely to benefit from adjuvant chemotherapy and also identifies those who are unlikely to benefit, allowing them to skip that treatment.

The results are from the phase 2 DYNAMIC trial.

“The strategy of using ctDNA results to inform treatment almost halved the number of patients who received chemotherapy postsurgery, from 28% down to 15%,” commented first author Jeanne Tie, MD, from the Walter and Eliza Hall Institute of Medical Research at the Peter MacCallum Cancer Centre, University of Melbourne.

The overall proportion of patients who were alive and cancer-free at 3 years after ctDNA-guided treatment was 92% – the same as in patients randomized to standard management, she added.

The chance of being alive and cancer-free was 86.4% and 92.5%, respectively, in ctDNA-positive patients who received adjuvant chemotherapy and in ctDNA-negative patients who did not, she said. Conversely, the risk of recurrence is greater than 80% without treatment in ctDNA-positive patients, said Dr. Tie.

Dr. Tie reported the results at the annual meeting of the American Society of Clinical Oncology, which were simultaneously published in the New England Journal of Medicine.

The study supports a ctDNA-guided approach to treatment in this patient population, Dr. Tie said, noting that this approach addresses what has been a clinical dilemma: Surgery can cure more than 80% of stage 2 patients, but the benefits of chemotherapy after surgery have been less clear – fewer than 1 in 20 patients will benefit, but the ability to predict which patients will benefit has been lacking.

The findings are practice-changing, commented Julie Gralow, MD, ASCO’s chief medical officer and executive vice president.

“I see this study as an important kind of new concept in cancers, where for the most part we have really very good survival and outcomes ... and now we’re starting to look at ways we can deescalate therapy in a subgroup who we know are going to do well while continuing the more intensive therapy, or even escalating therapy, in the group who we know are not going to do well with our conventional therapies,” Dr. Gralow said at a press briefing where the study was highlighted.

“I do believe the results are going to help us guide our selection of who benefits from chemo and who can avoid it – and all the toxicities of it – in stage 2 colon cancer,” she added.

They may also identify patients who may need more than standard treatment. This is a group in which “we might need to think outside the box and do even more besides just thinking about adjuvant chemo,” she told this news organization in a preconference interview. “Maybe this is a group we should be thinking about adjuvant immunotherapy, for example, or adjuvant EGFR-targeted therapy, or other things that we have shown [to have benefit] in the metastatic setting.”
 

Study details

For the DYNAMIC trial, Dr. Tie and colleagues enrolled 455 patients with resected stage 2 colon cancer at multiple centers between August 2015 and August 2019. Of those, 302 were randomized to receive ctDNA-guided chemotherapy and 153 received standard management based on conventional criteria, including tumor stage of disease, number of lymph nodes assessed, whether the tumor had perforated the bowel wall, and other factors.

The Safe-SeqS tumor-informed personalized ctDNA assay was used to detect ctDNA in the experimental group. Patients with a ctDNA-positive result at 4 or 7 weeks after surgery received oxaliplatin-based or fluoropyrimidine chemotherapy; those who were ctDNA-negative were observed during follow-up.

Fewer patients overall in the ctDNA-guided group, compared with the standard management group, received adjuvant chemotherapy (15.3% vs. 27.9%; odds ratio, 2.14).

Two-year recurrence-free survival (RFS) in the ctDNA-guided treatment group was noninferior to that in the standard management group (93.5% vs. 92.4%). Three-year RFS was 86.4% in ctDNA-positive patients who received chemotherapy, 92.5% in ctDNA-negative patients without chemotherapy, and 96.7% in a clinical low-risk subgroup.

ASCO expert Cathy Eng, MD, applauded the findings, stating in a press release that “thanks to the results of this study, we may now be able to use it to better identify which patient with stage 2 colon cancer would benefit from post surgery treatment with chemotherapy and which ones can be spared the additional treatment, without compromising relapse-free survival.”

Dr. Eng is the David H. Johnson Chair in Surgical and Medical Oncology, co-leader of the Gastrointestinal Cancer Research Program, co-director of GI oncology, and professor of medicine in hematology and oncology at Vanderbilt University, Nashville, Tenn.
 

Next steps

The authors note that a randomized trial is being considered in which ctDNA-positive and -negative patients would be randomized to treatment versus no treatment. This could provide more definitive evidence of treatment impact, or lack of impact, in each of the patient subsets, according to the press release.

The DYNAMIC trial was funded by the Australian National Health and Medical Research Council, U.S. National Institutes of Health, the Marcus Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, Lustgarten Foundation, the Conrad R. Hilton Foundation, the Sol Goldman Charitable Trust, John Templeton Foundation, and Eastern Health Research Foundation. Dr. Tie has reported receiving honoraria from Inivata and Servier and serving as a consultant or advisor for AstraZeneca/MedImmune, Bristol-Myers Squibb, Haystack Oncology, Inivata, MSD Oncology, and Pierre Fabre.  

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

CHICAGO -- A “liquid biopsy” that detects circulating tumor DNA (ctDNA) after surgery for stage 2 colon cancer helps identify patients most likely to benefit from adjuvant chemotherapy and also identifies those who are unlikely to benefit, allowing them to skip that treatment.

The results are from the phase 2 DYNAMIC trial.

“The strategy of using ctDNA results to inform treatment almost halved the number of patients who received chemotherapy postsurgery, from 28% down to 15%,” commented first author Jeanne Tie, MD, from the Walter and Eliza Hall Institute of Medical Research at the Peter MacCallum Cancer Centre, University of Melbourne.

The overall proportion of patients who were alive and cancer-free at 3 years after ctDNA-guided treatment was 92% – the same as in patients randomized to standard management, she added.

The chance of being alive and cancer-free was 86.4% and 92.5%, respectively, in ctDNA-positive patients who received adjuvant chemotherapy and in ctDNA-negative patients who did not, she said. Conversely, the risk of recurrence is greater than 80% without treatment in ctDNA-positive patients, said Dr. Tie.

Dr. Tie reported the results at the annual meeting of the American Society of Clinical Oncology, which were simultaneously published in the New England Journal of Medicine.

The study supports a ctDNA-guided approach to treatment in this patient population, Dr. Tie said, noting that this approach addresses what has been a clinical dilemma: Surgery can cure more than 80% of stage 2 patients, but the benefits of chemotherapy after surgery have been less clear – fewer than 1 in 20 patients will benefit, but the ability to predict which patients will benefit has been lacking.

The findings are practice-changing, commented Julie Gralow, MD, ASCO’s chief medical officer and executive vice president.

“I see this study as an important kind of new concept in cancers, where for the most part we have really very good survival and outcomes ... and now we’re starting to look at ways we can deescalate therapy in a subgroup who we know are going to do well while continuing the more intensive therapy, or even escalating therapy, in the group who we know are not going to do well with our conventional therapies,” Dr. Gralow said at a press briefing where the study was highlighted.

“I do believe the results are going to help us guide our selection of who benefits from chemo and who can avoid it – and all the toxicities of it – in stage 2 colon cancer,” she added.

They may also identify patients who may need more than standard treatment. This is a group in which “we might need to think outside the box and do even more besides just thinking about adjuvant chemo,” she told this news organization in a preconference interview. “Maybe this is a group we should be thinking about adjuvant immunotherapy, for example, or adjuvant EGFR-targeted therapy, or other things that we have shown [to have benefit] in the metastatic setting.”
 

Study details

For the DYNAMIC trial, Dr. Tie and colleagues enrolled 455 patients with resected stage 2 colon cancer at multiple centers between August 2015 and August 2019. Of those, 302 were randomized to receive ctDNA-guided chemotherapy and 153 received standard management based on conventional criteria, including tumor stage of disease, number of lymph nodes assessed, whether the tumor had perforated the bowel wall, and other factors.

The Safe-SeqS tumor-informed personalized ctDNA assay was used to detect ctDNA in the experimental group. Patients with a ctDNA-positive result at 4 or 7 weeks after surgery received oxaliplatin-based or fluoropyrimidine chemotherapy; those who were ctDNA-negative were observed during follow-up.

Fewer patients overall in the ctDNA-guided group, compared with the standard management group, received adjuvant chemotherapy (15.3% vs. 27.9%; odds ratio, 2.14).

Two-year recurrence-free survival (RFS) in the ctDNA-guided treatment group was noninferior to that in the standard management group (93.5% vs. 92.4%). Three-year RFS was 86.4% in ctDNA-positive patients who received chemotherapy, 92.5% in ctDNA-negative patients without chemotherapy, and 96.7% in a clinical low-risk subgroup.

ASCO expert Cathy Eng, MD, applauded the findings, stating in a press release that “thanks to the results of this study, we may now be able to use it to better identify which patient with stage 2 colon cancer would benefit from post surgery treatment with chemotherapy and which ones can be spared the additional treatment, without compromising relapse-free survival.”

Dr. Eng is the David H. Johnson Chair in Surgical and Medical Oncology, co-leader of the Gastrointestinal Cancer Research Program, co-director of GI oncology, and professor of medicine in hematology and oncology at Vanderbilt University, Nashville, Tenn.
 

Next steps

The authors note that a randomized trial is being considered in which ctDNA-positive and -negative patients would be randomized to treatment versus no treatment. This could provide more definitive evidence of treatment impact, or lack of impact, in each of the patient subsets, according to the press release.

The DYNAMIC trial was funded by the Australian National Health and Medical Research Council, U.S. National Institutes of Health, the Marcus Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, Lustgarten Foundation, the Conrad R. Hilton Foundation, the Sol Goldman Charitable Trust, John Templeton Foundation, and Eastern Health Research Foundation. Dr. Tie has reported receiving honoraria from Inivata and Servier and serving as a consultant or advisor for AstraZeneca/MedImmune, Bristol-Myers Squibb, Haystack Oncology, Inivata, MSD Oncology, and Pierre Fabre.  

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

CHICAGO -- A “liquid biopsy” that detects circulating tumor DNA (ctDNA) after surgery for stage 2 colon cancer helps identify patients most likely to benefit from adjuvant chemotherapy and also identifies those who are unlikely to benefit, allowing them to skip that treatment.

The results are from the phase 2 DYNAMIC trial.

“The strategy of using ctDNA results to inform treatment almost halved the number of patients who received chemotherapy postsurgery, from 28% down to 15%,” commented first author Jeanne Tie, MD, from the Walter and Eliza Hall Institute of Medical Research at the Peter MacCallum Cancer Centre, University of Melbourne.

The overall proportion of patients who were alive and cancer-free at 3 years after ctDNA-guided treatment was 92% – the same as in patients randomized to standard management, she added.

The chance of being alive and cancer-free was 86.4% and 92.5%, respectively, in ctDNA-positive patients who received adjuvant chemotherapy and in ctDNA-negative patients who did not, she said. Conversely, the risk of recurrence is greater than 80% without treatment in ctDNA-positive patients, said Dr. Tie.

Dr. Tie reported the results at the annual meeting of the American Society of Clinical Oncology, which were simultaneously published in the New England Journal of Medicine.

The study supports a ctDNA-guided approach to treatment in this patient population, Dr. Tie said, noting that this approach addresses what has been a clinical dilemma: Surgery can cure more than 80% of stage 2 patients, but the benefits of chemotherapy after surgery have been less clear – fewer than 1 in 20 patients will benefit, but the ability to predict which patients will benefit has been lacking.

The findings are practice-changing, commented Julie Gralow, MD, ASCO’s chief medical officer and executive vice president.

“I see this study as an important kind of new concept in cancers, where for the most part we have really very good survival and outcomes ... and now we’re starting to look at ways we can deescalate therapy in a subgroup who we know are going to do well while continuing the more intensive therapy, or even escalating therapy, in the group who we know are not going to do well with our conventional therapies,” Dr. Gralow said at a press briefing where the study was highlighted.

“I do believe the results are going to help us guide our selection of who benefits from chemo and who can avoid it – and all the toxicities of it – in stage 2 colon cancer,” she added.

They may also identify patients who may need more than standard treatment. This is a group in which “we might need to think outside the box and do even more besides just thinking about adjuvant chemo,” she told this news organization in a preconference interview. “Maybe this is a group we should be thinking about adjuvant immunotherapy, for example, or adjuvant EGFR-targeted therapy, or other things that we have shown [to have benefit] in the metastatic setting.”
 

Study details

For the DYNAMIC trial, Dr. Tie and colleagues enrolled 455 patients with resected stage 2 colon cancer at multiple centers between August 2015 and August 2019. Of those, 302 were randomized to receive ctDNA-guided chemotherapy and 153 received standard management based on conventional criteria, including tumor stage of disease, number of lymph nodes assessed, whether the tumor had perforated the bowel wall, and other factors.

The Safe-SeqS tumor-informed personalized ctDNA assay was used to detect ctDNA in the experimental group. Patients with a ctDNA-positive result at 4 or 7 weeks after surgery received oxaliplatin-based or fluoropyrimidine chemotherapy; those who were ctDNA-negative were observed during follow-up.

Fewer patients overall in the ctDNA-guided group, compared with the standard management group, received adjuvant chemotherapy (15.3% vs. 27.9%; odds ratio, 2.14).

Two-year recurrence-free survival (RFS) in the ctDNA-guided treatment group was noninferior to that in the standard management group (93.5% vs. 92.4%). Three-year RFS was 86.4% in ctDNA-positive patients who received chemotherapy, 92.5% in ctDNA-negative patients without chemotherapy, and 96.7% in a clinical low-risk subgroup.

ASCO expert Cathy Eng, MD, applauded the findings, stating in a press release that “thanks to the results of this study, we may now be able to use it to better identify which patient with stage 2 colon cancer would benefit from post surgery treatment with chemotherapy and which ones can be spared the additional treatment, without compromising relapse-free survival.”

Dr. Eng is the David H. Johnson Chair in Surgical and Medical Oncology, co-leader of the Gastrointestinal Cancer Research Program, co-director of GI oncology, and professor of medicine in hematology and oncology at Vanderbilt University, Nashville, Tenn.
 

Next steps

The authors note that a randomized trial is being considered in which ctDNA-positive and -negative patients would be randomized to treatment versus no treatment. This could provide more definitive evidence of treatment impact, or lack of impact, in each of the patient subsets, according to the press release.

The DYNAMIC trial was funded by the Australian National Health and Medical Research Council, U.S. National Institutes of Health, the Marcus Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, Lustgarten Foundation, the Conrad R. Hilton Foundation, the Sol Goldman Charitable Trust, John Templeton Foundation, and Eastern Health Research Foundation. Dr. Tie has reported receiving honoraria from Inivata and Servier and serving as a consultant or advisor for AstraZeneca/MedImmune, Bristol-Myers Squibb, Haystack Oncology, Inivata, MSD Oncology, and Pierre Fabre.  

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

The “twincretin” tirzepatide might become part of the “arsenal” against diabetic kidney disease, new research suggests. Notably, the drug significantly reduced the likelihood of macroalbuminuria, in a prespecified subanalysis of the SURPASS-4 clinical trial.

“Once-per-week tirzepatide compared to [daily] insulin glargine treatment resulted in a meaningful improvement in estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (UACR) and the risk of end stage kidney disease (ESKD) – with low risk of clinically relevant hypoglycemia in participants with type 2 diabetes at high cardiovascular risk and varying degrees of chronic kidney disease (CKD),” lead investigator Hiddo J. L. Heerspink, PhD, PharmD, summarized in an email to this news organization.

The U.S. Food and Drug Administration has just approved tirzepatide (Mounjaro, Eli Lilly) – a novel, glucose-dependent insulinotropic polypeptide (GIP) combined with a glucagonlike peptide-1 (GLP-1) receptor agonist – to treat glycemia in patients with type 2 diabetes, based on five pivotal SURPASS trials.

Dr. Heerspink presented the new findings about tirzepatide’s impact on kidney function in an oral session at the annual scientific sessions of the American Diabetes Association.

40% reduced risk of kidney function decline

The main results of SURPASS-4 were published in the Lancet in October 2021, and showed that tirzepatide appeared superior to insulin glargine in lowering hemoglobin A1c in patients with type 2 diabetes at high cardiovascular risk who were inadequately controlled on oral diabetes treatments.

Now, Dr. Heerspink has shown that patients who received tirzepatide as opposed to insulin glargine were significantly less likely to have kidney function decline that included new-onset macroalbuminuria (hazard ratio, 0.59; P < .05).

“These are very large benefits and clearly indicate the potential of tirzepatide to be a very strong kidney protective drug,” said Dr. Heerspink, from the department of clinical pharmacy and pharmacology, University Medical Center Groningen (the Netherlands).

“Based on results from the SURPASS-4 trial, tirzepatide has significant kidney-protective effects in adults with type 2 diabetes with high cardiovascular risk and largely normal kidney function,” Christine Limonte, MD, chair of the session in which the analysis was presented, agreed, in an email to this news organization.

The approximate 40% reduced risk of kidney function decline in this population “is important because it suggests that this novel agent may contribute to the growing arsenal for preventing and treating diabetic kidney disease,” added Dr. Limonte, a clinical research fellow in the division of nephrology, University of Washington, Seattle.

“Over the last several years,” she noted, “sodium glucose cotransporter-2 [SGLT2] inhibitors and GLP-1 receptor agonists have been identified as having significant kidney-protective effects in type 2 diabetes, and as such are becoming first-line agents in the treatment of diabetic kidney disease.”

Additional studies are needed, she added, to assess the impacts of tirzepatide compared to these agents (particularly GLP-1 receptor agonists, which overlap in their mechanism of action).

“With the growing number of therapeutic options for diabetic kidney disease, future research should also focus on identifying combinations of agents which benefit individuals in a ‘targeted’ manner,” according to Dr. Limonte.

“Ensuring accessibility to kidney-protective agents by promoting access to health care and reducing drug costs is essential to improving outcomes in diabetic kidney disease,” she added.

Strongest reduction seen in risk of new macroalbuminuria

One in three adults with diabetes has CKD, according to a press release issued by the ADA. Therefore, there is a need for therapies to reduce the development and progression of CKD in patients with type 2 diabetes.

The prespecified analysis of SUPRESS-4 investigated potential renoprotective effects of tirzepatide.

The trial enrolled 1,995 patients with type 2 diabetes who were at increased risk of cardiovascular disease. The patients had a mean age of 63.6 years and a mean hemoglobin A1c of 8.5%.

Most patients had normal kidney function. The mean eGFR based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was 81.3 mL/min per 1.73 m².

Few patients (17%) had moderately or severely reduced kidney function (eGFR <60 mL/min per 1.73 m²). Around a quarter of the patients (28%) had microalbuminuria (UACR 30-300 mg/g) and 8% had macroalbuminuria (UACR >300 mg/g).

The patients were randomized to receive a weekly injection of 5, 10, or 15 mg tirzepatide or a daily individualized injection of insulin glargine starting at 10 IU/day at bedtime, titrated to a fasting blood glucose <100 mg/dL, in addition to existing oral glucose-lowering agents. The primary outcomes in the subanalysis were:

• Endpoint 1: a composite of ≥40% decline in eGFR from baseline, renal death, progression to ESKD, and new-onset macroalbuminuria.
• Endpoint 2: the same as endpoint 1 excluding new-onset macroalbuminuria.

During a median follow up of 85 weeks and up to 104 weeks, patients who received tirzepatide versus insulin glargine were significantly less likely to reach endpoint 1 but not endpoint 2.

In addition, tirzepatide “very strongly” reduced the risk of new-onset macroalbuminuria, compared to insulin glargine, by approximately 60% in the complete study cohort (hazard ratio, 0.41; P < .05), Dr. Limonte noted.

Tirzepatide also reduced the risk of a >40% decline in eGFR, but this effect was not statistically significant, possibly because this outcome was underpowered. There were also too few kidney deaths and progressions to ESKD to meaningfully assess the effects of tirzepatide on these outcomes.

Therefore, Dr. Limonte noted, “it is likely that tirzepatide’s significant benefit on composite endpoint 1 was largely driven by this agent’s impact on reducing macroalbuminuria onset [explaining why a significant benefit was not seen with composite endpoint 2, which excluded new-onset macroalbuminuria].”

The study was funded by Eli Lilly. Dr. Heerspink disclosed that he is a consultant for AstraZeneca, Bayer AG, Boehringer Ingelheim, Chinook Therapeutics, CSL Behring, Gilead Sciences, Goldfinch Bio, Janssen Research & Development, Mitsubishi Tanabe Pharma, Mundipharma, and Traveere Pharmaceuticals, and has received research support from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk.

Dr. Limonte disclosed that she receives funds from the American Kidney Fund’s Clinical Scientist in Nephrology Award.

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

The “twincretin” tirzepatide might become part of the “arsenal” against diabetic kidney disease, new research suggests. Notably, the drug significantly reduced the likelihood of macroalbuminuria, in a prespecified subanalysis of the SURPASS-4 clinical trial.

“Once-per-week tirzepatide compared to [daily] insulin glargine treatment resulted in a meaningful improvement in estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (UACR) and the risk of end stage kidney disease (ESKD) – with low risk of clinically relevant hypoglycemia in participants with type 2 diabetes at high cardiovascular risk and varying degrees of chronic kidney disease (CKD),” lead investigator Hiddo J. L. Heerspink, PhD, PharmD, summarized in an email to this news organization.

The U.S. Food and Drug Administration has just approved tirzepatide (Mounjaro, Eli Lilly) – a novel, glucose-dependent insulinotropic polypeptide (GIP) combined with a glucagonlike peptide-1 (GLP-1) receptor agonist – to treat glycemia in patients with type 2 diabetes, based on five pivotal SURPASS trials.

Dr. Heerspink presented the new findings about tirzepatide’s impact on kidney function in an oral session at the annual scientific sessions of the American Diabetes Association.

40% reduced risk of kidney function decline

The main results of SURPASS-4 were published in the Lancet in October 2021, and showed that tirzepatide appeared superior to insulin glargine in lowering hemoglobin A1c in patients with type 2 diabetes at high cardiovascular risk who were inadequately controlled on oral diabetes treatments.

Now, Dr. Heerspink has shown that patients who received tirzepatide as opposed to insulin glargine were significantly less likely to have kidney function decline that included new-onset macroalbuminuria (hazard ratio, 0.59; P < .05).

“These are very large benefits and clearly indicate the potential of tirzepatide to be a very strong kidney protective drug,” said Dr. Heerspink, from the department of clinical pharmacy and pharmacology, University Medical Center Groningen (the Netherlands).

“Based on results from the SURPASS-4 trial, tirzepatide has significant kidney-protective effects in adults with type 2 diabetes with high cardiovascular risk and largely normal kidney function,” Christine Limonte, MD, chair of the session in which the analysis was presented, agreed, in an email to this news organization.

The approximate 40% reduced risk of kidney function decline in this population “is important because it suggests that this novel agent may contribute to the growing arsenal for preventing and treating diabetic kidney disease,” added Dr. Limonte, a clinical research fellow in the division of nephrology, University of Washington, Seattle.

“Over the last several years,” she noted, “sodium glucose cotransporter-2 [SGLT2] inhibitors and GLP-1 receptor agonists have been identified as having significant kidney-protective effects in type 2 diabetes, and as such are becoming first-line agents in the treatment of diabetic kidney disease.”

Additional studies are needed, she added, to assess the impacts of tirzepatide compared to these agents (particularly GLP-1 receptor agonists, which overlap in their mechanism of action).

“With the growing number of therapeutic options for diabetic kidney disease, future research should also focus on identifying combinations of agents which benefit individuals in a ‘targeted’ manner,” according to Dr. Limonte.

“Ensuring accessibility to kidney-protective agents by promoting access to health care and reducing drug costs is essential to improving outcomes in diabetic kidney disease,” she added.

Strongest reduction seen in risk of new macroalbuminuria

One in three adults with diabetes has CKD, according to a press release issued by the ADA. Therefore, there is a need for therapies to reduce the development and progression of CKD in patients with type 2 diabetes.

The prespecified analysis of SUPRESS-4 investigated potential renoprotective effects of tirzepatide.

The trial enrolled 1,995 patients with type 2 diabetes who were at increased risk of cardiovascular disease. The patients had a mean age of 63.6 years and a mean hemoglobin A1c of 8.5%.

Most patients had normal kidney function. The mean eGFR based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was 81.3 mL/min per 1.73 m².

Few patients (17%) had moderately or severely reduced kidney function (eGFR <60 mL/min per 1.73 m²). Around a quarter of the patients (28%) had microalbuminuria (UACR 30-300 mg/g) and 8% had macroalbuminuria (UACR >300 mg/g).

The patients were randomized to receive a weekly injection of 5, 10, or 15 mg tirzepatide or a daily individualized injection of insulin glargine starting at 10 IU/day at bedtime, titrated to a fasting blood glucose <100 mg/dL, in addition to existing oral glucose-lowering agents. The primary outcomes in the subanalysis were:

• Endpoint 1: a composite of ≥40% decline in eGFR from baseline, renal death, progression to ESKD, and new-onset macroalbuminuria.
• Endpoint 2: the same as endpoint 1 excluding new-onset macroalbuminuria.

During a median follow up of 85 weeks and up to 104 weeks, patients who received tirzepatide versus insulin glargine were significantly less likely to reach endpoint 1 but not endpoint 2.

In addition, tirzepatide “very strongly” reduced the risk of new-onset macroalbuminuria, compared to insulin glargine, by approximately 60% in the complete study cohort (hazard ratio, 0.41; P < .05), Dr. Limonte noted.

Tirzepatide also reduced the risk of a >40% decline in eGFR, but this effect was not statistically significant, possibly because this outcome was underpowered. There were also too few kidney deaths and progressions to ESKD to meaningfully assess the effects of tirzepatide on these outcomes.

Therefore, Dr. Limonte noted, “it is likely that tirzepatide’s significant benefit on composite endpoint 1 was largely driven by this agent’s impact on reducing macroalbuminuria onset [explaining why a significant benefit was not seen with composite endpoint 2, which excluded new-onset macroalbuminuria].”

The study was funded by Eli Lilly. Dr. Heerspink disclosed that he is a consultant for AstraZeneca, Bayer AG, Boehringer Ingelheim, Chinook Therapeutics, CSL Behring, Gilead Sciences, Goldfinch Bio, Janssen Research & Development, Mitsubishi Tanabe Pharma, Mundipharma, and Traveere Pharmaceuticals, and has received research support from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk.

Dr. Limonte disclosed that she receives funds from the American Kidney Fund’s Clinical Scientist in Nephrology Award.

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

The “twincretin” tirzepatide might become part of the “arsenal” against diabetic kidney disease, new research suggests. Notably, the drug significantly reduced the likelihood of macroalbuminuria, in a prespecified subanalysis of the SURPASS-4 clinical trial.

“Once-per-week tirzepatide compared to [daily] insulin glargine treatment resulted in a meaningful improvement in estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (UACR) and the risk of end stage kidney disease (ESKD) – with low risk of clinically relevant hypoglycemia in participants with type 2 diabetes at high cardiovascular risk and varying degrees of chronic kidney disease (CKD),” lead investigator Hiddo J. L. Heerspink, PhD, PharmD, summarized in an email to this news organization.

The U.S. Food and Drug Administration has just approved tirzepatide (Mounjaro, Eli Lilly) – a novel, glucose-dependent insulinotropic polypeptide (GIP) combined with a glucagonlike peptide-1 (GLP-1) receptor agonist – to treat glycemia in patients with type 2 diabetes, based on five pivotal SURPASS trials.

Dr. Heerspink presented the new findings about tirzepatide’s impact on kidney function in an oral session at the annual scientific sessions of the American Diabetes Association.

40% reduced risk of kidney function decline

The main results of SURPASS-4 were published in the Lancet in October 2021, and showed that tirzepatide appeared superior to insulin glargine in lowering hemoglobin A1c in patients with type 2 diabetes at high cardiovascular risk who were inadequately controlled on oral diabetes treatments.

Now, Dr. Heerspink has shown that patients who received tirzepatide as opposed to insulin glargine were significantly less likely to have kidney function decline that included new-onset macroalbuminuria (hazard ratio, 0.59; P < .05).

“These are very large benefits and clearly indicate the potential of tirzepatide to be a very strong kidney protective drug,” said Dr. Heerspink, from the department of clinical pharmacy and pharmacology, University Medical Center Groningen (the Netherlands).

“Based on results from the SURPASS-4 trial, tirzepatide has significant kidney-protective effects in adults with type 2 diabetes with high cardiovascular risk and largely normal kidney function,” Christine Limonte, MD, chair of the session in which the analysis was presented, agreed, in an email to this news organization.

The approximate 40% reduced risk of kidney function decline in this population “is important because it suggests that this novel agent may contribute to the growing arsenal for preventing and treating diabetic kidney disease,” added Dr. Limonte, a clinical research fellow in the division of nephrology, University of Washington, Seattle.

“Over the last several years,” she noted, “sodium glucose cotransporter-2 [SGLT2] inhibitors and GLP-1 receptor agonists have been identified as having significant kidney-protective effects in type 2 diabetes, and as such are becoming first-line agents in the treatment of diabetic kidney disease.”

Additional studies are needed, she added, to assess the impacts of tirzepatide compared to these agents (particularly GLP-1 receptor agonists, which overlap in their mechanism of action).

“With the growing number of therapeutic options for diabetic kidney disease, future research should also focus on identifying combinations of agents which benefit individuals in a ‘targeted’ manner,” according to Dr. Limonte.

“Ensuring accessibility to kidney-protective agents by promoting access to health care and reducing drug costs is essential to improving outcomes in diabetic kidney disease,” she added.

Strongest reduction seen in risk of new macroalbuminuria

One in three adults with diabetes has CKD, according to a press release issued by the ADA. Therefore, there is a need for therapies to reduce the development and progression of CKD in patients with type 2 diabetes.

The prespecified analysis of SUPRESS-4 investigated potential renoprotective effects of tirzepatide.

The trial enrolled 1,995 patients with type 2 diabetes who were at increased risk of cardiovascular disease. The patients had a mean age of 63.6 years and a mean hemoglobin A1c of 8.5%.

Most patients had normal kidney function. The mean eGFR based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was 81.3 mL/min per 1.73 m².

Few patients (17%) had moderately or severely reduced kidney function (eGFR <60 mL/min per 1.73 m²). Around a quarter of the patients (28%) had microalbuminuria (UACR 30-300 mg/g) and 8% had macroalbuminuria (UACR >300 mg/g).

The patients were randomized to receive a weekly injection of 5, 10, or 15 mg tirzepatide or a daily individualized injection of insulin glargine starting at 10 IU/day at bedtime, titrated to a fasting blood glucose <100 mg/dL, in addition to existing oral glucose-lowering agents. The primary outcomes in the subanalysis were:

• Endpoint 1: a composite of ≥40% decline in eGFR from baseline, renal death, progression to ESKD, and new-onset macroalbuminuria.
• Endpoint 2: the same as endpoint 1 excluding new-onset macroalbuminuria.

During a median follow up of 85 weeks and up to 104 weeks, patients who received tirzepatide versus insulin glargine were significantly less likely to reach endpoint 1 but not endpoint 2.

In addition, tirzepatide “very strongly” reduced the risk of new-onset macroalbuminuria, compared to insulin glargine, by approximately 60% in the complete study cohort (hazard ratio, 0.41; P < .05), Dr. Limonte noted.

Tirzepatide also reduced the risk of a >40% decline in eGFR, but this effect was not statistically significant, possibly because this outcome was underpowered. There were also too few kidney deaths and progressions to ESKD to meaningfully assess the effects of tirzepatide on these outcomes.

Therefore, Dr. Limonte noted, “it is likely that tirzepatide’s significant benefit on composite endpoint 1 was largely driven by this agent’s impact on reducing macroalbuminuria onset [explaining why a significant benefit was not seen with composite endpoint 2, which excluded new-onset macroalbuminuria].”

The study was funded by Eli Lilly. Dr. Heerspink disclosed that he is a consultant for AstraZeneca, Bayer AG, Boehringer Ingelheim, Chinook Therapeutics, CSL Behring, Gilead Sciences, Goldfinch Bio, Janssen Research & Development, Mitsubishi Tanabe Pharma, Mundipharma, and Traveere Pharmaceuticals, and has received research support from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk.

Dr. Limonte disclosed that she receives funds from the American Kidney Fund’s Clinical Scientist in Nephrology Award.

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

SAN FRANCISCO – Interstitial lung disease is a difficult diagnosis to make, but a combination of artificial intelligence (AI) techniques and automated language processing could help clinicians identify the early signs of ILD and start patients on therapy, investigators say.

For example, applying an AI algorithm to spirometry readings taken from patients whose data were registered in the UK Biobank identified 27% as having ILD, and of this group, 66% had ostensibly normal lung function on spirometry but were later diagnosed with ILD, reported Marko Topalovic, PhD, from the AI company ArtiQ in Leuven, Belgium, at the American Thoracic Society’s international conference.

Neil Osterweil/MDedge News

“A diagnosis of ILD is very challenging, so you have patients who are going to be misdiagnosed or have a very late diagnosis, so we aimed to apply our AI algorithm on spirometry to see whether we could detect ILD much earlier,” he said in an interview conducted during a poster discussion session.

AI detected ILD up to 6.8 years before a clinician’s diagnosis, Dr. Topalovic said.
 

Reading between the lines

In a separate study, investigators at the University of California, Davis, used language analysis software to scour electronic health records for words indicative of early ILD, and found that the technique dramatically shortened the median time to a pulmonary referral, compared with historical controls.

“This is a language processing program that can essentially look through the radiology reports and look for the key words that often describe interstitial lung disease, like traction, honeycomb, fibrotic, etc. With those studies being flagged, an actual pulmonologist will then further review the scan, and see whether it meets criteria for one of the interstitial lung diseases,” lead author William Leon, MD, a resident in the department of internal medicine at the University of California, Davis, said in an interview.

Neil Osterweil/MDedge News

“We then sent the primary care doctor a message to say: ‘Hey, this patient has ILD. You need to send them to a pulmonologist,’ ” he added.
 

Putting it together

Philip L. Molyneaux, MRCP (UK), MBBS, BS (Hons), from Imperial College London, who comoderated the session but was not involved in the studies, speculated that combining these and other, nontechnical interventions also discussed could help to improve diagnosis of ILD and allow clinicians to prescribe therapy earlier in the disease course.

“What’s going to give you the biggest impact for patients? Everyone working individually is coming up with great advances, and if you put them all together it’s going to provide much greater benefit for our patients,” he said in an interview.
 

AI Spirometry details

In collaboration with colleagues at the Laboratory of Respiratory Disease at University Hospital in Leuven, Dr. Topalovic applied AI to results of spirometry performed prior to diagnosis of ILD among 109 patients registered in the UK Biobank, a repository of information on more than 500,000 volunteers.

The patients selected had ILD listed as their cause of death, had spirometry performed up to 7 years before their deaths, and did not receive a diagnosis of ILD on the day of the index spirometry.

In all 73% of patients were men, 27% women, with an average age of 64.6 years. A large majority of the sample (77.15%) had a history of smoking, and 60 of the patients (55%) died within one year of an ILD diagnosis.

The investigators plugged the spirometry data and each patients demographic information – including gender, age, height, weight, race, and smoking status – into the AI clinical decision support program, which yielded a statistical probability for each subject of having normal lung function, asthma, COPD, ILD, another obstructive disease, or another unidentifiable respiratory disease.

In 29 patients (27%) the software listed ILD as the highest probability, and of this group 19 patients (66%) had normal lung function according to standard interpretation guidelines.

Spirometry parameters among patients identified as having probable ILD were different from those where ILD was not detected. For example, forced vital capacity (FVC) was 76% of predicted among patients with likely ILD versus 87% of predicted in those who had a diagnosis later (P = .003). Similar differences were seen in the forced expiratory volume in 1 second to FVC ratio, at 0.82 vs. 0.75, respectively (P = .007).

There were no differences in mortality or in median time between spirometry and clinician diagnosis between the groups.
 

Language processing details

Dr. Leon and colleagues used a language analysis software package to review CT chest reports. Reports were flagged if they contained the words traction, honeycomb, fibrotic, fibrosis, reticular, or reticulation.

The CT scan accompanying each flagged reported was reviewed by a pulmonologist for the presence of ILD, and scans with ILD identified were referred to pulmonary specialists. The results of 2,198 prospective scans followed by prospective screening were compared with those of 1,690 historical controls seen in 2015 and 2016.

The investigators found that 85 incident cases of ILD were identified in the historical controls, compared with 143 in the prospective cohort, leading to 38 and 120 pulmonary referrals, respectively.

For the primary outcome of median time from CT to pulmonary referral, the authors found that it was 1.27 months for the prospective cohort, compared with not reached (censored after 18 months) in historical controls.

The hazard ratio for a pulmonary referral in the prospective versus historical cohort was 2.79, an association that was strengthened after adjusting for sex, age, race, smoking pack-years, cough, crackles, and dyspnea (HR, 4.54; both comparisons significant according to confidence intervals).

The studies were internally funded. Dr. Topalovic is CEO and cofounder of ArtiQ. Dr. Leon and Dr. Molyneaux reported no relevant conflicts of interest.

SAN FRANCISCO – Interstitial lung disease is a difficult diagnosis to make, but a combination of artificial intelligence (AI) techniques and automated language processing could help clinicians identify the early signs of ILD and start patients on therapy, investigators say.

For example, applying an AI algorithm to spirometry readings taken from patients whose data were registered in the UK Biobank identified 27% as having ILD, and of this group, 66% had ostensibly normal lung function on spirometry but were later diagnosed with ILD, reported Marko Topalovic, PhD, from the AI company ArtiQ in Leuven, Belgium, at the American Thoracic Society’s international conference.

Neil Osterweil/MDedge News

“A diagnosis of ILD is very challenging, so you have patients who are going to be misdiagnosed or have a very late diagnosis, so we aimed to apply our AI algorithm on spirometry to see whether we could detect ILD much earlier,” he said in an interview conducted during a poster discussion session.

AI detected ILD up to 6.8 years before a clinician’s diagnosis, Dr. Topalovic said.
 

Reading between the lines

In a separate study, investigators at the University of California, Davis, used language analysis software to scour electronic health records for words indicative of early ILD, and found that the technique dramatically shortened the median time to a pulmonary referral, compared with historical controls.

“This is a language processing program that can essentially look through the radiology reports and look for the key words that often describe interstitial lung disease, like traction, honeycomb, fibrotic, etc. With those studies being flagged, an actual pulmonologist will then further review the scan, and see whether it meets criteria for one of the interstitial lung diseases,” lead author William Leon, MD, a resident in the department of internal medicine at the University of California, Davis, said in an interview.

Neil Osterweil/MDedge News

“We then sent the primary care doctor a message to say: ‘Hey, this patient has ILD. You need to send them to a pulmonologist,’ ” he added.
 

Putting it together

Philip L. Molyneaux, MRCP (UK), MBBS, BS (Hons), from Imperial College London, who comoderated the session but was not involved in the studies, speculated that combining these and other, nontechnical interventions also discussed could help to improve diagnosis of ILD and allow clinicians to prescribe therapy earlier in the disease course.

“What’s going to give you the biggest impact for patients? Everyone working individually is coming up with great advances, and if you put them all together it’s going to provide much greater benefit for our patients,” he said in an interview.
 

AI Spirometry details

In collaboration with colleagues at the Laboratory of Respiratory Disease at University Hospital in Leuven, Dr. Topalovic applied AI to results of spirometry performed prior to diagnosis of ILD among 109 patients registered in the UK Biobank, a repository of information on more than 500,000 volunteers.

The patients selected had ILD listed as their cause of death, had spirometry performed up to 7 years before their deaths, and did not receive a diagnosis of ILD on the day of the index spirometry.

In all 73% of patients were men, 27% women, with an average age of 64.6 years. A large majority of the sample (77.15%) had a history of smoking, and 60 of the patients (55%) died within one year of an ILD diagnosis.

The investigators plugged the spirometry data and each patients demographic information – including gender, age, height, weight, race, and smoking status – into the AI clinical decision support program, which yielded a statistical probability for each subject of having normal lung function, asthma, COPD, ILD, another obstructive disease, or another unidentifiable respiratory disease.

In 29 patients (27%) the software listed ILD as the highest probability, and of this group 19 patients (66%) had normal lung function according to standard interpretation guidelines.

Spirometry parameters among patients identified as having probable ILD were different from those where ILD was not detected. For example, forced vital capacity (FVC) was 76% of predicted among patients with likely ILD versus 87% of predicted in those who had a diagnosis later (P = .003). Similar differences were seen in the forced expiratory volume in 1 second to FVC ratio, at 0.82 vs. 0.75, respectively (P = .007).

There were no differences in mortality or in median time between spirometry and clinician diagnosis between the groups.
 

Language processing details

Dr. Leon and colleagues used a language analysis software package to review CT chest reports. Reports were flagged if they contained the words traction, honeycomb, fibrotic, fibrosis, reticular, or reticulation.

The CT scan accompanying each flagged reported was reviewed by a pulmonologist for the presence of ILD, and scans with ILD identified were referred to pulmonary specialists. The results of 2,198 prospective scans followed by prospective screening were compared with those of 1,690 historical controls seen in 2015 and 2016.

The investigators found that 85 incident cases of ILD were identified in the historical controls, compared with 143 in the prospective cohort, leading to 38 and 120 pulmonary referrals, respectively.

For the primary outcome of median time from CT to pulmonary referral, the authors found that it was 1.27 months for the prospective cohort, compared with not reached (censored after 18 months) in historical controls.

The hazard ratio for a pulmonary referral in the prospective versus historical cohort was 2.79, an association that was strengthened after adjusting for sex, age, race, smoking pack-years, cough, crackles, and dyspnea (HR, 4.54; both comparisons significant according to confidence intervals).

The studies were internally funded. Dr. Topalovic is CEO and cofounder of ArtiQ. Dr. Leon and Dr. Molyneaux reported no relevant conflicts of interest.

SAN FRANCISCO – Interstitial lung disease is a difficult diagnosis to make, but a combination of artificial intelligence (AI) techniques and automated language processing could help clinicians identify the early signs of ILD and start patients on therapy, investigators say.

For example, applying an AI algorithm to spirometry readings taken from patients whose data were registered in the UK Biobank identified 27% as having ILD, and of this group, 66% had ostensibly normal lung function on spirometry but were later diagnosed with ILD, reported Marko Topalovic, PhD, from the AI company ArtiQ in Leuven, Belgium, at the American Thoracic Society’s international conference.

Neil Osterweil/MDedge News

“A diagnosis of ILD is very challenging, so you have patients who are going to be misdiagnosed or have a very late diagnosis, so we aimed to apply our AI algorithm on spirometry to see whether we could detect ILD much earlier,” he said in an interview conducted during a poster discussion session.

AI detected ILD up to 6.8 years before a clinician’s diagnosis, Dr. Topalovic said.
 

Reading between the lines

In a separate study, investigators at the University of California, Davis, used language analysis software to scour electronic health records for words indicative of early ILD, and found that the technique dramatically shortened the median time to a pulmonary referral, compared with historical controls.

“This is a language processing program that can essentially look through the radiology reports and look for the key words that often describe interstitial lung disease, like traction, honeycomb, fibrotic, etc. With those studies being flagged, an actual pulmonologist will then further review the scan, and see whether it meets criteria for one of the interstitial lung diseases,” lead author William Leon, MD, a resident in the department of internal medicine at the University of California, Davis, said in an interview.

Neil Osterweil/MDedge News

“We then sent the primary care doctor a message to say: ‘Hey, this patient has ILD. You need to send them to a pulmonologist,’ ” he added.
 

Putting it together

Philip L. Molyneaux, MRCP (UK), MBBS, BS (Hons), from Imperial College London, who comoderated the session but was not involved in the studies, speculated that combining these and other, nontechnical interventions also discussed could help to improve diagnosis of ILD and allow clinicians to prescribe therapy earlier in the disease course.

“What’s going to give you the biggest impact for patients? Everyone working individually is coming up with great advances, and if you put them all together it’s going to provide much greater benefit for our patients,” he said in an interview.
 

AI Spirometry details

In collaboration with colleagues at the Laboratory of Respiratory Disease at University Hospital in Leuven, Dr. Topalovic applied AI to results of spirometry performed prior to diagnosis of ILD among 109 patients registered in the UK Biobank, a repository of information on more than 500,000 volunteers.

The patients selected had ILD listed as their cause of death, had spirometry performed up to 7 years before their deaths, and did not receive a diagnosis of ILD on the day of the index spirometry.

In all 73% of patients were men, 27% women, with an average age of 64.6 years. A large majority of the sample (77.15%) had a history of smoking, and 60 of the patients (55%) died within one year of an ILD diagnosis.

The investigators plugged the spirometry data and each patients demographic information – including gender, age, height, weight, race, and smoking status – into the AI clinical decision support program, which yielded a statistical probability for each subject of having normal lung function, asthma, COPD, ILD, another obstructive disease, or another unidentifiable respiratory disease.

In 29 patients (27%) the software listed ILD as the highest probability, and of this group 19 patients (66%) had normal lung function according to standard interpretation guidelines.

Spirometry parameters among patients identified as having probable ILD were different from those where ILD was not detected. For example, forced vital capacity (FVC) was 76% of predicted among patients with likely ILD versus 87% of predicted in those who had a diagnosis later (P = .003). Similar differences were seen in the forced expiratory volume in 1 second to FVC ratio, at 0.82 vs. 0.75, respectively (P = .007).

There were no differences in mortality or in median time between spirometry and clinician diagnosis between the groups.
 

Language processing details

Dr. Leon and colleagues used a language analysis software package to review CT chest reports. Reports were flagged if they contained the words traction, honeycomb, fibrotic, fibrosis, reticular, or reticulation.

The CT scan accompanying each flagged reported was reviewed by a pulmonologist for the presence of ILD, and scans with ILD identified were referred to pulmonary specialists. The results of 2,198 prospective scans followed by prospective screening were compared with those of 1,690 historical controls seen in 2015 and 2016.

The investigators found that 85 incident cases of ILD were identified in the historical controls, compared with 143 in the prospective cohort, leading to 38 and 120 pulmonary referrals, respectively.

For the primary outcome of median time from CT to pulmonary referral, the authors found that it was 1.27 months for the prospective cohort, compared with not reached (censored after 18 months) in historical controls.

The hazard ratio for a pulmonary referral in the prospective versus historical cohort was 2.79, an association that was strengthened after adjusting for sex, age, race, smoking pack-years, cough, crackles, and dyspnea (HR, 4.54; both comparisons significant according to confidence intervals).

The studies were internally funded. Dr. Topalovic is CEO and cofounder of ArtiQ. Dr. Leon and Dr. Molyneaux reported no relevant conflicts of interest.

COPENHAGEN – Temporary methotrexate in clinically suspected arthralgia delays but does not prevent clinical arthritis development; however, it does lead to sustained reduction of disease burden and MRI-detected inflammation in all at-risk groups, shows the 2-year Treat Earlier study.

“These data provide the first evidence for disease modification when intervening in ‘pre-RA [rheumatoid arthritis]’ or arthralgia,” said Doortje Krijbolder, MD, of Leiden (the Netherlands) University Medical Center, who presented her study at the annual European Congress of Rheumatology.  

The randomized, double-blind, study aimed to find out if giving methotrexate in the pre-arthritis phase of arthralgia (with subclinical joint inflammation) prevents the development of clinical arthritis or reduces the burden of disease.  

“This is the first trial that aims to reduce the burden of disease, and as such, in pre-RA, it is important that disease modification is sustained after temporary treatment otherwise patients will start regressing with disease activity,” said Dr. Krijbolder.

She explained that methotrexate is usually initiated as first-line treatment when arthritis becomes clinically apparent with joint swelling, but “disease processes begin long before this, and only become clinically recognizable when patients develop symptoms.” 

 

Clinically detectable arthritis development

All 236 patients included in the study had arthralgia of the small joints that, because of the character of the symptoms, was found clinically suspect for progression to RA over time.

“Importantly, these participants had not yet developed clinical arthritis that could be detected on physical joint examination, and were clinically suspected of progressing to RA. They had all undergone an MRI and subclinical joint-inflammation had been detected that was more than prevalent in symptom-free controls,” said Dr. Krijbolder.

Patients were randomized (1:1) to either a single intramuscular glucocorticoid injection (120 mg methylprednisolone [Depo Medrol]) and a 1-year course of oral methotrexate (up to 25 mg/week), or to placebo injection and placebo tablets, and were then followed for a further year without medication to see whether disease progressed.  

Treatment and placebo groups were matched with an average age of 46-47 years, 62%-68% were women, they had had symptoms (joint pain) for 27-28 weeks, C-reactive protein was increased in 27%-30%, and 20%-26% were anti-citrullinated protein autoantibody (ACPA) positive.  

The primary endpoint was the development of clinically detectable arthritis (fulfilling the 2010 RA-criteria or involving ≥ 2 joints) that persisted for at least 2 weeks. The main secondary endpoints were related to disease burden, including patient-reported physical functioning, along with symptoms and workability (presenteeism at work – the percentage of productivity lost caused by the joint complaints), and measured every 4 months, said Dr. Krijbolder.

She and her colleagues also followed the course of MRI-detected inflammation, which comprised the sum of tenosynovitis, synovitis, and osteitis scored with the RA-MRI Scoring (RAMRIS) method.  

Analysis was carried out on an intention-to-treat basis, and two prespecified subgroup analyses were also performed to obtain a better understanding of the effect of methotrexate and glucocorticoids in participants with high risk of clinical arthritis development (positive predictive value (PPV) ≥ 70%), and in patients stratified for ACPA status.  

 

Delays but does not prevent

There was no difference between treatment and placebo groups in the development of persistent clinical arthritis over 2 years (80% vs. 82%, hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.45, 1.48]); however, in the high-risk group subanalysis, 67% in the placebo group developed persistent clinical arthritis. For the treatment group, 7%developed persistent clinical arthritis at 6 months, 27% at 12 months, 40% at 18 months, and 67% at 24 months. For the placebo group: 56% developed persistent clinical arthritis at 6 months, and 67% at 12 months, 18 months, and 24 months. 

“Strikingly, in the treatment group there was a statistically significant difference between 6 and 12 months, but in year 2, this difference disappeared, suggesting a delayed arthritis development but no prevention,” said Dr. Krijbolder. 

Persistent clinical arthritis became similar at 24 months, at 67% in both groups. A similar, but less pronounced, delaying effect was seen with the ACPA-positive patients, with 48% and 52% developing persistent clinical arthritis at 24 months.  

In joint pain, there was a decline in the treatment group compared with the placebo group and this persisted over 2 years (–9 on scale of 0 to 100: (95%CI, –12,–4; P < .001), and a similar effect was seen in high-risk and ACPA subgroups, reported Dr. Krijbolder.  

Physical functioning improved more in the treatment-group compared with the placebo group during the first months and remained better (mean between-group difference over 2 years HAQ [health assessment questionnaire] –0.1 [–0.2, –0.03; P = .004]), and morning stiffness (–12 [95%CI, –16, –8; P < .001]), and presenteeism (–8% [95%CI, –13%, –3%; P = .001]) also showed improvement over time compared with placebo.  

MRI-detected joint-inflammation was also persistently improved with a mean difference over 2 years –1.4 points (95%CI, –2.0, –0.9; P < .001). “As we know that symptoms and functional impairments are associated with MRI-detected joint inflammation, it was not surprising that treatment induced a decline in joint inflammation that persisted over time, also after the stop of the treatment in the second year,” explained Dr. Krijbolder.  

In the high-risk subgroup, as well as in both ACPA-positive and ACPA-negative participants, a comparable statistically significant decline in MRI-detected inflammation was found.

“It may seem counterintuitive that on the one hand we found a delaying effect of treatment on persistent clinical arthritis but no prevention, while on the other, we saw a sustained treatment effect on MRI-detected joint-inflammation and related symptoms and functional impairments,” added Dr. Krijbolder.

To help understand this, the researchers performed a post hoc analysis in high-risk participants, comparing those who did not progress with those who did progress to arthritis. “Both progressors and nonprogressors showed a sustained treatment effect for pain and MRI-detected joint-inflammation, and in nonprogressors, there was almost a complete relief of pain and they nearly returned to the normal range of MRI-detected joint-inflammation as seen in symptom-free controls,” reported Dr. Krijbolder. 

“In those who progressed to arthritis, there was less pain and less MRI-detected joint inflammation in the treatment group, but also at the time when they developed clinical arthritis. So both progressors and nonprogressors benefit from treatment,” she noted.  

The number of serious adverse events was the same between the groups and adverse events were as expected from methotrexate.  

Dr. Krijbolder said, “the results are encouraging and will open up a new treatment landscape in pre-RA at the future, but at the moment it is too early to give recommendations for clinical practice; we definitely do not want to advocate the start of treatment in all at-risk individuals from now on.”

More research should unravel the mechanisms within the joint that contribute to the development of clinical arthritis and disease chronicity, she said. “If we understand these, we may be able to use more targeted interventions in the future and prevent the development of clinical arthritis all together.

“We are also looking forward to learning more about the long-term beneficial effects of this early treatment in our ongoing observational extension of the trial.” 

Hendrik Schulze-Koops, MD, of Ludwig-Maximilians-University of Munich, who moderated the session, asked Dr. Krijbolder, “As well as giving methotrexate to the participants in the treatment group, you also gave a single glucocorticoid injection at baseline, and a placebo injection in the placebo group, can you comment on that?”

EULAR

COPENHAGEN – Temporary methotrexate in clinically suspected arthralgia delays but does not prevent clinical arthritis development; however, it does lead to sustained reduction of disease burden and MRI-detected inflammation in all at-risk groups, shows the 2-year Treat Earlier study.

“These data provide the first evidence for disease modification when intervening in ‘pre-RA [rheumatoid arthritis]’ or arthralgia,” said Doortje Krijbolder, MD, of Leiden (the Netherlands) University Medical Center, who presented her study at the annual European Congress of Rheumatology.  

The randomized, double-blind, study aimed to find out if giving methotrexate in the pre-arthritis phase of arthralgia (with subclinical joint inflammation) prevents the development of clinical arthritis or reduces the burden of disease.  

“This is the first trial that aims to reduce the burden of disease, and as such, in pre-RA, it is important that disease modification is sustained after temporary treatment otherwise patients will start regressing with disease activity,” said Dr. Krijbolder.

She explained that methotrexate is usually initiated as first-line treatment when arthritis becomes clinically apparent with joint swelling, but “disease processes begin long before this, and only become clinically recognizable when patients develop symptoms.” 

 

Clinically detectable arthritis development

All 236 patients included in the study had arthralgia of the small joints that, because of the character of the symptoms, was found clinically suspect for progression to RA over time.

“Importantly, these participants had not yet developed clinical arthritis that could be detected on physical joint examination, and were clinically suspected of progressing to RA. They had all undergone an MRI and subclinical joint-inflammation had been detected that was more than prevalent in symptom-free controls,” said Dr. Krijbolder.

Patients were randomized (1:1) to either a single intramuscular glucocorticoid injection (120 mg methylprednisolone [Depo Medrol]) and a 1-year course of oral methotrexate (up to 25 mg/week), or to placebo injection and placebo tablets, and were then followed for a further year without medication to see whether disease progressed.  

Treatment and placebo groups were matched with an average age of 46-47 years, 62%-68% were women, they had had symptoms (joint pain) for 27-28 weeks, C-reactive protein was increased in 27%-30%, and 20%-26% were anti-citrullinated protein autoantibody (ACPA) positive.  

The primary endpoint was the development of clinically detectable arthritis (fulfilling the 2010 RA-criteria or involving ≥ 2 joints) that persisted for at least 2 weeks. The main secondary endpoints were related to disease burden, including patient-reported physical functioning, along with symptoms and workability (presenteeism at work – the percentage of productivity lost caused by the joint complaints), and measured every 4 months, said Dr. Krijbolder.

She and her colleagues also followed the course of MRI-detected inflammation, which comprised the sum of tenosynovitis, synovitis, and osteitis scored with the RA-MRI Scoring (RAMRIS) method.  

Analysis was carried out on an intention-to-treat basis, and two prespecified subgroup analyses were also performed to obtain a better understanding of the effect of methotrexate and glucocorticoids in participants with high risk of clinical arthritis development (positive predictive value (PPV) ≥ 70%), and in patients stratified for ACPA status.  

 

Delays but does not prevent

There was no difference between treatment and placebo groups in the development of persistent clinical arthritis over 2 years (80% vs. 82%, hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.45, 1.48]); however, in the high-risk group subanalysis, 67% in the placebo group developed persistent clinical arthritis. For the treatment group, 7%developed persistent clinical arthritis at 6 months, 27% at 12 months, 40% at 18 months, and 67% at 24 months. For the placebo group: 56% developed persistent clinical arthritis at 6 months, and 67% at 12 months, 18 months, and 24 months. 

“Strikingly, in the treatment group there was a statistically significant difference between 6 and 12 months, but in year 2, this difference disappeared, suggesting a delayed arthritis development but no prevention,” said Dr. Krijbolder. 

Persistent clinical arthritis became similar at 24 months, at 67% in both groups. A similar, but less pronounced, delaying effect was seen with the ACPA-positive patients, with 48% and 52% developing persistent clinical arthritis at 24 months.  

In joint pain, there was a decline in the treatment group compared with the placebo group and this persisted over 2 years (–9 on scale of 0 to 100: (95%CI, –12,–4; P < .001), and a similar effect was seen in high-risk and ACPA subgroups, reported Dr. Krijbolder.  

Physical functioning improved more in the treatment-group compared with the placebo group during the first months and remained better (mean between-group difference over 2 years HAQ [health assessment questionnaire] –0.1 [–0.2, –0.03; P = .004]), and morning stiffness (–12 [95%CI, –16, –8; P < .001]), and presenteeism (–8% [95%CI, –13%, –3%; P = .001]) also showed improvement over time compared with placebo.  

MRI-detected joint-inflammation was also persistently improved with a mean difference over 2 years –1.4 points (95%CI, –2.0, –0.9; P < .001). “As we know that symptoms and functional impairments are associated with MRI-detected joint inflammation, it was not surprising that treatment induced a decline in joint inflammation that persisted over time, also after the stop of the treatment in the second year,” explained Dr. Krijbolder.  

In the high-risk subgroup, as well as in both ACPA-positive and ACPA-negative participants, a comparable statistically significant decline in MRI-detected inflammation was found.

“It may seem counterintuitive that on the one hand we found a delaying effect of treatment on persistent clinical arthritis but no prevention, while on the other, we saw a sustained treatment effect on MRI-detected joint-inflammation and related symptoms and functional impairments,” added Dr. Krijbolder.

To help understand this, the researchers performed a post hoc analysis in high-risk participants, comparing those who did not progress with those who did progress to arthritis. “Both progressors and nonprogressors showed a sustained treatment effect for pain and MRI-detected joint-inflammation, and in nonprogressors, there was almost a complete relief of pain and they nearly returned to the normal range of MRI-detected joint-inflammation as seen in symptom-free controls,” reported Dr. Krijbolder. 

“In those who progressed to arthritis, there was less pain and less MRI-detected joint inflammation in the treatment group, but also at the time when they developed clinical arthritis. So both progressors and nonprogressors benefit from treatment,” she noted.  

The number of serious adverse events was the same between the groups and adverse events were as expected from methotrexate.  

Dr. Krijbolder said, “the results are encouraging and will open up a new treatment landscape in pre-RA at the future, but at the moment it is too early to give recommendations for clinical practice; we definitely do not want to advocate the start of treatment in all at-risk individuals from now on.”

More research should unravel the mechanisms within the joint that contribute to the development of clinical arthritis and disease chronicity, she said. “If we understand these, we may be able to use more targeted interventions in the future and prevent the development of clinical arthritis all together.

“We are also looking forward to learning more about the long-term beneficial effects of this early treatment in our ongoing observational extension of the trial.” 

Hendrik Schulze-Koops, MD, of Ludwig-Maximilians-University of Munich, who moderated the session, asked Dr. Krijbolder, “As well as giving methotrexate to the participants in the treatment group, you also gave a single glucocorticoid injection at baseline, and a placebo injection in the placebo group, can you comment on that?”

EULAR

COPENHAGEN – Temporary methotrexate in clinically suspected arthralgia delays but does not prevent clinical arthritis development; however, it does lead to sustained reduction of disease burden and MRI-detected inflammation in all at-risk groups, shows the 2-year Treat Earlier study.

“These data provide the first evidence for disease modification when intervening in ‘pre-RA [rheumatoid arthritis]’ or arthralgia,” said Doortje Krijbolder, MD, of Leiden (the Netherlands) University Medical Center, who presented her study at the annual European Congress of Rheumatology.  

The randomized, double-blind, study aimed to find out if giving methotrexate in the pre-arthritis phase of arthralgia (with subclinical joint inflammation) prevents the development of clinical arthritis or reduces the burden of disease.  

“This is the first trial that aims to reduce the burden of disease, and as such, in pre-RA, it is important that disease modification is sustained after temporary treatment otherwise patients will start regressing with disease activity,” said Dr. Krijbolder.

She explained that methotrexate is usually initiated as first-line treatment when arthritis becomes clinically apparent with joint swelling, but “disease processes begin long before this, and only become clinically recognizable when patients develop symptoms.” 

 

Clinically detectable arthritis development

All 236 patients included in the study had arthralgia of the small joints that, because of the character of the symptoms, was found clinically suspect for progression to RA over time.

“Importantly, these participants had not yet developed clinical arthritis that could be detected on physical joint examination, and were clinically suspected of progressing to RA. They had all undergone an MRI and subclinical joint-inflammation had been detected that was more than prevalent in symptom-free controls,” said Dr. Krijbolder.

Patients were randomized (1:1) to either a single intramuscular glucocorticoid injection (120 mg methylprednisolone [Depo Medrol]) and a 1-year course of oral methotrexate (up to 25 mg/week), or to placebo injection and placebo tablets, and were then followed for a further year without medication to see whether disease progressed.  

Treatment and placebo groups were matched with an average age of 46-47 years, 62%-68% were women, they had had symptoms (joint pain) for 27-28 weeks, C-reactive protein was increased in 27%-30%, and 20%-26% were anti-citrullinated protein autoantibody (ACPA) positive.  

The primary endpoint was the development of clinically detectable arthritis (fulfilling the 2010 RA-criteria or involving ≥ 2 joints) that persisted for at least 2 weeks. The main secondary endpoints were related to disease burden, including patient-reported physical functioning, along with symptoms and workability (presenteeism at work – the percentage of productivity lost caused by the joint complaints), and measured every 4 months, said Dr. Krijbolder.

She and her colleagues also followed the course of MRI-detected inflammation, which comprised the sum of tenosynovitis, synovitis, and osteitis scored with the RA-MRI Scoring (RAMRIS) method.  

Analysis was carried out on an intention-to-treat basis, and two prespecified subgroup analyses were also performed to obtain a better understanding of the effect of methotrexate and glucocorticoids in participants with high risk of clinical arthritis development (positive predictive value (PPV) ≥ 70%), and in patients stratified for ACPA status.  

 

Delays but does not prevent

There was no difference between treatment and placebo groups in the development of persistent clinical arthritis over 2 years (80% vs. 82%, hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.45, 1.48]); however, in the high-risk group subanalysis, 67% in the placebo group developed persistent clinical arthritis. For the treatment group, 7%developed persistent clinical arthritis at 6 months, 27% at 12 months, 40% at 18 months, and 67% at 24 months. For the placebo group: 56% developed persistent clinical arthritis at 6 months, and 67% at 12 months, 18 months, and 24 months. 

“Strikingly, in the treatment group there was a statistically significant difference between 6 and 12 months, but in year 2, this difference disappeared, suggesting a delayed arthritis development but no prevention,” said Dr. Krijbolder. 

Persistent clinical arthritis became similar at 24 months, at 67% in both groups. A similar, but less pronounced, delaying effect was seen with the ACPA-positive patients, with 48% and 52% developing persistent clinical arthritis at 24 months.  

In joint pain, there was a decline in the treatment group compared with the placebo group and this persisted over 2 years (–9 on scale of 0 to 100: (95%CI, –12,–4; P < .001), and a similar effect was seen in high-risk and ACPA subgroups, reported Dr. Krijbolder.  

Physical functioning improved more in the treatment-group compared with the placebo group during the first months and remained better (mean between-group difference over 2 years HAQ [health assessment questionnaire] –0.1 [–0.2, –0.03; P = .004]), and morning stiffness (–12 [95%CI, –16, –8; P < .001]), and presenteeism (–8% [95%CI, –13%, –3%; P = .001]) also showed improvement over time compared with placebo.  

MRI-detected joint-inflammation was also persistently improved with a mean difference over 2 years –1.4 points (95%CI, –2.0, –0.9; P < .001). “As we know that symptoms and functional impairments are associated with MRI-detected joint inflammation, it was not surprising that treatment induced a decline in joint inflammation that persisted over time, also after the stop of the treatment in the second year,” explained Dr. Krijbolder.  

In the high-risk subgroup, as well as in both ACPA-positive and ACPA-negative participants, a comparable statistically significant decline in MRI-detected inflammation was found.

“It may seem counterintuitive that on the one hand we found a delaying effect of treatment on persistent clinical arthritis but no prevention, while on the other, we saw a sustained treatment effect on MRI-detected joint-inflammation and related symptoms and functional impairments,” added Dr. Krijbolder.

To help understand this, the researchers performed a post hoc analysis in high-risk participants, comparing those who did not progress with those who did progress to arthritis. “Both progressors and nonprogressors showed a sustained treatment effect for pain and MRI-detected joint-inflammation, and in nonprogressors, there was almost a complete relief of pain and they nearly returned to the normal range of MRI-detected joint-inflammation as seen in symptom-free controls,” reported Dr. Krijbolder. 

“In those who progressed to arthritis, there was less pain and less MRI-detected joint inflammation in the treatment group, but also at the time when they developed clinical arthritis. So both progressors and nonprogressors benefit from treatment,” she noted.  

The number of serious adverse events was the same between the groups and adverse events were as expected from methotrexate.  

Dr. Krijbolder said, “the results are encouraging and will open up a new treatment landscape in pre-RA at the future, but at the moment it is too early to give recommendations for clinical practice; we definitely do not want to advocate the start of treatment in all at-risk individuals from now on.”

More research should unravel the mechanisms within the joint that contribute to the development of clinical arthritis and disease chronicity, she said. “If we understand these, we may be able to use more targeted interventions in the future and prevent the development of clinical arthritis all together.

“We are also looking forward to learning more about the long-term beneficial effects of this early treatment in our ongoing observational extension of the trial.” 

Hendrik Schulze-Koops, MD, of Ludwig-Maximilians-University of Munich, who moderated the session, asked Dr. Krijbolder, “As well as giving methotrexate to the participants in the treatment group, you also gave a single glucocorticoid injection at baseline, and a placebo injection in the placebo group, can you comment on that?”

EULAR

The biggest cancer conference in the world is back in person after 2 years online during the COVID pandemic. And it appears many are eager to attend the American Society of Clinical Oncology annual meeting in person now that they can.

By early May, ASCO already had 30,000 registrations, of which 80% were in person – there were 27,000 hotel reservations.

“That’s almost identical to where we were in terms of numbers in 2019 at the same point in time,” Julie Gralow, MD, chief medical officer at ASCO, said in an interview.

These figures, which are from May 11, are likely to increase. In past years, there has been an upswing in registrations right before the meeting starts.

The annual meeting begins on Friday, June 3, and runs until Tuesday, June 7. It will be held in Chicago, yet again, in the vast McCormick Place, sections of which were transformed into field hospital wards when the pandemic hit in 2020.

But the meeting will also continue to be transmitted virtually, as it has been for the past 2 years, for those not attending in person.

“I do think that the hybrid model will move forward,” Dr. Gralow said. “We can get a lot of attendees, especially from very distant places, who can’t travel, or can’t easily travel, and we have learned how to make that experience better for them as well.”

Attendees can also change their minds if, for example, rising numbers of COVID cases as the meeting nears put them off traveling. “We are allowing people to change to virtual. So I think there may be a little bit of that, depending on what happens to COVID in different parts of the world,” Dr. Gralow commented.

For those who do attend, the organization is “doing the best that we can to keep people safe,” said Dr. Gralow, who was previously a professor of global health and is now a breast medical oncologist and clinical trialist.

To attend in person, ASCO is mandating proof of vaccination (which in the United States means two doses of the COVID vaccine). “If you prove in advance that you are vaccinated, we will send you your badge, so you don’t have to stand in line,” she added.

“As far as masks go, we are saying right now that we are complying with Chicago’s rules, which mean there is no mandatory indoor masking,” she continued. “We are recommending masking because this is a group of physicians who treat immunocompromised patients. So we are recommending that.”

This stance has gotten some push-back on Twitter from both physicians and patient advocates, with some surprised that masking is not mandatory.

“I know that ‘mask-optional’ meetings mean most will omit masks; I literally just saw this at my last meeting as one of the few masked MDs,” commented radiation oncologist Fumiko Ladd Chino, MD. She appealed to the organizers with a plea: “There’s still time to change #ASCO22 policies. We’re in it for patient health.”

Patient advocate Manju George, MVSc, PhD, a rectal cancer survivor, was also campaigning for a change in policy by setting up a letter that others could sign, adding that “ASCO leadership is being flooded with pleads from concerned HCPs.”

When asked whether it was considering a change in mask policy, ASCO replied: “As far as health and safety go, the protocols we’ve put in place meet or exceed current [World Health Organization, [Centers for Disease Control and Prevention, and city of Chicago guidelines. ASCO is also closely coordinating with both the city and the convention center and we are actively monitoring local conditions.”

“To protect the health and safety of all meeting attendees, our protocols require attendees to be fully vaccinated and self-test negative for COVID-19 within 48 hours prior to their arrival at the meeting. In addition, we expect all attendees to be masked when indoors and are encouraging regular self-testing. We fully expect members of our community to do their part to help keep everyone safe, and we’re making it easy for attendees to comply with our policies by providing medical-grade masks as well as both rapid antigen and [polymerase chain reaction] COVID-19 tests,” the organization said.

There will also be a notification system so attendees can select how they identify for closeness, with red meaning stand back, no hugs, no handshakes; yellow signifying something more intermediate; and green signaling the person is okay with contact with a handshake or a hug. This system has already been used during smaller ASCO subspecialty meetings earlier this year, and feedback from delegates was positive, Dr. Gralow commented.
 

Advancing equitable care

The theme of the 2022 meeting, chosen by ASCO President Everett Vokes, MD, is advancing equitable cancer care through innovation.

It builds on the theme of equity from 2021, chosen by previous president Lori Pierce, MD, which was “Equity: Every Patient. Every Day. Everywhere.”

Some of this relates to disparities in equity, commented Dr. Gralow. This is the focus of a premeeting press briefing on May 26 that will highlight a few abstracts that focus on disparities and what can be done to address them. One study (abstract 6511) focuses on telemedicine, which was increasingly used during the pandemic, but the results show not all U.S. patient populations could access the specialty care they needed in this way.
 

De-escalation of therapy

De-escalation of therapy is another theme running through the meeting.

“There are some cancers where we have achieved such good outcomes that it is time to look at de-escalating therapy because we know that we are probably way overtreating a component of those patients. ... So we are looking at whether we can find subpopulations where we can back off on therapy,” commented Dr. Gralow.

One example is the LUMINA trial in breast cancer (abstract LBA501), which looked at omitting radiotherapy after surgery. “In standard practice we have already been doing this, not based on solid data, but based on an accumulation of retrospective analyses and similar evidence,” commented Dr. Gralow. This trial tested the approach prospectively, lowered the age range of patients, and better defined which patients were likely to benefit.

Another example is the DYNAMIC trial in colorectal cancer (abstract LBA-100), which looks at omitting chemotherapy based on levels of circulating tumor DNA after surgery. These patients had stage 2 disease and generally do very well with surgery and adjuvant chemotherapy, Dr. Gralow stated. This trial aims to find the subset of patients who could do just as well without the chemotherapy; it may also identify those patients at the other end of the scale, who perhaps need a bit more treatment, she added.
 

Spotlight on innovation

The focus on innovation includes exploring drugs developed outside the United States. One example is nimotuzumab, which is already approved in China for use in nasopharyngeal cancer but is also being explored in other cancer types. At ASCO, data will be presented in patients with KRAS wild-type pancreatic cancer (abstract 4011). This study, like the other trials with nimotuzumab, was conducted in China.

This brings up an important point about the data the Food and Drug Administration requires for new drug approvals, commented Dr. Gralow.

She noted that the FDA recently rejected an application for sintilimab, a drug also developed in China, on the basis that all trial data submitted for approval were from China. The agency said it would like to see multiregional clinical trials and trials that reflect the U.S. cancer population.
 

Advice for attendees

A large trial in a rare cancer promises to establish a new standard of care, where previously a number of different regimens have been used in various parts of the world, and even at different hospitals within the same country. These are the results from an international trial in children and adolescents/young adults with Ewing’s sarcoma (abstract LBA-02). “I have been told by experts in the field that these results will change practice ... [and] will have a global impact,” commented Dr. Gralow.

In addition to the scientific sessions that will see new data, there are a number of educational sessions that will tackle tricky issues that clinicians sometimes face. “Microaggressions, Bias, and Equity in the Workplace” will be discussed in one session, while another promises, “Strategies to Address Moral Distress in Clinicians: What Should We Do When We Don’t Know What to Do?”

There is also a special session featuring the “Cancer Groundshot: Addressing the Global and National Inequities in Cancer Care.” This is a move spearheaded by Bishal Gyawali, MD, PhD, from Brigham and Women’s Hospital, Boston, who was reacting to the lofty goals of the presidential Cancer Moonshot, including the aim of “ending cancer as we know it.” In a blog post in 2016 he suggested “forget the moon; let’s get back to blood and flesh reality on the ground ... [and] research that can be immediately applied to every global community.” He recounts the journey from ‘Blog Post to ASCO Session’ in a recent commentary.

Dr. Gyawali also has some advice for those attending the ASCO annual meeting: Reach out to people you respect, trust that connections will happen, scrutinize the data, listen critically for jargon, and perhaps most importantly, have fun.

“There’s more to life than your job,” he wrote. “Don’t stress. Think about the bigger picture. Think about your patients. And remember, life is beautiful, even when it feels like it isn’t.”

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

The biggest cancer conference in the world is back in person after 2 years online during the COVID pandemic. And it appears many are eager to attend the American Society of Clinical Oncology annual meeting in person now that they can.

By early May, ASCO already had 30,000 registrations, of which 80% were in person – there were 27,000 hotel reservations.

“That’s almost identical to where we were in terms of numbers in 2019 at the same point in time,” Julie Gralow, MD, chief medical officer at ASCO, said in an interview.

These figures, which are from May 11, are likely to increase. In past years, there has been an upswing in registrations right before the meeting starts.

The annual meeting begins on Friday, June 3, and runs until Tuesday, June 7. It will be held in Chicago, yet again, in the vast McCormick Place, sections of which were transformed into field hospital wards when the pandemic hit in 2020.

But the meeting will also continue to be transmitted virtually, as it has been for the past 2 years, for those not attending in person.

“I do think that the hybrid model will move forward,” Dr. Gralow said. “We can get a lot of attendees, especially from very distant places, who can’t travel, or can’t easily travel, and we have learned how to make that experience better for them as well.”

Attendees can also change their minds if, for example, rising numbers of COVID cases as the meeting nears put them off traveling. “We are allowing people to change to virtual. So I think there may be a little bit of that, depending on what happens to COVID in different parts of the world,” Dr. Gralow commented.

For those who do attend, the organization is “doing the best that we can to keep people safe,” said Dr. Gralow, who was previously a professor of global health and is now a breast medical oncologist and clinical trialist.

To attend in person, ASCO is mandating proof of vaccination (which in the United States means two doses of the COVID vaccine). “If you prove in advance that you are vaccinated, we will send you your badge, so you don’t have to stand in line,” she added.

“As far as masks go, we are saying right now that we are complying with Chicago’s rules, which mean there is no mandatory indoor masking,” she continued. “We are recommending masking because this is a group of physicians who treat immunocompromised patients. So we are recommending that.”

This stance has gotten some push-back on Twitter from both physicians and patient advocates, with some surprised that masking is not mandatory.

“I know that ‘mask-optional’ meetings mean most will omit masks; I literally just saw this at my last meeting as one of the few masked MDs,” commented radiation oncologist Fumiko Ladd Chino, MD. She appealed to the organizers with a plea: “There’s still time to change #ASCO22 policies. We’re in it for patient health.”

Patient advocate Manju George, MVSc, PhD, a rectal cancer survivor, was also campaigning for a change in policy by setting up a letter that others could sign, adding that “ASCO leadership is being flooded with pleads from concerned HCPs.”

When asked whether it was considering a change in mask policy, ASCO replied: “As far as health and safety go, the protocols we’ve put in place meet or exceed current [World Health Organization, [Centers for Disease Control and Prevention, and city of Chicago guidelines. ASCO is also closely coordinating with both the city and the convention center and we are actively monitoring local conditions.”

“To protect the health and safety of all meeting attendees, our protocols require attendees to be fully vaccinated and self-test negative for COVID-19 within 48 hours prior to their arrival at the meeting. In addition, we expect all attendees to be masked when indoors and are encouraging regular self-testing. We fully expect members of our community to do their part to help keep everyone safe, and we’re making it easy for attendees to comply with our policies by providing medical-grade masks as well as both rapid antigen and [polymerase chain reaction] COVID-19 tests,” the organization said.

There will also be a notification system so attendees can select how they identify for closeness, with red meaning stand back, no hugs, no handshakes; yellow signifying something more intermediate; and green signaling the person is okay with contact with a handshake or a hug. This system has already been used during smaller ASCO subspecialty meetings earlier this year, and feedback from delegates was positive, Dr. Gralow commented.
 

Advancing equitable care

The theme of the 2022 meeting, chosen by ASCO President Everett Vokes, MD, is advancing equitable cancer care through innovation.

It builds on the theme of equity from 2021, chosen by previous president Lori Pierce, MD, which was “Equity: Every Patient. Every Day. Everywhere.”

Some of this relates to disparities in equity, commented Dr. Gralow. This is the focus of a premeeting press briefing on May 26 that will highlight a few abstracts that focus on disparities and what can be done to address them. One study (abstract 6511) focuses on telemedicine, which was increasingly used during the pandemic, but the results show not all U.S. patient populations could access the specialty care they needed in this way.
 

De-escalation of therapy

De-escalation of therapy is another theme running through the meeting.

“There are some cancers where we have achieved such good outcomes that it is time to look at de-escalating therapy because we know that we are probably way overtreating a component of those patients. ... So we are looking at whether we can find subpopulations where we can back off on therapy,” commented Dr. Gralow.

One example is the LUMINA trial in breast cancer (abstract LBA501), which looked at omitting radiotherapy after surgery. “In standard practice we have already been doing this, not based on solid data, but based on an accumulation of retrospective analyses and similar evidence,” commented Dr. Gralow. This trial tested the approach prospectively, lowered the age range of patients, and better defined which patients were likely to benefit.

Another example is the DYNAMIC trial in colorectal cancer (abstract LBA-100), which looks at omitting chemotherapy based on levels of circulating tumor DNA after surgery. These patients had stage 2 disease and generally do very well with surgery and adjuvant chemotherapy, Dr. Gralow stated. This trial aims to find the subset of patients who could do just as well without the chemotherapy; it may also identify those patients at the other end of the scale, who perhaps need a bit more treatment, she added.
 

Spotlight on innovation

The focus on innovation includes exploring drugs developed outside the United States. One example is nimotuzumab, which is already approved in China for use in nasopharyngeal cancer but is also being explored in other cancer types. At ASCO, data will be presented in patients with KRAS wild-type pancreatic cancer (abstract 4011). This study, like the other trials with nimotuzumab, was conducted in China.

This brings up an important point about the data the Food and Drug Administration requires for new drug approvals, commented Dr. Gralow.

She noted that the FDA recently rejected an application for sintilimab, a drug also developed in China, on the basis that all trial data submitted for approval were from China. The agency said it would like to see multiregional clinical trials and trials that reflect the U.S. cancer population.
 

Advice for attendees

A large trial in a rare cancer promises to establish a new standard of care, where previously a number of different regimens have been used in various parts of the world, and even at different hospitals within the same country. These are the results from an international trial in children and adolescents/young adults with Ewing’s sarcoma (abstract LBA-02). “I have been told by experts in the field that these results will change practice ... [and] will have a global impact,” commented Dr. Gralow.

In addition to the scientific sessions that will see new data, there are a number of educational sessions that will tackle tricky issues that clinicians sometimes face. “Microaggressions, Bias, and Equity in the Workplace” will be discussed in one session, while another promises, “Strategies to Address Moral Distress in Clinicians: What Should We Do When We Don’t Know What to Do?”

There is also a special session featuring the “Cancer Groundshot: Addressing the Global and National Inequities in Cancer Care.” This is a move spearheaded by Bishal Gyawali, MD, PhD, from Brigham and Women’s Hospital, Boston, who was reacting to the lofty goals of the presidential Cancer Moonshot, including the aim of “ending cancer as we know it.” In a blog post in 2016 he suggested “forget the moon; let’s get back to blood and flesh reality on the ground ... [and] research that can be immediately applied to every global community.” He recounts the journey from ‘Blog Post to ASCO Session’ in a recent commentary.

Dr. Gyawali also has some advice for those attending the ASCO annual meeting: Reach out to people you respect, trust that connections will happen, scrutinize the data, listen critically for jargon, and perhaps most importantly, have fun.

“There’s more to life than your job,” he wrote. “Don’t stress. Think about the bigger picture. Think about your patients. And remember, life is beautiful, even when it feels like it isn’t.”

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

The biggest cancer conference in the world is back in person after 2 years online during the COVID pandemic. And it appears many are eager to attend the American Society of Clinical Oncology annual meeting in person now that they can.

By early May, ASCO already had 30,000 registrations, of which 80% were in person – there were 27,000 hotel reservations.

“That’s almost identical to where we were in terms of numbers in 2019 at the same point in time,” Julie Gralow, MD, chief medical officer at ASCO, said in an interview.

These figures, which are from May 11, are likely to increase. In past years, there has been an upswing in registrations right before the meeting starts.

The annual meeting begins on Friday, June 3, and runs until Tuesday, June 7. It will be held in Chicago, yet again, in the vast McCormick Place, sections of which were transformed into field hospital wards when the pandemic hit in 2020.

But the meeting will also continue to be transmitted virtually, as it has been for the past 2 years, for those not attending in person.

“I do think that the hybrid model will move forward,” Dr. Gralow said. “We can get a lot of attendees, especially from very distant places, who can’t travel, or can’t easily travel, and we have learned how to make that experience better for them as well.”

Attendees can also change their minds if, for example, rising numbers of COVID cases as the meeting nears put them off traveling. “We are allowing people to change to virtual. So I think there may be a little bit of that, depending on what happens to COVID in different parts of the world,” Dr. Gralow commented.

For those who do attend, the organization is “doing the best that we can to keep people safe,” said Dr. Gralow, who was previously a professor of global health and is now a breast medical oncologist and clinical trialist.

To attend in person, ASCO is mandating proof of vaccination (which in the United States means two doses of the COVID vaccine). “If you prove in advance that you are vaccinated, we will send you your badge, so you don’t have to stand in line,” she added.

“As far as masks go, we are saying right now that we are complying with Chicago’s rules, which mean there is no mandatory indoor masking,” she continued. “We are recommending masking because this is a group of physicians who treat immunocompromised patients. So we are recommending that.”

This stance has gotten some push-back on Twitter from both physicians and patient advocates, with some surprised that masking is not mandatory.

“I know that ‘mask-optional’ meetings mean most will omit masks; I literally just saw this at my last meeting as one of the few masked MDs,” commented radiation oncologist Fumiko Ladd Chino, MD. She appealed to the organizers with a plea: “There’s still time to change #ASCO22 policies. We’re in it for patient health.”

Patient advocate Manju George, MVSc, PhD, a rectal cancer survivor, was also campaigning for a change in policy by setting up a letter that others could sign, adding that “ASCO leadership is being flooded with pleads from concerned HCPs.”

When asked whether it was considering a change in mask policy, ASCO replied: “As far as health and safety go, the protocols we’ve put in place meet or exceed current [World Health Organization, [Centers for Disease Control and Prevention, and city of Chicago guidelines. ASCO is also closely coordinating with both the city and the convention center and we are actively monitoring local conditions.”

“To protect the health and safety of all meeting attendees, our protocols require attendees to be fully vaccinated and self-test negative for COVID-19 within 48 hours prior to their arrival at the meeting. In addition, we expect all attendees to be masked when indoors and are encouraging regular self-testing. We fully expect members of our community to do their part to help keep everyone safe, and we’re making it easy for attendees to comply with our policies by providing medical-grade masks as well as both rapid antigen and [polymerase chain reaction] COVID-19 tests,” the organization said.

There will also be a notification system so attendees can select how they identify for closeness, with red meaning stand back, no hugs, no handshakes; yellow signifying something more intermediate; and green signaling the person is okay with contact with a handshake or a hug. This system has already been used during smaller ASCO subspecialty meetings earlier this year, and feedback from delegates was positive, Dr. Gralow commented.
 

Advancing equitable care

The theme of the 2022 meeting, chosen by ASCO President Everett Vokes, MD, is advancing equitable cancer care through innovation.

It builds on the theme of equity from 2021, chosen by previous president Lori Pierce, MD, which was “Equity: Every Patient. Every Day. Everywhere.”

Some of this relates to disparities in equity, commented Dr. Gralow. This is the focus of a premeeting press briefing on May 26 that will highlight a few abstracts that focus on disparities and what can be done to address them. One study (abstract 6511) focuses on telemedicine, which was increasingly used during the pandemic, but the results show not all U.S. patient populations could access the specialty care they needed in this way.
 

De-escalation of therapy

De-escalation of therapy is another theme running through the meeting.

“There are some cancers where we have achieved such good outcomes that it is time to look at de-escalating therapy because we know that we are probably way overtreating a component of those patients. ... So we are looking at whether we can find subpopulations where we can back off on therapy,” commented Dr. Gralow.

One example is the LUMINA trial in breast cancer (abstract LBA501), which looked at omitting radiotherapy after surgery. “In standard practice we have already been doing this, not based on solid data, but based on an accumulation of retrospective analyses and similar evidence,” commented Dr. Gralow. This trial tested the approach prospectively, lowered the age range of patients, and better defined which patients were likely to benefit.

Another example is the DYNAMIC trial in colorectal cancer (abstract LBA-100), which looks at omitting chemotherapy based on levels of circulating tumor DNA after surgery. These patients had stage 2 disease and generally do very well with surgery and adjuvant chemotherapy, Dr. Gralow stated. This trial aims to find the subset of patients who could do just as well without the chemotherapy; it may also identify those patients at the other end of the scale, who perhaps need a bit more treatment, she added.
 

Spotlight on innovation

The focus on innovation includes exploring drugs developed outside the United States. One example is nimotuzumab, which is already approved in China for use in nasopharyngeal cancer but is also being explored in other cancer types. At ASCO, data will be presented in patients with KRAS wild-type pancreatic cancer (abstract 4011). This study, like the other trials with nimotuzumab, was conducted in China.

This brings up an important point about the data the Food and Drug Administration requires for new drug approvals, commented Dr. Gralow.

She noted that the FDA recently rejected an application for sintilimab, a drug also developed in China, on the basis that all trial data submitted for approval were from China. The agency said it would like to see multiregional clinical trials and trials that reflect the U.S. cancer population.
 

Advice for attendees

A large trial in a rare cancer promises to establish a new standard of care, where previously a number of different regimens have been used in various parts of the world, and even at different hospitals within the same country. These are the results from an international trial in children and adolescents/young adults with Ewing’s sarcoma (abstract LBA-02). “I have been told by experts in the field that these results will change practice ... [and] will have a global impact,” commented Dr. Gralow.

In addition to the scientific sessions that will see new data, there are a number of educational sessions that will tackle tricky issues that clinicians sometimes face. “Microaggressions, Bias, and Equity in the Workplace” will be discussed in one session, while another promises, “Strategies to Address Moral Distress in Clinicians: What Should We Do When We Don’t Know What to Do?”

There is also a special session featuring the “Cancer Groundshot: Addressing the Global and National Inequities in Cancer Care.” This is a move spearheaded by Bishal Gyawali, MD, PhD, from Brigham and Women’s Hospital, Boston, who was reacting to the lofty goals of the presidential Cancer Moonshot, including the aim of “ending cancer as we know it.” In a blog post in 2016 he suggested “forget the moon; let’s get back to blood and flesh reality on the ground ... [and] research that can be immediately applied to every global community.” He recounts the journey from ‘Blog Post to ASCO Session’ in a recent commentary.

Dr. Gyawali also has some advice for those attending the ASCO annual meeting: Reach out to people you respect, trust that connections will happen, scrutinize the data, listen critically for jargon, and perhaps most importantly, have fun.

“There’s more to life than your job,” he wrote. “Don’t stress. Think about the bigger picture. Think about your patients. And remember, life is beautiful, even when it feels like it isn’t.”

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

CHICAGO – The COVID pandemic pushed telemedicine forward as a safe, accessible, and more widely reimbursed approach to care delivery for patients with cancer, but uptake of telemedicine was plagued by inequities, a retrospective study suggests.

Before March 2020, only a very small percentage of patients with cancer used telemedicine services.

By November 2021, nearly 16% of patients initiating cancer treatment were using this approach.

However, certain groups were less likely to use telemedicine, in particular, patients who were Black, uninsured, did not live in cities, and were less affluent, noted lead author Jenny S. Guadamuz, PhD, a quantitative scientist at Flatiron Health and a postdoctoral research associate at the University of Southern California, Los Angeles.

The results are concerning because they suggest that telemedicine expansion could widen cancer care disparities, Dr. Guadamuz said. Previous studies found racial disparities in care access and outcomes early on in the pandemic.

“These findings are critically important considering recent efforts to make coverage of telemedicine services permanent, instead of tied to the [Health and Human Services] public health emergency declaration,” she said. “There are also efforts to increase reimbursement rates for telemedicine services by Medicare, several Medicaid programs, and private insurers.”

This study was highlighted at a press briefing held in advance of the American Society of Clinical Oncology annual meeting, where it will be presented at a poster session (abstract 6511).

ASCO President Everett E. Vokes, MD, said telemedicine is “an important tool to communicate with patients” but that it is important to consider the “digital divide.”

He also emphasized the need “to expand and learn to use telehealth not in a crisis but as part of our regular care moving forward.” In July 2021, as telemedicine services were expanding, ASCO released practice recommendations specific to telehealth and oncology.

“Telemedicine can improve access to timely cancer care, but, as this study points out, telemedicine must be available equitably, so that every patient can access the care they need and deserve,” he said in a press statement.
 

Study details

For the study, Dr. Guadamuz and colleagues assessed telemedicine uptake by nearly 27,000 patients in a Flatiron electronic health record–derived deidentified database of patients who initiated treatment for any of 21 common cancers at about 280 community oncology clinics between March 2020 and November 2021.

They found that Black patients were significantly less likely than were White patients to use telemedicine (13.2% vs. 15.6%; odds ratio [OR], 0.82), as were patients without documented insurance, compared with those who were well insured (11.6% vs. 16.4%; OR, 0.68).

Those in rural and suburban areas were less likely than were those in urban areas to use telemedicine (9.7% and 13.0% vs. 17.7%; ORs, 0.50 and 0.69, respectively), and those in less affluent vs. more affluent areas were also less likely to use telemedicine (10.6% vs. 23.6%, OR, 0.39).

Dr. Guadamuz noted that the differences remained statistically significant after adjustment for clinical characteristics and that racial inequities were seen across cancer types and over time.

Future work should assess other potential characteristics associated with telemedicine inequities, evaluate whether health care delivered via telemedicine is of similar quality as in-person services, and determine the types of practice that are providing telemedicine more equitably to their patients, she concluded.

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

CHICAGO – The COVID pandemic pushed telemedicine forward as a safe, accessible, and more widely reimbursed approach to care delivery for patients with cancer, but uptake of telemedicine was plagued by inequities, a retrospective study suggests.

Before March 2020, only a very small percentage of patients with cancer used telemedicine services.

By November 2021, nearly 16% of patients initiating cancer treatment were using this approach.

However, certain groups were less likely to use telemedicine, in particular, patients who were Black, uninsured, did not live in cities, and were less affluent, noted lead author Jenny S. Guadamuz, PhD, a quantitative scientist at Flatiron Health and a postdoctoral research associate at the University of Southern California, Los Angeles.

The results are concerning because they suggest that telemedicine expansion could widen cancer care disparities, Dr. Guadamuz said. Previous studies found racial disparities in care access and outcomes early on in the pandemic.

“These findings are critically important considering recent efforts to make coverage of telemedicine services permanent, instead of tied to the [Health and Human Services] public health emergency declaration,” she said. “There are also efforts to increase reimbursement rates for telemedicine services by Medicare, several Medicaid programs, and private insurers.”

This study was highlighted at a press briefing held in advance of the American Society of Clinical Oncology annual meeting, where it will be presented at a poster session (abstract 6511).

ASCO President Everett E. Vokes, MD, said telemedicine is “an important tool to communicate with patients” but that it is important to consider the “digital divide.”

He also emphasized the need “to expand and learn to use telehealth not in a crisis but as part of our regular care moving forward.” In July 2021, as telemedicine services were expanding, ASCO released practice recommendations specific to telehealth and oncology.

“Telemedicine can improve access to timely cancer care, but, as this study points out, telemedicine must be available equitably, so that every patient can access the care they need and deserve,” he said in a press statement.
 

Study details

For the study, Dr. Guadamuz and colleagues assessed telemedicine uptake by nearly 27,000 patients in a Flatiron electronic health record–derived deidentified database of patients who initiated treatment for any of 21 common cancers at about 280 community oncology clinics between March 2020 and November 2021.

They found that Black patients were significantly less likely than were White patients to use telemedicine (13.2% vs. 15.6%; odds ratio [OR], 0.82), as were patients without documented insurance, compared with those who were well insured (11.6% vs. 16.4%; OR, 0.68).

Those in rural and suburban areas were less likely than were those in urban areas to use telemedicine (9.7% and 13.0% vs. 17.7%; ORs, 0.50 and 0.69, respectively), and those in less affluent vs. more affluent areas were also less likely to use telemedicine (10.6% vs. 23.6%, OR, 0.39).

Dr. Guadamuz noted that the differences remained statistically significant after adjustment for clinical characteristics and that racial inequities were seen across cancer types and over time.

Future work should assess other potential characteristics associated with telemedicine inequities, evaluate whether health care delivered via telemedicine is of similar quality as in-person services, and determine the types of practice that are providing telemedicine more equitably to their patients, she concluded.

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

CHICAGO – The COVID pandemic pushed telemedicine forward as a safe, accessible, and more widely reimbursed approach to care delivery for patients with cancer, but uptake of telemedicine was plagued by inequities, a retrospective study suggests.

Before March 2020, only a very small percentage of patients with cancer used telemedicine services.

By November 2021, nearly 16% of patients initiating cancer treatment were using this approach.

However, certain groups were less likely to use telemedicine, in particular, patients who were Black, uninsured, did not live in cities, and were less affluent, noted lead author Jenny S. Guadamuz, PhD, a quantitative scientist at Flatiron Health and a postdoctoral research associate at the University of Southern California, Los Angeles.

The results are concerning because they suggest that telemedicine expansion could widen cancer care disparities, Dr. Guadamuz said. Previous studies found racial disparities in care access and outcomes early on in the pandemic.

“These findings are critically important considering recent efforts to make coverage of telemedicine services permanent, instead of tied to the [Health and Human Services] public health emergency declaration,” she said. “There are also efforts to increase reimbursement rates for telemedicine services by Medicare, several Medicaid programs, and private insurers.”

This study was highlighted at a press briefing held in advance of the American Society of Clinical Oncology annual meeting, where it will be presented at a poster session (abstract 6511).

ASCO President Everett E. Vokes, MD, said telemedicine is “an important tool to communicate with patients” but that it is important to consider the “digital divide.”

He also emphasized the need “to expand and learn to use telehealth not in a crisis but as part of our regular care moving forward.” In July 2021, as telemedicine services were expanding, ASCO released practice recommendations specific to telehealth and oncology.

“Telemedicine can improve access to timely cancer care, but, as this study points out, telemedicine must be available equitably, so that every patient can access the care they need and deserve,” he said in a press statement.
 

Study details

For the study, Dr. Guadamuz and colleagues assessed telemedicine uptake by nearly 27,000 patients in a Flatiron electronic health record–derived deidentified database of patients who initiated treatment for any of 21 common cancers at about 280 community oncology clinics between March 2020 and November 2021.

They found that Black patients were significantly less likely than were White patients to use telemedicine (13.2% vs. 15.6%; odds ratio [OR], 0.82), as were patients without documented insurance, compared with those who were well insured (11.6% vs. 16.4%; OR, 0.68).

Those in rural and suburban areas were less likely than were those in urban areas to use telemedicine (9.7% and 13.0% vs. 17.7%; ORs, 0.50 and 0.69, respectively), and those in less affluent vs. more affluent areas were also less likely to use telemedicine (10.6% vs. 23.6%, OR, 0.39).

Dr. Guadamuz noted that the differences remained statistically significant after adjustment for clinical characteristics and that racial inequities were seen across cancer types and over time.

Future work should assess other potential characteristics associated with telemedicine inequities, evaluate whether health care delivered via telemedicine is of similar quality as in-person services, and determine the types of practice that are providing telemedicine more equitably to their patients, she concluded.

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

Increasing social services spending by 10% led to improved survival for non-Hispanic Black adults with cancer, according to new research.

Five-year overall survival increased among non-Hispanic Black patients by 2.02% in conjunction with a 10% increase in spending. In addition, there was a decrease in racial disparities in survival between non-Hispanic Black patients and White patients for many types of cancers.

However, public welfare spending had no real impact on the overall 5-year survival for the entire cohort (0.25 % per 10% increase in spending; P = .78) or for non-Hispanic White patients (0.52% per 10% increase in spending, P = .58).

“We know from prior research that outcomes are worse for minorities,” said lead author Justin Michael Barnes, MD, from the department of radiation oncology at Washington University in St. Louis, Mo. “It’s thought that some of the differences are related to impaired access to health care for minorities, which is related to social determinants of health. This includes socioeconomic factors, educational attainment, place of residence, as well as environmental stressors.

“Our data show that greater state welfare expenditures were associated with greater 5-year survival among Black patients and decreased Black–White disparities,” said Dr. Barnes. “I think these data are thought provoking, but they certainly aren’t the end. I see these data as a proof-of-concept project.”

Dr. Barnes reported the findings at a press conference held in advance of the annual meeting of the American Society of Clinical Oncology, during which the study will be presented (Abstract 6509).
 

Improved 5-year survival in Black patients

For the study, Dr. Barnes and colleagues evaluated the association of 5-year overall survival and public welfare spending in 2,925,550 individuals aged 18 years and older who were diagnosed with cancer during the period 2007-2016. The cohort was drawn from the Surveillance, Epidemiology, and End Results Program. In addition, annual state spending data were obtained from the U.S. Census Bureau. The team examined survival outcomes by race and ethnicity as well as by cancer site. The investigators accounted for factors such as age, sex, metropolitan residence, state, county-level income and education, insurance status, cancer site, stage at diagnosis, and year of diagnosis.

Much of public welfare spending was related to Medicaid but also included programs that provide subsidy assistance for individuals, such as Supplemental Security Income.

As compared with White patients, the 5-year overall survival rate was 10.8% lower among non-Hispanic Black patients. But there was a 4.46% (P for interaction <.001) narrowing of the 5-year overall survival disparity in non-Hispanic Black patients in comparison with White patients per 10% increase in spending, or a 42% closure of the 10.8% disparity.

Regarding specific cancer types, increased public welfare spending was associated with a narrowing of the 5-year overall survival disparity between Black patients and non-Hispanic White patients for the following cancers: breast (a 6.15% survival increase for Black patients led to a 39% closing of the disparity), cervix (a 11.9% survival increase led to a 46% closing of the disparity), colorectum (a 4.42% survival increase led to a 48% closing of the disparity), head and neck (a 9.41% survival increase led to a 38% closing of the disparity), liver (a 7.02% survival increase led to a 49% closing of the disparity), ovary (an 8.95% survival increase led to a 41% closing of the disparity), bladder (an 8.18% survival increase led to a 44% closing of the disparity), and uterus (a 14.1% survival increase led to a 40% closing of the disparity).

“Some type of public welfare seems to be helping improve oncologic outcomes for some of our most socioeconomically at-risk patients, but we don’t know the specifics,” Dr. Barnes concluded. “Additional work is needed to identify the most influential public health expenditures. If we can do this, we can more rigorously evaluate state-level policies and their association with cancer outcomes.”
 

Public welfare improves outcomes

Weighing in on the data, Sarah P. Cate, MD, director, Special Surveillance and Breast Program, Mount Sinai Health System, New York, noted that racial disparities have been identified in many areas of health care and with respect to many diseases. “In the world of oncology, time to diagnosis and treatment significantly impacts overall survival,” she told this news organization. “Many studies are currently underway to investigate why certain ethnic groups have worse cancer outcomes.”

This study is important, she noted, in that it “highlights a discrete source of correcting these disparities in a large group of patients. Obviously there are multiple barriers to care, but increased public welfare spending in oncology should decrease some of these disparities.”

Julie R. Gralow, MD, ASCO’s chief medical officer and executive vice president, commented that it is known that state public welfare spending can mitigate structural racism and at least partially address social determinants of health, such as financial stability, education, place of residence, and insurance status. “This research found that states that increased their public health spending improved overall survival in Black patients with a variety of solid tumors and also resulted in a decrease in racial disparities in survival,” she said. “This important data provides clear support for the benefits of investment in public welfare spending at the state level, including Medicaid expansion.”

The study did not receive funding. Dr. Barnes and Dr. Cate have disclosed no relevant financial relationships. Dr. Gralow has relationships with Genentech, AstraZeneca Hexal, Puma BioTechnology, Roche, Novartis, Seagen, and Genomic Health.

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

Increasing social services spending by 10% led to improved survival for non-Hispanic Black adults with cancer, according to new research.

Five-year overall survival increased among non-Hispanic Black patients by 2.02% in conjunction with a 10% increase in spending. In addition, there was a decrease in racial disparities in survival between non-Hispanic Black patients and White patients for many types of cancers.

However, public welfare spending had no real impact on the overall 5-year survival for the entire cohort (0.25 % per 10% increase in spending; P = .78) or for non-Hispanic White patients (0.52% per 10% increase in spending, P = .58).

“We know from prior research that outcomes are worse for minorities,” said lead author Justin Michael Barnes, MD, from the department of radiation oncology at Washington University in St. Louis, Mo. “It’s thought that some of the differences are related to impaired access to health care for minorities, which is related to social determinants of health. This includes socioeconomic factors, educational attainment, place of residence, as well as environmental stressors.

“Our data show that greater state welfare expenditures were associated with greater 5-year survival among Black patients and decreased Black–White disparities,” said Dr. Barnes. “I think these data are thought provoking, but they certainly aren’t the end. I see these data as a proof-of-concept project.”

Dr. Barnes reported the findings at a press conference held in advance of the annual meeting of the American Society of Clinical Oncology, during which the study will be presented (Abstract 6509).
 

Improved 5-year survival in Black patients

For the study, Dr. Barnes and colleagues evaluated the association of 5-year overall survival and public welfare spending in 2,925,550 individuals aged 18 years and older who were diagnosed with cancer during the period 2007-2016. The cohort was drawn from the Surveillance, Epidemiology, and End Results Program. In addition, annual state spending data were obtained from the U.S. Census Bureau. The team examined survival outcomes by race and ethnicity as well as by cancer site. The investigators accounted for factors such as age, sex, metropolitan residence, state, county-level income and education, insurance status, cancer site, stage at diagnosis, and year of diagnosis.

Much of public welfare spending was related to Medicaid but also included programs that provide subsidy assistance for individuals, such as Supplemental Security Income.

As compared with White patients, the 5-year overall survival rate was 10.8% lower among non-Hispanic Black patients. But there was a 4.46% (P for interaction <.001) narrowing of the 5-year overall survival disparity in non-Hispanic Black patients in comparison with White patients per 10% increase in spending, or a 42% closure of the 10.8% disparity.

Regarding specific cancer types, increased public welfare spending was associated with a narrowing of the 5-year overall survival disparity between Black patients and non-Hispanic White patients for the following cancers: breast (a 6.15% survival increase for Black patients led to a 39% closing of the disparity), cervix (a 11.9% survival increase led to a 46% closing of the disparity), colorectum (a 4.42% survival increase led to a 48% closing of the disparity), head and neck (a 9.41% survival increase led to a 38% closing of the disparity), liver (a 7.02% survival increase led to a 49% closing of the disparity), ovary (an 8.95% survival increase led to a 41% closing of the disparity), bladder (an 8.18% survival increase led to a 44% closing of the disparity), and uterus (a 14.1% survival increase led to a 40% closing of the disparity).

“Some type of public welfare seems to be helping improve oncologic outcomes for some of our most socioeconomically at-risk patients, but we don’t know the specifics,” Dr. Barnes concluded. “Additional work is needed to identify the most influential public health expenditures. If we can do this, we can more rigorously evaluate state-level policies and their association with cancer outcomes.”
 

Public welfare improves outcomes

Weighing in on the data, Sarah P. Cate, MD, director, Special Surveillance and Breast Program, Mount Sinai Health System, New York, noted that racial disparities have been identified in many areas of health care and with respect to many diseases. “In the world of oncology, time to diagnosis and treatment significantly impacts overall survival,” she told this news organization. “Many studies are currently underway to investigate why certain ethnic groups have worse cancer outcomes.”

This study is important, she noted, in that it “highlights a discrete source of correcting these disparities in a large group of patients. Obviously there are multiple barriers to care, but increased public welfare spending in oncology should decrease some of these disparities.”

Julie R. Gralow, MD, ASCO’s chief medical officer and executive vice president, commented that it is known that state public welfare spending can mitigate structural racism and at least partially address social determinants of health, such as financial stability, education, place of residence, and insurance status. “This research found that states that increased their public health spending improved overall survival in Black patients with a variety of solid tumors and also resulted in a decrease in racial disparities in survival,” she said. “This important data provides clear support for the benefits of investment in public welfare spending at the state level, including Medicaid expansion.”

The study did not receive funding. Dr. Barnes and Dr. Cate have disclosed no relevant financial relationships. Dr. Gralow has relationships with Genentech, AstraZeneca Hexal, Puma BioTechnology, Roche, Novartis, Seagen, and Genomic Health.

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

Increasing social services spending by 10% led to improved survival for non-Hispanic Black adults with cancer, according to new research.

Five-year overall survival increased among non-Hispanic Black patients by 2.02% in conjunction with a 10% increase in spending. In addition, there was a decrease in racial disparities in survival between non-Hispanic Black patients and White patients for many types of cancers.

However, public welfare spending had no real impact on the overall 5-year survival for the entire cohort (0.25 % per 10% increase in spending; P = .78) or for non-Hispanic White patients (0.52% per 10% increase in spending, P = .58).

“We know from prior research that outcomes are worse for minorities,” said lead author Justin Michael Barnes, MD, from the department of radiation oncology at Washington University in St. Louis, Mo. “It’s thought that some of the differences are related to impaired access to health care for minorities, which is related to social determinants of health. This includes socioeconomic factors, educational attainment, place of residence, as well as environmental stressors.

“Our data show that greater state welfare expenditures were associated with greater 5-year survival among Black patients and decreased Black–White disparities,” said Dr. Barnes. “I think these data are thought provoking, but they certainly aren’t the end. I see these data as a proof-of-concept project.”

Dr. Barnes reported the findings at a press conference held in advance of the annual meeting of the American Society of Clinical Oncology, during which the study will be presented (Abstract 6509).
 

Improved 5-year survival in Black patients

For the study, Dr. Barnes and colleagues evaluated the association of 5-year overall survival and public welfare spending in 2,925,550 individuals aged 18 years and older who were diagnosed with cancer during the period 2007-2016. The cohort was drawn from the Surveillance, Epidemiology, and End Results Program. In addition, annual state spending data were obtained from the U.S. Census Bureau. The team examined survival outcomes by race and ethnicity as well as by cancer site. The investigators accounted for factors such as age, sex, metropolitan residence, state, county-level income and education, insurance status, cancer site, stage at diagnosis, and year of diagnosis.

Much of public welfare spending was related to Medicaid but also included programs that provide subsidy assistance for individuals, such as Supplemental Security Income.

As compared with White patients, the 5-year overall survival rate was 10.8% lower among non-Hispanic Black patients. But there was a 4.46% (P for interaction <.001) narrowing of the 5-year overall survival disparity in non-Hispanic Black patients in comparison with White patients per 10% increase in spending, or a 42% closure of the 10.8% disparity.

Regarding specific cancer types, increased public welfare spending was associated with a narrowing of the 5-year overall survival disparity between Black patients and non-Hispanic White patients for the following cancers: breast (a 6.15% survival increase for Black patients led to a 39% closing of the disparity), cervix (a 11.9% survival increase led to a 46% closing of the disparity), colorectum (a 4.42% survival increase led to a 48% closing of the disparity), head and neck (a 9.41% survival increase led to a 38% closing of the disparity), liver (a 7.02% survival increase led to a 49% closing of the disparity), ovary (an 8.95% survival increase led to a 41% closing of the disparity), bladder (an 8.18% survival increase led to a 44% closing of the disparity), and uterus (a 14.1% survival increase led to a 40% closing of the disparity).

“Some type of public welfare seems to be helping improve oncologic outcomes for some of our most socioeconomically at-risk patients, but we don’t know the specifics,” Dr. Barnes concluded. “Additional work is needed to identify the most influential public health expenditures. If we can do this, we can more rigorously evaluate state-level policies and their association with cancer outcomes.”
 

Public welfare improves outcomes

Weighing in on the data, Sarah P. Cate, MD, director, Special Surveillance and Breast Program, Mount Sinai Health System, New York, noted that racial disparities have been identified in many areas of health care and with respect to many diseases. “In the world of oncology, time to diagnosis and treatment significantly impacts overall survival,” she told this news organization. “Many studies are currently underway to investigate why certain ethnic groups have worse cancer outcomes.”

This study is important, she noted, in that it “highlights a discrete source of correcting these disparities in a large group of patients. Obviously there are multiple barriers to care, but increased public welfare spending in oncology should decrease some of these disparities.”

Julie R. Gralow, MD, ASCO’s chief medical officer and executive vice president, commented that it is known that state public welfare spending can mitigate structural racism and at least partially address social determinants of health, such as financial stability, education, place of residence, and insurance status. “This research found that states that increased their public health spending improved overall survival in Black patients with a variety of solid tumors and also resulted in a decrease in racial disparities in survival,” she said. “This important data provides clear support for the benefits of investment in public welfare spending at the state level, including Medicaid expansion.”

The study did not receive funding. Dr. Barnes and Dr. Cate have disclosed no relevant financial relationships. Dr. Gralow has relationships with Genentech, AstraZeneca Hexal, Puma BioTechnology, Roche, Novartis, Seagen, and Genomic Health.

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

NEW ORLEANS – Patients with new-onset schizophrenia often ask psychiatrist Stephen R. Marder, MD, whether they’ll need to be on medications forever to treat the disorder. Now, he said, research is showing that the answer isn’t always yes.

In many cases, “it’s an open question” whether lifelong medical treatment is needed, said Dr. Marder, a professor at the Semel Institute for Neuroscience and Human Behavior at the University of California, Los Angeles, who spoke in a presentation about schizophrenia treatment at the annual meeting of the American Psychiatric Association.

According to Dr. Marder, research about relapses suggests that there may be a subpopulation of patients who can come off antipsychotics and remain in remission or partial remission. “The problem,” he said, “is that group is very hard to identify.”

Indeed, he highlighted a 2017 study that suggested perhaps 20% of patients with schizophrenia may remain stable over the long term after stopping medication. The study noted choosing the best candidates isn’t simple, as “we do not have clinical measures or biomarkers that allow us to identify them prospectively. Because relapses and delays in the treatment of psychosis have been associated with poorer outcomes, there may be risk associated with withholding or discontinuing medication.”

There are more complications. There’s some evidence that antipsychotic drugs reduce brain volume, Dr. Marder said. But on the other hand, each psychotic episode can itself be harmful. “There is clear evidence that for each psychotic episode, they can take longer to improve, and they need higher doses.”

What to do? “My suggestion for most patients is to keep them on a relatively mild dose of an antipsychotic,” Dr. Marder said, “then to have a gradual decrease in the dose. I’ve done it in many patients.”

Which drug is best over the long term – oral or long-acting injectable antipsychotics? “It’s a hard question to answer because if you rely on randomized clinical trials – with patients who signed consent and are willing to be in a study like that – the subjects are sometimes not the ones who benefit the most from the long-acting drugs. So for many of the randomized clinical trials, the data was incomplete, and it was hard to make the case.”

But if you combine meta-analyses and cohort studies, as a 2021 study did, “you come up with a really clear answer: LAIs [long-acting injectables] are superior. They lead to a superior outcomes when it comes to rehospitalization and psychotic relapse,” Dr. Marder said.

That study reported that “LAIs were more beneficial than oral antipsychotics in 60 [18.3%] of 328 comparisons, not different in 252 [76.8%] comparisons, and less beneficial in 16 [4.9%] comparisons.”
 

More schizophrenia treatment pearls

People with schizophrenia – including those who aren’t on medication – face three times the risk of developing type 2 diabetes as the general population, “maybe because there’s a shared genetic risk for both disorders,” Dr. Marder said. “Those of you who have a lot of schizophrenia patients, I suspect you’re monitoring if they’re treating their type 2 diabetes and their obesity.”

Which antipsychotics are the best option for these patients? He highlighted a 2020 systematic review and meta-analysis that offers helpful insight into connections between 18 drugs and factors like weight and cholesterol.

Dr. Marder added that “if somebody has an elevation in their triglycerides or [hemoglobin] A1c in one single fasting blood glucose during the first 6 weeks of treatment, even if they haven’t been rated, it suggests that they’re developing insulin resistance.” At that point, he said, it’s a good idea to reconsider the medication choice.

Also, he said, keep in mind that “there’s substantial evidence that metformin is the appropriate treatment for patients who begin to demonstrate insulin resistance. It also works sometimes for weight loss.”

Exercise in people with schizophrenia can pay important dividends. A 2016 meta-analysis suggests that “not only does exercise for people with schizophrenia lead to better cardiovascular health, it’s good for the brain and improves cognitive functioning,” Dr. Marder said. “It’s not easy sometimes to get people with schizophrenia to exercise, but it’s many times worth the effort.”

Dr. Marder reported consulting for Boehringer Ingelheim, Lundbeck, Otsuka, Roche, Neurocrine, Sunovion, Newron, Merck, and Biogen; editor of UptoDate and Schizophrenia Bulletin Open; and research support from Boehringer Ingelheim.
 

NEW ORLEANS – Patients with new-onset schizophrenia often ask psychiatrist Stephen R. Marder, MD, whether they’ll need to be on medications forever to treat the disorder. Now, he said, research is showing that the answer isn’t always yes.

In many cases, “it’s an open question” whether lifelong medical treatment is needed, said Dr. Marder, a professor at the Semel Institute for Neuroscience and Human Behavior at the University of California, Los Angeles, who spoke in a presentation about schizophrenia treatment at the annual meeting of the American Psychiatric Association.

According to Dr. Marder, research about relapses suggests that there may be a subpopulation of patients who can come off antipsychotics and remain in remission or partial remission. “The problem,” he said, “is that group is very hard to identify.”

Indeed, he highlighted a 2017 study that suggested perhaps 20% of patients with schizophrenia may remain stable over the long term after stopping medication. The study noted choosing the best candidates isn’t simple, as “we do not have clinical measures or biomarkers that allow us to identify them prospectively. Because relapses and delays in the treatment of psychosis have been associated with poorer outcomes, there may be risk associated with withholding or discontinuing medication.”

There are more complications. There’s some evidence that antipsychotic drugs reduce brain volume, Dr. Marder said. But on the other hand, each psychotic episode can itself be harmful. “There is clear evidence that for each psychotic episode, they can take longer to improve, and they need higher doses.”

What to do? “My suggestion for most patients is to keep them on a relatively mild dose of an antipsychotic,” Dr. Marder said, “then to have a gradual decrease in the dose. I’ve done it in many patients.”

Which drug is best over the long term – oral or long-acting injectable antipsychotics? “It’s a hard question to answer because if you rely on randomized clinical trials – with patients who signed consent and are willing to be in a study like that – the subjects are sometimes not the ones who benefit the most from the long-acting drugs. So for many of the randomized clinical trials, the data was incomplete, and it was hard to make the case.”

But if you combine meta-analyses and cohort studies, as a 2021 study did, “you come up with a really clear answer: LAIs [long-acting injectables] are superior. They lead to a superior outcomes when it comes to rehospitalization and psychotic relapse,” Dr. Marder said.

That study reported that “LAIs were more beneficial than oral antipsychotics in 60 [18.3%] of 328 comparisons, not different in 252 [76.8%] comparisons, and less beneficial in 16 [4.9%] comparisons.”
 

More schizophrenia treatment pearls

People with schizophrenia – including those who aren’t on medication – face three times the risk of developing type 2 diabetes as the general population, “maybe because there’s a shared genetic risk for both disorders,” Dr. Marder said. “Those of you who have a lot of schizophrenia patients, I suspect you’re monitoring if they’re treating their type 2 diabetes and their obesity.”

Which antipsychotics are the best option for these patients? He highlighted a 2020 systematic review and meta-analysis that offers helpful insight into connections between 18 drugs and factors like weight and cholesterol.

Dr. Marder added that “if somebody has an elevation in their triglycerides or [hemoglobin] A1c in one single fasting blood glucose during the first 6 weeks of treatment, even if they haven’t been rated, it suggests that they’re developing insulin resistance.” At that point, he said, it’s a good idea to reconsider the medication choice.

Also, he said, keep in mind that “there’s substantial evidence that metformin is the appropriate treatment for patients who begin to demonstrate insulin resistance. It also works sometimes for weight loss.”

Exercise in people with schizophrenia can pay important dividends. A 2016 meta-analysis suggests that “not only does exercise for people with schizophrenia lead to better cardiovascular health, it’s good for the brain and improves cognitive functioning,” Dr. Marder said. “It’s not easy sometimes to get people with schizophrenia to exercise, but it’s many times worth the effort.”

Dr. Marder reported consulting for Boehringer Ingelheim, Lundbeck, Otsuka, Roche, Neurocrine, Sunovion, Newron, Merck, and Biogen; editor of UptoDate and Schizophrenia Bulletin Open; and research support from Boehringer Ingelheim.
 

NEW ORLEANS – Patients with new-onset schizophrenia often ask psychiatrist Stephen R. Marder, MD, whether they’ll need to be on medications forever to treat the disorder. Now, he said, research is showing that the answer isn’t always yes.

In many cases, “it’s an open question” whether lifelong medical treatment is needed, said Dr. Marder, a professor at the Semel Institute for Neuroscience and Human Behavior at the University of California, Los Angeles, who spoke in a presentation about schizophrenia treatment at the annual meeting of the American Psychiatric Association.

According to Dr. Marder, research about relapses suggests that there may be a subpopulation of patients who can come off antipsychotics and remain in remission or partial remission. “The problem,” he said, “is that group is very hard to identify.”

Indeed, he highlighted a 2017 study that suggested perhaps 20% of patients with schizophrenia may remain stable over the long term after stopping medication. The study noted choosing the best candidates isn’t simple, as “we do not have clinical measures or biomarkers that allow us to identify them prospectively. Because relapses and delays in the treatment of psychosis have been associated with poorer outcomes, there may be risk associated with withholding or discontinuing medication.”

There are more complications. There’s some evidence that antipsychotic drugs reduce brain volume, Dr. Marder said. But on the other hand, each psychotic episode can itself be harmful. “There is clear evidence that for each psychotic episode, they can take longer to improve, and they need higher doses.”

What to do? “My suggestion for most patients is to keep them on a relatively mild dose of an antipsychotic,” Dr. Marder said, “then to have a gradual decrease in the dose. I’ve done it in many patients.”

Which drug is best over the long term – oral or long-acting injectable antipsychotics? “It’s a hard question to answer because if you rely on randomized clinical trials – with patients who signed consent and are willing to be in a study like that – the subjects are sometimes not the ones who benefit the most from the long-acting drugs. So for many of the randomized clinical trials, the data was incomplete, and it was hard to make the case.”

But if you combine meta-analyses and cohort studies, as a 2021 study did, “you come up with a really clear answer: LAIs [long-acting injectables] are superior. They lead to a superior outcomes when it comes to rehospitalization and psychotic relapse,” Dr. Marder said.

That study reported that “LAIs were more beneficial than oral antipsychotics in 60 [18.3%] of 328 comparisons, not different in 252 [76.8%] comparisons, and less beneficial in 16 [4.9%] comparisons.”
 

More schizophrenia treatment pearls

People with schizophrenia – including those who aren’t on medication – face three times the risk of developing type 2 diabetes as the general population, “maybe because there’s a shared genetic risk for both disorders,” Dr. Marder said. “Those of you who have a lot of schizophrenia patients, I suspect you’re monitoring if they’re treating their type 2 diabetes and their obesity.”

Which antipsychotics are the best option for these patients? He highlighted a 2020 systematic review and meta-analysis that offers helpful insight into connections between 18 drugs and factors like weight and cholesterol.

Dr. Marder added that “if somebody has an elevation in their triglycerides or [hemoglobin] A1c in one single fasting blood glucose during the first 6 weeks of treatment, even if they haven’t been rated, it suggests that they’re developing insulin resistance.” At that point, he said, it’s a good idea to reconsider the medication choice.

Also, he said, keep in mind that “there’s substantial evidence that metformin is the appropriate treatment for patients who begin to demonstrate insulin resistance. It also works sometimes for weight loss.”

Exercise in people with schizophrenia can pay important dividends. A 2016 meta-analysis suggests that “not only does exercise for people with schizophrenia lead to better cardiovascular health, it’s good for the brain and improves cognitive functioning,” Dr. Marder said. “It’s not easy sometimes to get people with schizophrenia to exercise, but it’s many times worth the effort.”

Dr. Marder reported consulting for Boehringer Ingelheim, Lundbeck, Otsuka, Roche, Neurocrine, Sunovion, Newron, Merck, and Biogen; editor of UptoDate and Schizophrenia Bulletin Open; and research support from Boehringer Ingelheim.
 

Scientists have confirmed that a receptor long suspected to be linked to lupus is, in fact, a major driver of the autoimmune disease for at least some subset of patients, according to a study recently published in Nature. Researchers discovered the crucial role of toll-like receptor 7 (TLR7) because of a rare mutation in a pediatric patient with systemic lupus erythematosus (SLE) who had a particularly severe presentation.

“Sometimes it’s valuable to find these very severe cases where there is one mutation that has a strong effect because if we understand how those mutations work, the lessons we learn can generally tell us about disease mechanisms,” explained senior author Carola G. Vinuesa, MD, PhD, of the Centre for Personalised Immunology at Australian National University in Canberra and The Francis Crick Institute in London.

courtesy Michael Bowles

“It’s quite difficult to find one mutation that can alone cause the entire disease,” Dr. Vinuesa added, but what it reveals about how the disease develops may lead to more effective targeted therapies than the immune suppressants most often used to treat lupus currently.

The mutation they found was in the TLR7 gene that encodes the TLR7 protein. TLR7 is a receptor used by immune cells to identify viral RNA so they can fight off viral infections, including COVID-19. But if the body’s own genetic material binds to TLR7 in susceptible individuals, it can lead to an overproduction of type 1 interferons, which are cytokines that trigger or exacerbate the immune reactions that lead to lupus symptoms. The TLR7 gene occurs on the X chromosome, which may explain men’s greater susceptibility to COVID-19 and the greater incidence of lupus in women, who have two X chromosomes instead of the one that men have, Dr. Vinuesa said.

Previous research had shown an association between TLR7 and lupus, but this new study is the first to provide definitive proof that a TLR7 mutation by itself can directly cause human lupus. After discovering the variant in the patient, Dr. Vinuesa’s team used CRISPR to edit the genome of a mouse model and introduce the same mutation the patient had. “And they developed full-blown disease, just with this one single base-pair substitution – 1 letter in the 3 billion letters of the genome,” Dr. Vinuesa said. “It tells us that these receptors are not just there to recognize viral RNA, that in some circumstances, they could be triggered by our own nucleic acids.”
 

One pathway among many?

The finding does not mean that every lupus patient has this mutation, which remains rare, but suggests that overactivity in this receptor already reported in many lupus patients may be causally related to disease, Dr. Vinuesa said.

Noa Schwartz, MD, an assistant professor of medicine at Albert Einstein College of Medicine, New York, and director of the Montefiore-Einstein Institute for Lupus Care and Research, said in an interview that lupus is thought of as a syndrome, a collection of different but similar diseases that don’t necessarily have a single cause. But finding a single gene mutation that could potentially lead to lupus is an important piece of the puzzle, said Dr. Schwartz, who was not involved in the study. Based on past research in mice models, “we’ve hypothesized that TLR7 is important in humans as well, but this is the last nail in the coffin.”

One of the key questions this finding has prompted is how many patients’ disease results from TLR7 activity. “Because of the evidence from Ignacio Sanz’s group demonstrating TLR7 overactivity in a significant fraction of SLE patients, we believe that it is probably going to be pretty important,” Dr. Vinuesa said. “My feeling is that it is going to be quite a central pathway in lupus pathogenesis, if not the central pathway.”

Dr. Schwartz was more cautious, noting that it is probably important for a subset of patients but may “have a limited effect on the general lupus population.” While it’s not yet clear how large that subset is, it is possible it will include people with cutaneous lupus, those with primarily dermatologic symptoms.

“Hydroxychloroquine works particularly well for cutaneous manifestations of lupus, and one of the ways that works is by inhibiting TLR7 and TLR9, so this [finding] potentially matters for skin disease and lupus, but it’s very early,” Dr. Schwartz said. If it does turn out that TLR7 activity is particularly associated with cutaneous lupus, it may mean therapies with fewer side effects, she said. “Specifically for cutaneous lupus, the concept of suppressing the entire immune system for skin illness sometimes feels, especially to patients, very extreme, so they are [patients] who directed therapy could be so especially relevant for.”

Laura Lewandowski, MD, an assistant clinical investigator and head of the lupus genomics and global health disparities unit at the National Institute of Arthritis and Musculoskeletal and Skin Disease, described this study as particularly remarkable in the way it revealed the mechanism leading to lupus symptoms.

“As whole genome sequencing becomes faster and less expensive, more and more people are employing them in their studies,” most of which report changes in certain genes, Dr. Lewandowski said. “One of the most striking findings about this paper was that they took it to the next step and did a really elegant study on the exact way this gain-of-function TLR7 mutation leads to the autoimmunity that we see in lupus. The detail of mechanism in this paper is really unique.”
 

A step toward personalized medicine

Dr. Lewandowski is part of a team that recently presented a poster related to genomic sequencing in lupus patients at the annual meeting of the Childhood Arthritis and Rheumatology Research Alliance. Her study reported on the whole genome sequencing of patients with childhood-onset SLE who were already enrolled in the CARRA Lupus Registry. Children with lupus may be more likely than adults to have rare genetic variants, so a registry of childhood-onset SLE patients with fully sequenced genomes provides an opportunity to look for single-gene mutations specifically linked to lupus, said Dr. Lewandowski, who has recently begun a research collaboration with Dr. Vinuesa.

“As we move forward and more and more patients are included in these studies, we will understand a little bit more about the genetic architecture of patients who have rare variations leading to disease, or even common variations,” Dr. Lewandowski said about the intersection between her research and Dr. Vinuesa’s study. The more data they gather, the more they can explore the possible interactions of rare and common variants that play a role in SLE as well as what environmental triggers, such as viral infection or pollution exposure, might tip someone into having an autoimmune disease. “We’re just starting to peek under the hood,” Dr. Lewandowski said.

If further research can reveal the relative contribution of genetics to the disease and what those genetic drivers are, it may allow for greater precision in therapies and “ultimately improve the quality of life for our patients, the ultimate goal of all of these studies,” Dr. Lewandowski said.

Drugs that target TLR7 already exist for other indications, and clinical trials have already begun to see if these TLR7 inhibitors benefit lupus patients.

“If the clinical trials work, this will be quite a nice, targeted therapy with potentially much less side effects than other therapies on the market at the moment,” Dr. Vinuesa said. She is cautiously hopeful, saying it’s likely to make an impact on lupus treatment, but it’s too early to say precisely how much.

“It allows us to understand the disease mechanisms a little bit better and to try and assess what percentage of patients’ disease can be explained by overactivity in this receptor,” Dr. Vinuesa said. She thinks it’s possible that TLR7 over activation may be relevant to other systemic autoimmune diseases as well, such as Sjögren’s syndrome, rheumatoid arthritis, or juvenile dermatomyositis, but it will take more studies to find out.

“Right now, we have medicines that broadly inhibit the immune system and aren’t as targeted, but we have a lot more clinical and scientific work to do before we move this field forward for lupus patients,” Dr. Lewandowski said. “This is one case where they were able to find the exact molecular defect, and it’s not the end of the path of precision medicine — it’s the beginning.”

Dr. Vinuesa, Dr. Schwartz, and Dr. Lewandowski reported no disclosures.

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

Scientists have confirmed that a receptor long suspected to be linked to lupus is, in fact, a major driver of the autoimmune disease for at least some subset of patients, according to a study recently published in Nature. Researchers discovered the crucial role of toll-like receptor 7 (TLR7) because of a rare mutation in a pediatric patient with systemic lupus erythematosus (SLE) who had a particularly severe presentation.

“Sometimes it’s valuable to find these very severe cases where there is one mutation that has a strong effect because if we understand how those mutations work, the lessons we learn can generally tell us about disease mechanisms,” explained senior author Carola G. Vinuesa, MD, PhD, of the Centre for Personalised Immunology at Australian National University in Canberra and The Francis Crick Institute in London.

courtesy Michael Bowles

“It’s quite difficult to find one mutation that can alone cause the entire disease,” Dr. Vinuesa added, but what it reveals about how the disease develops may lead to more effective targeted therapies than the immune suppressants most often used to treat lupus currently.

The mutation they found was in the TLR7 gene that encodes the TLR7 protein. TLR7 is a receptor used by immune cells to identify viral RNA so they can fight off viral infections, including COVID-19. But if the body’s own genetic material binds to TLR7 in susceptible individuals, it can lead to an overproduction of type 1 interferons, which are cytokines that trigger or exacerbate the immune reactions that lead to lupus symptoms. The TLR7 gene occurs on the X chromosome, which may explain men’s greater susceptibility to COVID-19 and the greater incidence of lupus in women, who have two X chromosomes instead of the one that men have, Dr. Vinuesa said.

Previous research had shown an association between TLR7 and lupus, but this new study is the first to provide definitive proof that a TLR7 mutation by itself can directly cause human lupus. After discovering the variant in the patient, Dr. Vinuesa’s team used CRISPR to edit the genome of a mouse model and introduce the same mutation the patient had. “And they developed full-blown disease, just with this one single base-pair substitution – 1 letter in the 3 billion letters of the genome,” Dr. Vinuesa said. “It tells us that these receptors are not just there to recognize viral RNA, that in some circumstances, they could be triggered by our own nucleic acids.”
 

One pathway among many?

The finding does not mean that every lupus patient has this mutation, which remains rare, but suggests that overactivity in this receptor already reported in many lupus patients may be causally related to disease, Dr. Vinuesa said.

Noa Schwartz, MD, an assistant professor of medicine at Albert Einstein College of Medicine, New York, and director of the Montefiore-Einstein Institute for Lupus Care and Research, said in an interview that lupus is thought of as a syndrome, a collection of different but similar diseases that don’t necessarily have a single cause. But finding a single gene mutation that could potentially lead to lupus is an important piece of the puzzle, said Dr. Schwartz, who was not involved in the study. Based on past research in mice models, “we’ve hypothesized that TLR7 is important in humans as well, but this is the last nail in the coffin.”

One of the key questions this finding has prompted is how many patients’ disease results from TLR7 activity. “Because of the evidence from Ignacio Sanz’s group demonstrating TLR7 overactivity in a significant fraction of SLE patients, we believe that it is probably going to be pretty important,” Dr. Vinuesa said. “My feeling is that it is going to be quite a central pathway in lupus pathogenesis, if not the central pathway.”

Dr. Schwartz was more cautious, noting that it is probably important for a subset of patients but may “have a limited effect on the general lupus population.” While it’s not yet clear how large that subset is, it is possible it will include people with cutaneous lupus, those with primarily dermatologic symptoms.

“Hydroxychloroquine works particularly well for cutaneous manifestations of lupus, and one of the ways that works is by inhibiting TLR7 and TLR9, so this [finding] potentially matters for skin disease and lupus, but it’s very early,” Dr. Schwartz said. If it does turn out that TLR7 activity is particularly associated with cutaneous lupus, it may mean therapies with fewer side effects, she said. “Specifically for cutaneous lupus, the concept of suppressing the entire immune system for skin illness sometimes feels, especially to patients, very extreme, so they are [patients] who directed therapy could be so especially relevant for.”

Laura Lewandowski, MD, an assistant clinical investigator and head of the lupus genomics and global health disparities unit at the National Institute of Arthritis and Musculoskeletal and Skin Disease, described this study as particularly remarkable in the way it revealed the mechanism leading to lupus symptoms.

“As whole genome sequencing becomes faster and less expensive, more and more people are employing them in their studies,” most of which report changes in certain genes, Dr. Lewandowski said. “One of the most striking findings about this paper was that they took it to the next step and did a really elegant study on the exact way this gain-of-function TLR7 mutation leads to the autoimmunity that we see in lupus. The detail of mechanism in this paper is really unique.”
 

A step toward personalized medicine

Dr. Lewandowski is part of a team that recently presented a poster related to genomic sequencing in lupus patients at the annual meeting of the Childhood Arthritis and Rheumatology Research Alliance. Her study reported on the whole genome sequencing of patients with childhood-onset SLE who were already enrolled in the CARRA Lupus Registry. Children with lupus may be more likely than adults to have rare genetic variants, so a registry of childhood-onset SLE patients with fully sequenced genomes provides an opportunity to look for single-gene mutations specifically linked to lupus, said Dr. Lewandowski, who has recently begun a research collaboration with Dr. Vinuesa.

“As we move forward and more and more patients are included in these studies, we will understand a little bit more about the genetic architecture of patients who have rare variations leading to disease, or even common variations,” Dr. Lewandowski said about the intersection between her research and Dr. Vinuesa’s study. The more data they gather, the more they can explore the possible interactions of rare and common variants that play a role in SLE as well as what environmental triggers, such as viral infection or pollution exposure, might tip someone into having an autoimmune disease. “We’re just starting to peek under the hood,” Dr. Lewandowski said.

If further research can reveal the relative contribution of genetics to the disease and what those genetic drivers are, it may allow for greater precision in therapies and “ultimately improve the quality of life for our patients, the ultimate goal of all of these studies,” Dr. Lewandowski said.

Drugs that target TLR7 already exist for other indications, and clinical trials have already begun to see if these TLR7 inhibitors benefit lupus patients.

“If the clinical trials work, this will be quite a nice, targeted therapy with potentially much less side effects than other therapies on the market at the moment,” Dr. Vinuesa said. She is cautiously hopeful, saying it’s likely to make an impact on lupus treatment, but it’s too early to say precisely how much.

“It allows us to understand the disease mechanisms a little bit better and to try and assess what percentage of patients’ disease can be explained by overactivity in this receptor,” Dr. Vinuesa said. She thinks it’s possible that TLR7 over activation may be relevant to other systemic autoimmune diseases as well, such as Sjögren’s syndrome, rheumatoid arthritis, or juvenile dermatomyositis, but it will take more studies to find out.

“Right now, we have medicines that broadly inhibit the immune system and aren’t as targeted, but we have a lot more clinical and scientific work to do before we move this field forward for lupus patients,” Dr. Lewandowski said. “This is one case where they were able to find the exact molecular defect, and it’s not the end of the path of precision medicine — it’s the beginning.”

Dr. Vinuesa, Dr. Schwartz, and Dr. Lewandowski reported no disclosures.

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

Scientists have confirmed that a receptor long suspected to be linked to lupus is, in fact, a major driver of the autoimmune disease for at least some subset of patients, according to a study recently published in Nature. Researchers discovered the crucial role of toll-like receptor 7 (TLR7) because of a rare mutation in a pediatric patient with systemic lupus erythematosus (SLE) who had a particularly severe presentation.

“Sometimes it’s valuable to find these very severe cases where there is one mutation that has a strong effect because if we understand how those mutations work, the lessons we learn can generally tell us about disease mechanisms,” explained senior author Carola G. Vinuesa, MD, PhD, of the Centre for Personalised Immunology at Australian National University in Canberra and The Francis Crick Institute in London.

courtesy Michael Bowles

“It’s quite difficult to find one mutation that can alone cause the entire disease,” Dr. Vinuesa added, but what it reveals about how the disease develops may lead to more effective targeted therapies than the immune suppressants most often used to treat lupus currently.

The mutation they found was in the TLR7 gene that encodes the TLR7 protein. TLR7 is a receptor used by immune cells to identify viral RNA so they can fight off viral infections, including COVID-19. But if the body’s own genetic material binds to TLR7 in susceptible individuals, it can lead to an overproduction of type 1 interferons, which are cytokines that trigger or exacerbate the immune reactions that lead to lupus symptoms. The TLR7 gene occurs on the X chromosome, which may explain men’s greater susceptibility to COVID-19 and the greater incidence of lupus in women, who have two X chromosomes instead of the one that men have, Dr. Vinuesa said.

Previous research had shown an association between TLR7 and lupus, but this new study is the first to provide definitive proof that a TLR7 mutation by itself can directly cause human lupus. After discovering the variant in the patient, Dr. Vinuesa’s team used CRISPR to edit the genome of a mouse model and introduce the same mutation the patient had. “And they developed full-blown disease, just with this one single base-pair substitution – 1 letter in the 3 billion letters of the genome,” Dr. Vinuesa said. “It tells us that these receptors are not just there to recognize viral RNA, that in some circumstances, they could be triggered by our own nucleic acids.”
 

One pathway among many?

The finding does not mean that every lupus patient has this mutation, which remains rare, but suggests that overactivity in this receptor already reported in many lupus patients may be causally related to disease, Dr. Vinuesa said.

Noa Schwartz, MD, an assistant professor of medicine at Albert Einstein College of Medicine, New York, and director of the Montefiore-Einstein Institute for Lupus Care and Research, said in an interview that lupus is thought of as a syndrome, a collection of different but similar diseases that don’t necessarily have a single cause. But finding a single gene mutation that could potentially lead to lupus is an important piece of the puzzle, said Dr. Schwartz, who was not involved in the study. Based on past research in mice models, “we’ve hypothesized that TLR7 is important in humans as well, but this is the last nail in the coffin.”

One of the key questions this finding has prompted is how many patients’ disease results from TLR7 activity. “Because of the evidence from Ignacio Sanz’s group demonstrating TLR7 overactivity in a significant fraction of SLE patients, we believe that it is probably going to be pretty important,” Dr. Vinuesa said. “My feeling is that it is going to be quite a central pathway in lupus pathogenesis, if not the central pathway.”

Dr. Schwartz was more cautious, noting that it is probably important for a subset of patients but may “have a limited effect on the general lupus population.” While it’s not yet clear how large that subset is, it is possible it will include people with cutaneous lupus, those with primarily dermatologic symptoms.

“Hydroxychloroquine works particularly well for cutaneous manifestations of lupus, and one of the ways that works is by inhibiting TLR7 and TLR9, so this [finding] potentially matters for skin disease and lupus, but it’s very early,” Dr. Schwartz said. If it does turn out that TLR7 activity is particularly associated with cutaneous lupus, it may mean therapies with fewer side effects, she said. “Specifically for cutaneous lupus, the concept of suppressing the entire immune system for skin illness sometimes feels, especially to patients, very extreme, so they are [patients] who directed therapy could be so especially relevant for.”

Laura Lewandowski, MD, an assistant clinical investigator and head of the lupus genomics and global health disparities unit at the National Institute of Arthritis and Musculoskeletal and Skin Disease, described this study as particularly remarkable in the way it revealed the mechanism leading to lupus symptoms.

“As whole genome sequencing becomes faster and less expensive, more and more people are employing them in their studies,” most of which report changes in certain genes, Dr. Lewandowski said. “One of the most striking findings about this paper was that they took it to the next step and did a really elegant study on the exact way this gain-of-function TLR7 mutation leads to the autoimmunity that we see in lupus. The detail of mechanism in this paper is really unique.”
 

A step toward personalized medicine

Dr. Lewandowski is part of a team that recently presented a poster related to genomic sequencing in lupus patients at the annual meeting of the Childhood Arthritis and Rheumatology Research Alliance. Her study reported on the whole genome sequencing of patients with childhood-onset SLE who were already enrolled in the CARRA Lupus Registry. Children with lupus may be more likely than adults to have rare genetic variants, so a registry of childhood-onset SLE patients with fully sequenced genomes provides an opportunity to look for single-gene mutations specifically linked to lupus, said Dr. Lewandowski, who has recently begun a research collaboration with Dr. Vinuesa.

“As we move forward and more and more patients are included in these studies, we will understand a little bit more about the genetic architecture of patients who have rare variations leading to disease, or even common variations,” Dr. Lewandowski said about the intersection between her research and Dr. Vinuesa’s study. The more data they gather, the more they can explore the possible interactions of rare and common variants that play a role in SLE as well as what environmental triggers, such as viral infection or pollution exposure, might tip someone into having an autoimmune disease. “We’re just starting to peek under the hood,” Dr. Lewandowski said.

If further research can reveal the relative contribution of genetics to the disease and what those genetic drivers are, it may allow for greater precision in therapies and “ultimately improve the quality of life for our patients, the ultimate goal of all of these studies,” Dr. Lewandowski said.

Drugs that target TLR7 already exist for other indications, and clinical trials have already begun to see if these TLR7 inhibitors benefit lupus patients.

“If the clinical trials work, this will be quite a nice, targeted therapy with potentially much less side effects than other therapies on the market at the moment,” Dr. Vinuesa said. She is cautiously hopeful, saying it’s likely to make an impact on lupus treatment, but it’s too early to say precisely how much.

“It allows us to understand the disease mechanisms a little bit better and to try and assess what percentage of patients’ disease can be explained by overactivity in this receptor,” Dr. Vinuesa said. She thinks it’s possible that TLR7 over activation may be relevant to other systemic autoimmune diseases as well, such as Sjögren’s syndrome, rheumatoid arthritis, or juvenile dermatomyositis, but it will take more studies to find out.

“Right now, we have medicines that broadly inhibit the immune system and aren’t as targeted, but we have a lot more clinical and scientific work to do before we move this field forward for lupus patients,” Dr. Lewandowski said. “This is one case where they were able to find the exact molecular defect, and it’s not the end of the path of precision medicine — it’s the beginning.”

Dr. Vinuesa, Dr. Schwartz, and Dr. Lewandowski reported no disclosures.

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