Lung Cancer

GENEVA – Pembrolizumab monotherapy is as safe and effective in elderly patients with non–small cell lung cancer (NSCLC) as it is younger patients, according to investigators.

Will Pass/MDedge News

They reached this conclusion after analyzing pooled data from 264 patients 75 years or older involved in the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 phase 3 trials, reported lead author Kaname Nosaki, MD, of the National Hospital Organization Kyushu Cancer Center in Fukuoka, Japan, and his colleagues.

“Approximately 70% of newly-diagnosed NSCLC cases occur in the elderly, and more than half are locally advanced or metastatic,” the investigators noted in their abstract. Despite this, patients aged 75 years or older are underrepresented in clinical trials, Dr. Nosaki said during a presentation at the European Lung Cancer Conference.

All patients in the three KEYNOTE trials had PD-L1 positive NSCLC, with variations between studies with respect to PD-L1 tumor proportion score (TPS) and dosing regimen. While KEYNOTE-010 and KEYNOTE-042 involved patients with a TPS of at least 1%, KEYNOTE-024 raised the minimum TPS threshold to 50%. KEYNOTE-010 pembrolizumab dose was set at 2 mg/kg or 10 mg/kg, compared with the other two studies, which set a consistent dose of the checkpoint inhibitor at 200 mg.

As with younger patients, higher TPS expression generally predicted better outcomes. Independent of treatment line, elderly patients with a TPS of at least 50% had a hazard ratio of 0.40 in favor of pembrolizumab over chemotherapy, compared with all PD-L1-positive elderly patients, who had a hazard ratio of 0.76.

Generally, adverse events were comparable between age groups, with 68% of elderly patients experiencing at least one treatment-related adverse event, compared with 65% of younger patients. Grade 3 or 4 adverse events were slightly more common among elderly patients than younger patients (23% vs. 16%), with a mild concomitant increase in adverse event–related treatment discontinuations (11% vs. 7%). The rate of immune-mediated adverse events and infusion reactions, however, held steady regardless of age group, occurring in one out of four patients (25%). In contrast with these similarities, almost all elderly patients receiving chemotherapy (94%) had adverse events, compared with two out of three elderly patients receiving pembrolizumab. Rates of grade 3 or 4 adverse events also favored pembrolizumab over chemotherapy (23% vs. 59%).

“These data support the use of pembrolizumab monotherapy in elderly patients more than 75 years old with advanced PD-L1-expressing NSCLC,” Dr. Nosaki concluded.

Invited discussant Sanjay Popat, PhD, of Imperial College London, described the knowledge gap addressed by this study. “If we look at U.S. statistics, we see that lung cancer is the leading cause of death for patients above the age of 80, both for males and females,” Dr. Popat said at the meeting, presented by the European Society for Medical Oncology. “The real question is should this group of patients be getting any form of checkpoint inhibitors at all, and if so, what is the benefit to risk ratio?

Will Pass/MDedge News

“Our patients are getting older, we’re all living slightly longer, and the burden of geriatric oncology is predicted to rise quite markedly with age, so it’s important to get a good feel for how we should be managing our senior population,” he added.

According to Dr. Popat, elderly patients naturally undergo immune senescence, meaning the immune system deteriorates with age, and this phenomenon could theoretically mitigate efficacy of immunotherapies; however, previous studies have not found decreased efficacy among elderly patients. Still, some “so-called elderly population subsets we’ve been analyzing are actually around the median age [of diagnosis with NSCLC],” Dr. Popat said, noting that among these studies, those with wider age ranges offer more reliable data.

“Today we looked at the novel cutoff, this 75-year group cutoff, which I very much welcome,” Dr. Popat said, “because this much more reflects what we see in routine clinical care.”

Regarding the results, Dr. Popat suggested that chemotherapy leads to an “excess of mortality” among elderly patients, “likely due to toxicities,” thereby explaining part of the relative advantage provided by pembrolizumab. Considering these findings in addition to previous experiences with pembrolizumab in the elderly, Dr. Popat said that “if you choose your patient population well, fit patients well enough to go to a trial, they don’t have an excess of toxicities regardless of their age.”

Taken as a whole, the present analysis supports the routine use of pembrolizumab in fit, elderly patients, Dr. Popat said.

The study was funded by MSD. The investigators reported financial relationships with AstraZeneca, Eli Lilly, Taiho, Chugai, and others.

SOURCE: Nosaki et al. ELCC 2019. Abstract 103O_PR.

GENEVA – Pembrolizumab monotherapy is as safe and effective in elderly patients with non–small cell lung cancer (NSCLC) as it is younger patients, according to investigators.

Will Pass/MDedge News

They reached this conclusion after analyzing pooled data from 264 patients 75 years or older involved in the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 phase 3 trials, reported lead author Kaname Nosaki, MD, of the National Hospital Organization Kyushu Cancer Center in Fukuoka, Japan, and his colleagues.

“Approximately 70% of newly-diagnosed NSCLC cases occur in the elderly, and more than half are locally advanced or metastatic,” the investigators noted in their abstract. Despite this, patients aged 75 years or older are underrepresented in clinical trials, Dr. Nosaki said during a presentation at the European Lung Cancer Conference.

All patients in the three KEYNOTE trials had PD-L1 positive NSCLC, with variations between studies with respect to PD-L1 tumor proportion score (TPS) and dosing regimen. While KEYNOTE-010 and KEYNOTE-042 involved patients with a TPS of at least 1%, KEYNOTE-024 raised the minimum TPS threshold to 50%. KEYNOTE-010 pembrolizumab dose was set at 2 mg/kg or 10 mg/kg, compared with the other two studies, which set a consistent dose of the checkpoint inhibitor at 200 mg.

As with younger patients, higher TPS expression generally predicted better outcomes. Independent of treatment line, elderly patients with a TPS of at least 50% had a hazard ratio of 0.40 in favor of pembrolizumab over chemotherapy, compared with all PD-L1-positive elderly patients, who had a hazard ratio of 0.76.

Generally, adverse events were comparable between age groups, with 68% of elderly patients experiencing at least one treatment-related adverse event, compared with 65% of younger patients. Grade 3 or 4 adverse events were slightly more common among elderly patients than younger patients (23% vs. 16%), with a mild concomitant increase in adverse event–related treatment discontinuations (11% vs. 7%). The rate of immune-mediated adverse events and infusion reactions, however, held steady regardless of age group, occurring in one out of four patients (25%). In contrast with these similarities, almost all elderly patients receiving chemotherapy (94%) had adverse events, compared with two out of three elderly patients receiving pembrolizumab. Rates of grade 3 or 4 adverse events also favored pembrolizumab over chemotherapy (23% vs. 59%).

“These data support the use of pembrolizumab monotherapy in elderly patients more than 75 years old with advanced PD-L1-expressing NSCLC,” Dr. Nosaki concluded.

Invited discussant Sanjay Popat, PhD, of Imperial College London, described the knowledge gap addressed by this study. “If we look at U.S. statistics, we see that lung cancer is the leading cause of death for patients above the age of 80, both for males and females,” Dr. Popat said at the meeting, presented by the European Society for Medical Oncology. “The real question is should this group of patients be getting any form of checkpoint inhibitors at all, and if so, what is the benefit to risk ratio?

Will Pass/MDedge News

“Our patients are getting older, we’re all living slightly longer, and the burden of geriatric oncology is predicted to rise quite markedly with age, so it’s important to get a good feel for how we should be managing our senior population,” he added.

According to Dr. Popat, elderly patients naturally undergo immune senescence, meaning the immune system deteriorates with age, and this phenomenon could theoretically mitigate efficacy of immunotherapies; however, previous studies have not found decreased efficacy among elderly patients. Still, some “so-called elderly population subsets we’ve been analyzing are actually around the median age [of diagnosis with NSCLC],” Dr. Popat said, noting that among these studies, those with wider age ranges offer more reliable data.

“Today we looked at the novel cutoff, this 75-year group cutoff, which I very much welcome,” Dr. Popat said, “because this much more reflects what we see in routine clinical care.”

Regarding the results, Dr. Popat suggested that chemotherapy leads to an “excess of mortality” among elderly patients, “likely due to toxicities,” thereby explaining part of the relative advantage provided by pembrolizumab. Considering these findings in addition to previous experiences with pembrolizumab in the elderly, Dr. Popat said that “if you choose your patient population well, fit patients well enough to go to a trial, they don’t have an excess of toxicities regardless of their age.”

Taken as a whole, the present analysis supports the routine use of pembrolizumab in fit, elderly patients, Dr. Popat said.

The study was funded by MSD. The investigators reported financial relationships with AstraZeneca, Eli Lilly, Taiho, Chugai, and others.

SOURCE: Nosaki et al. ELCC 2019. Abstract 103O_PR.

GENEVA – Pembrolizumab monotherapy is as safe and effective in elderly patients with non–small cell lung cancer (NSCLC) as it is younger patients, according to investigators.

Will Pass/MDedge News

They reached this conclusion after analyzing pooled data from 264 patients 75 years or older involved in the KEYNOTE-010, KEYNOTE-024, and KEYNOTE-042 phase 3 trials, reported lead author Kaname Nosaki, MD, of the National Hospital Organization Kyushu Cancer Center in Fukuoka, Japan, and his colleagues.

“Approximately 70% of newly-diagnosed NSCLC cases occur in the elderly, and more than half are locally advanced or metastatic,” the investigators noted in their abstract. Despite this, patients aged 75 years or older are underrepresented in clinical trials, Dr. Nosaki said during a presentation at the European Lung Cancer Conference.

All patients in the three KEYNOTE trials had PD-L1 positive NSCLC, with variations between studies with respect to PD-L1 tumor proportion score (TPS) and dosing regimen. While KEYNOTE-010 and KEYNOTE-042 involved patients with a TPS of at least 1%, KEYNOTE-024 raised the minimum TPS threshold to 50%. KEYNOTE-010 pembrolizumab dose was set at 2 mg/kg or 10 mg/kg, compared with the other two studies, which set a consistent dose of the checkpoint inhibitor at 200 mg.

As with younger patients, higher TPS expression generally predicted better outcomes. Independent of treatment line, elderly patients with a TPS of at least 50% had a hazard ratio of 0.40 in favor of pembrolizumab over chemotherapy, compared with all PD-L1-positive elderly patients, who had a hazard ratio of 0.76.

Generally, adverse events were comparable between age groups, with 68% of elderly patients experiencing at least one treatment-related adverse event, compared with 65% of younger patients. Grade 3 or 4 adverse events were slightly more common among elderly patients than younger patients (23% vs. 16%), with a mild concomitant increase in adverse event–related treatment discontinuations (11% vs. 7%). The rate of immune-mediated adverse events and infusion reactions, however, held steady regardless of age group, occurring in one out of four patients (25%). In contrast with these similarities, almost all elderly patients receiving chemotherapy (94%) had adverse events, compared with two out of three elderly patients receiving pembrolizumab. Rates of grade 3 or 4 adverse events also favored pembrolizumab over chemotherapy (23% vs. 59%).

“These data support the use of pembrolizumab monotherapy in elderly patients more than 75 years old with advanced PD-L1-expressing NSCLC,” Dr. Nosaki concluded.

Invited discussant Sanjay Popat, PhD, of Imperial College London, described the knowledge gap addressed by this study. “If we look at U.S. statistics, we see that lung cancer is the leading cause of death for patients above the age of 80, both for males and females,” Dr. Popat said at the meeting, presented by the European Society for Medical Oncology. “The real question is should this group of patients be getting any form of checkpoint inhibitors at all, and if so, what is the benefit to risk ratio?

Will Pass/MDedge News

“Our patients are getting older, we’re all living slightly longer, and the burden of geriatric oncology is predicted to rise quite markedly with age, so it’s important to get a good feel for how we should be managing our senior population,” he added.

According to Dr. Popat, elderly patients naturally undergo immune senescence, meaning the immune system deteriorates with age, and this phenomenon could theoretically mitigate efficacy of immunotherapies; however, previous studies have not found decreased efficacy among elderly patients. Still, some “so-called elderly population subsets we’ve been analyzing are actually around the median age [of diagnosis with NSCLC],” Dr. Popat said, noting that among these studies, those with wider age ranges offer more reliable data.

“Today we looked at the novel cutoff, this 75-year group cutoff, which I very much welcome,” Dr. Popat said, “because this much more reflects what we see in routine clinical care.”

Regarding the results, Dr. Popat suggested that chemotherapy leads to an “excess of mortality” among elderly patients, “likely due to toxicities,” thereby explaining part of the relative advantage provided by pembrolizumab. Considering these findings in addition to previous experiences with pembrolizumab in the elderly, Dr. Popat said that “if you choose your patient population well, fit patients well enough to go to a trial, they don’t have an excess of toxicities regardless of their age.”

Taken as a whole, the present analysis supports the routine use of pembrolizumab in fit, elderly patients, Dr. Popat said.

The study was funded by MSD. The investigators reported financial relationships with AstraZeneca, Eli Lilly, Taiho, Chugai, and others.

SOURCE: Nosaki et al. ELCC 2019. Abstract 103O_PR.

GENEVA – For patients with malignant pleural mesothelioma, adding tumor-treating fields (TTFields) to standard pemetrexed plus platinum compound chemotherapy could boost median overall survival by about 6 months, according to final results from the phase 2 STELLAR trial.

Will Pass/MDedge News

The survival benefit of TTFields was greatest among patients with epithelioid mesothelioma, reported lead author Giovanni Luca Ceresoli, MD, of Humanitas Gavazzeni in Bergamo, Italy. According to Dr. Ceresoli, who presented findings at the at the European Lung Cancer Conference, TTFields offer a safe way to improve mesothelioma outcomes without increasing the risk of serious adverse events.

“TTFields are a locoregional treatment comprising low-intensity alternating electric fields delivered through a portable medical device,” Dr. Ceresoli explained at the meeting, presented by the European Society for Medical Oncology. “Their main mode of action is an anti-mitotic mechanism.” He noted that TTFields are already approved by the Food and Drug Administration for newly diagnosed glioblastoma.

The STELLAR trial involved 80 patients with mesothelioma who were treated with TTFields in combination with standard first-line chemotherapy, a combination of pemetrexed with cisplatin or carboplatin. Patients were instructed to self-administer continuous 150 kHz TTFields for at least 18 hours a day. Eligibility required an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Both ECOG status and cancer-related pain were followed with a visual analog scale until disease progression. Median overall survival (OS) was the primary endpoint.

The patient population was predominantly male (84%), with median age of 67 years. About 44% of the patients had an ECOG performance status of 1 and 66% had epithelioid histology. Median treatment time per day was 16.3 hours.

After a minimum follow-up of 1 year, patients treated with TTFields in combination with standard chemotherapy had a median overall survival of 18.2 months, compared with 12.1 months for standard chemotherapy alone, which Dr. Ceresoli cited as the historical benchmark. The survival benefit was 3 months longer among patients with epithelioid mesothelioma, who had a median overall survival of 21.2 months.

In addition to survival benefits, the investigators found that median time to decreased performance status was just over 1 year (13.1 months), and that pain did not increase to a clinically significant degree (33%) until an average of 8.4 months. Although no device-related serious adverse events occurred, 37 patients (46%) experienced TTFields-related dermatitis; 4 of these patients had grade 3 dermatitis. Dr. Ceresoli noted that dermatitis was typically “easily managed” with topical application of a corticosteroid, while patients with severe dermatitis took short treatment breaks.

“In conclusion, in the STELLAR trial, TTFields in combination with standard chemotherapy were effective and safe for first-line treatment of unresectable malignant pleural mesothelioma, and median overall survival was significantly longer as compared to historical controls,” Dr. Ceresoli said, pointing out better survival than in recent trials MAPS and LUME-Meso.

When asked by the invited discussant about future research, Dr. Ceresoli described a narrower focus for upcoming TTFields studies for mesothelioma. “As you well know, most patients have epithelioid histology, and in our hands, the patients with epithelioid histology had better prognoses,” he said. “So, in the future, I think we will focus on epithelioid tumors.”

Dr. Ceresoli disclosed travel funding from Novocure.

SOURCE: Ceresoli et al. ELCC 2019. Abstract 55O.

GENEVA – For patients with malignant pleural mesothelioma, adding tumor-treating fields (TTFields) to standard pemetrexed plus platinum compound chemotherapy could boost median overall survival by about 6 months, according to final results from the phase 2 STELLAR trial.

Will Pass/MDedge News

The survival benefit of TTFields was greatest among patients with epithelioid mesothelioma, reported lead author Giovanni Luca Ceresoli, MD, of Humanitas Gavazzeni in Bergamo, Italy. According to Dr. Ceresoli, who presented findings at the at the European Lung Cancer Conference, TTFields offer a safe way to improve mesothelioma outcomes without increasing the risk of serious adverse events.

“TTFields are a locoregional treatment comprising low-intensity alternating electric fields delivered through a portable medical device,” Dr. Ceresoli explained at the meeting, presented by the European Society for Medical Oncology. “Their main mode of action is an anti-mitotic mechanism.” He noted that TTFields are already approved by the Food and Drug Administration for newly diagnosed glioblastoma.

The STELLAR trial involved 80 patients with mesothelioma who were treated with TTFields in combination with standard first-line chemotherapy, a combination of pemetrexed with cisplatin or carboplatin. Patients were instructed to self-administer continuous 150 kHz TTFields for at least 18 hours a day. Eligibility required an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Both ECOG status and cancer-related pain were followed with a visual analog scale until disease progression. Median overall survival (OS) was the primary endpoint.

The patient population was predominantly male (84%), with median age of 67 years. About 44% of the patients had an ECOG performance status of 1 and 66% had epithelioid histology. Median treatment time per day was 16.3 hours.

After a minimum follow-up of 1 year, patients treated with TTFields in combination with standard chemotherapy had a median overall survival of 18.2 months, compared with 12.1 months for standard chemotherapy alone, which Dr. Ceresoli cited as the historical benchmark. The survival benefit was 3 months longer among patients with epithelioid mesothelioma, who had a median overall survival of 21.2 months.

In addition to survival benefits, the investigators found that median time to decreased performance status was just over 1 year (13.1 months), and that pain did not increase to a clinically significant degree (33%) until an average of 8.4 months. Although no device-related serious adverse events occurred, 37 patients (46%) experienced TTFields-related dermatitis; 4 of these patients had grade 3 dermatitis. Dr. Ceresoli noted that dermatitis was typically “easily managed” with topical application of a corticosteroid, while patients with severe dermatitis took short treatment breaks.

“In conclusion, in the STELLAR trial, TTFields in combination with standard chemotherapy were effective and safe for first-line treatment of unresectable malignant pleural mesothelioma, and median overall survival was significantly longer as compared to historical controls,” Dr. Ceresoli said, pointing out better survival than in recent trials MAPS and LUME-Meso.

When asked by the invited discussant about future research, Dr. Ceresoli described a narrower focus for upcoming TTFields studies for mesothelioma. “As you well know, most patients have epithelioid histology, and in our hands, the patients with epithelioid histology had better prognoses,” he said. “So, in the future, I think we will focus on epithelioid tumors.”

Dr. Ceresoli disclosed travel funding from Novocure.

SOURCE: Ceresoli et al. ELCC 2019. Abstract 55O.

GENEVA – For patients with malignant pleural mesothelioma, adding tumor-treating fields (TTFields) to standard pemetrexed plus platinum compound chemotherapy could boost median overall survival by about 6 months, according to final results from the phase 2 STELLAR trial.

Will Pass/MDedge News

The survival benefit of TTFields was greatest among patients with epithelioid mesothelioma, reported lead author Giovanni Luca Ceresoli, MD, of Humanitas Gavazzeni in Bergamo, Italy. According to Dr. Ceresoli, who presented findings at the at the European Lung Cancer Conference, TTFields offer a safe way to improve mesothelioma outcomes without increasing the risk of serious adverse events.

“TTFields are a locoregional treatment comprising low-intensity alternating electric fields delivered through a portable medical device,” Dr. Ceresoli explained at the meeting, presented by the European Society for Medical Oncology. “Their main mode of action is an anti-mitotic mechanism.” He noted that TTFields are already approved by the Food and Drug Administration for newly diagnosed glioblastoma.

The STELLAR trial involved 80 patients with mesothelioma who were treated with TTFields in combination with standard first-line chemotherapy, a combination of pemetrexed with cisplatin or carboplatin. Patients were instructed to self-administer continuous 150 kHz TTFields for at least 18 hours a day. Eligibility required an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Both ECOG status and cancer-related pain were followed with a visual analog scale until disease progression. Median overall survival (OS) was the primary endpoint.

The patient population was predominantly male (84%), with median age of 67 years. About 44% of the patients had an ECOG performance status of 1 and 66% had epithelioid histology. Median treatment time per day was 16.3 hours.

After a minimum follow-up of 1 year, patients treated with TTFields in combination with standard chemotherapy had a median overall survival of 18.2 months, compared with 12.1 months for standard chemotherapy alone, which Dr. Ceresoli cited as the historical benchmark. The survival benefit was 3 months longer among patients with epithelioid mesothelioma, who had a median overall survival of 21.2 months.

In addition to survival benefits, the investigators found that median time to decreased performance status was just over 1 year (13.1 months), and that pain did not increase to a clinically significant degree (33%) until an average of 8.4 months. Although no device-related serious adverse events occurred, 37 patients (46%) experienced TTFields-related dermatitis; 4 of these patients had grade 3 dermatitis. Dr. Ceresoli noted that dermatitis was typically “easily managed” with topical application of a corticosteroid, while patients with severe dermatitis took short treatment breaks.

“In conclusion, in the STELLAR trial, TTFields in combination with standard chemotherapy were effective and safe for first-line treatment of unresectable malignant pleural mesothelioma, and median overall survival was significantly longer as compared to historical controls,” Dr. Ceresoli said, pointing out better survival than in recent trials MAPS and LUME-Meso.

When asked by the invited discussant about future research, Dr. Ceresoli described a narrower focus for upcoming TTFields studies for mesothelioma. “As you well know, most patients have epithelioid histology, and in our hands, the patients with epithelioid histology had better prognoses,” he said. “So, in the future, I think we will focus on epithelioid tumors.”

Dr. Ceresoli disclosed travel funding from Novocure.

SOURCE: Ceresoli et al. ELCC 2019. Abstract 55O.

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the first-line treatment of patients with stage III non–small cell lung cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation, and for stage IV NSCLC.

Patients’ tumors must express programmed death-ligand 1 (PD-L1) as determined by an FDA-approved test (tumor proportion score ≥1%) and have no epidermal growth factor receptor or anaplastic lymphoma kinase mutations.

The checkpoint inhibitor was previously approved as a single agent for the first-line treatment of patients with metastatic disease with PD-L1 expression at a higher level (TPS ≥50%), the FDA said in a press statement.

Approval was based on statistically significant overall survival improvement with pembrolizumab, compared with investigator’s choice of a carboplatin-containing regimen with either pemetrexed or paclitaxel in KEYNOTE‑042. The trial enrolled 1,274 patients with stage III or IV NSCLC who had not received prior systemic treatment for metastatic NSCLC and whose tumors expressed PD-L1 (TPS ≥1%).

Overall survival was improved in all three subgroups for pembrolizumab, compared with chemotherapy: in the TPS ≥50% subgroup, the TPS ≥20% subgroup, and the overall population (TPS ≥1%). The median overall survival in the TPS ≥1% population was 16.7 for pembrolizumab and 12.1 months for the chemotherapy arms (hazard ratio, 0.81; 95% confidence interval, 0.71-0.93; P = .0036). For the TPS ≥50% subgroup, the estimated median overall survival was 20 months for pembrolizumab and 12.2 months for the chemotherapy arm (HR, 0.69; 95% CI, 0.56-0.85; P = .0006).

The most common adverse reactions reported for patients who received pembrolizumab included fatigue, decreased appetite, dyspnea, cough, rash, constipation, diarrhea, nausea, hypothyroidism, pneumonia, pyrexia, and weight loss, the FDA said.

The recommended dose for NSCLC is 200 mg as an IV infusion over 30 minutes every 3 weeks.






 

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the first-line treatment of patients with stage III non–small cell lung cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation, and for stage IV NSCLC.

Patients’ tumors must express programmed death-ligand 1 (PD-L1) as determined by an FDA-approved test (tumor proportion score ≥1%) and have no epidermal growth factor receptor or anaplastic lymphoma kinase mutations.

The checkpoint inhibitor was previously approved as a single agent for the first-line treatment of patients with metastatic disease with PD-L1 expression at a higher level (TPS ≥50%), the FDA said in a press statement.

Approval was based on statistically significant overall survival improvement with pembrolizumab, compared with investigator’s choice of a carboplatin-containing regimen with either pemetrexed or paclitaxel in KEYNOTE‑042. The trial enrolled 1,274 patients with stage III or IV NSCLC who had not received prior systemic treatment for metastatic NSCLC and whose tumors expressed PD-L1 (TPS ≥1%).

Overall survival was improved in all three subgroups for pembrolizumab, compared with chemotherapy: in the TPS ≥50% subgroup, the TPS ≥20% subgroup, and the overall population (TPS ≥1%). The median overall survival in the TPS ≥1% population was 16.7 for pembrolizumab and 12.1 months for the chemotherapy arms (hazard ratio, 0.81; 95% confidence interval, 0.71-0.93; P = .0036). For the TPS ≥50% subgroup, the estimated median overall survival was 20 months for pembrolizumab and 12.2 months for the chemotherapy arm (HR, 0.69; 95% CI, 0.56-0.85; P = .0006).

The most common adverse reactions reported for patients who received pembrolizumab included fatigue, decreased appetite, dyspnea, cough, rash, constipation, diarrhea, nausea, hypothyroidism, pneumonia, pyrexia, and weight loss, the FDA said.

The recommended dose for NSCLC is 200 mg as an IV infusion over 30 minutes every 3 weeks.






 

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the first-line treatment of patients with stage III non–small cell lung cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation, and for stage IV NSCLC.

Patients’ tumors must express programmed death-ligand 1 (PD-L1) as determined by an FDA-approved test (tumor proportion score ≥1%) and have no epidermal growth factor receptor or anaplastic lymphoma kinase mutations.

The checkpoint inhibitor was previously approved as a single agent for the first-line treatment of patients with metastatic disease with PD-L1 expression at a higher level (TPS ≥50%), the FDA said in a press statement.

Approval was based on statistically significant overall survival improvement with pembrolizumab, compared with investigator’s choice of a carboplatin-containing regimen with either pemetrexed or paclitaxel in KEYNOTE‑042. The trial enrolled 1,274 patients with stage III or IV NSCLC who had not received prior systemic treatment for metastatic NSCLC and whose tumors expressed PD-L1 (TPS ≥1%).

Overall survival was improved in all three subgroups for pembrolizumab, compared with chemotherapy: in the TPS ≥50% subgroup, the TPS ≥20% subgroup, and the overall population (TPS ≥1%). The median overall survival in the TPS ≥1% population was 16.7 for pembrolizumab and 12.1 months for the chemotherapy arms (hazard ratio, 0.81; 95% confidence interval, 0.71-0.93; P = .0036). For the TPS ≥50% subgroup, the estimated median overall survival was 20 months for pembrolizumab and 12.2 months for the chemotherapy arm (HR, 0.69; 95% CI, 0.56-0.85; P = .0006).

The most common adverse reactions reported for patients who received pembrolizumab included fatigue, decreased appetite, dyspnea, cough, rash, constipation, diarrhea, nausea, hypothyroidism, pneumonia, pyrexia, and weight loss, the FDA said.

The recommended dose for NSCLC is 200 mg as an IV infusion over 30 minutes every 3 weeks.






 

GENEVA – Radiogenomic MRI signatures may be able to identify anaplastic lymphoma kinase (ALK)–positive brain metastases in non–small cell lung cancer (NSCLC), offering a minimally invasive option that could allow for initiation of treatment while waiting for molecular results, according to investigators.

Will Pass/MDedge News

In the future, artificial intelligence may be able to detect these imaging patterns, allowing for rapid and accurate mutation subtyping, reported lead author Shweta Wadhwa, MD, of Tata Memorial Centre in Mumbai, India, who presented the findings at the European Lung Cancer Conference.

“Radiogenomics is a concept used to associate genetic information with medical images,” Dr. Wadhwa explained at the meeting presented by the European Society for Medical Oncology. “It creates imaging biomarkers noninvasively without using biopsy. … The aim of my study was to analyze certain MRI data genomic parameters and correlate with the ALK mutation status.”

Dr. Wadhwa and her colleagues retrospectively analyzed data from 75 patients with ALK-positive NSCLC who underwent multiparametric MRI at the time of diagnosis. Univariate logistic regression analysis was conducted to look for associations between ALK mutation status and various clinical factors, including sex, age, smoking, histology, TNM stage, and imaging characteristics.

Out of 75 patients, 46 were ALK positive and 29 were ALK negative. Analysis showed that ALK positivity was associated with a variety of lesion morphology characteristics. ALK-positive lesions more often exhibited a fuzzy and infiltrative T2w border with hypointense peripheral solid rim, compared with ALK-negative lesions, which frequently had a well-defined T2w border with no solid rim (P less than .001). On T1w, most ALK-positive lesions were heterogeneous, whereas ALK-negative lesions were predominantly hypointense (P less than .001). Diffusion-weighted images showed that ALK-positive lesions often had peripheral restriction of the solid rim, compared with ALK-negative lesions, which were associated with central restriction (P = .001). MRI also revealed that about half of ALK-positive patients (54.3%) had meningeal involvement, compared with just 17.2% of ALK-negative patients (P = .02). ALK positivity was also associated with younger age and lack of smoking history. Considering these findings, Dr. Wadhwa concluded that “radiogenomics has a potential role in personalized management of ALK-positive NSCLC brain metastases.”

In an interview, Dr. Wadhwa provided more insight regarding the clinical need for this technology. “We have to wait for 10 days [for molecular diagnostic results], and ALK is usually aggressive disease, so if we wait for 10 days, patients can undergo rapid progression.”

Dr. Wadhwa noted that these results are similar to that of her colleague, Abhishek Mahajan, MD, who recently published results showing potential for radiogenomic detection of epidermal growth factor receptor (EGFR) status. According to Dr. Wadhwa, the two investigators plan to build on their collective findings in an effort to automate radiogenomic detection of NSCLC mutation subtypes.

“My upcoming project with my coinvestigator is to take a bigger sample,” Dr. Wadhwa said. “We will be further generalizing [this process] to all patients in a prospective study. We will also be sending this to the University of Pennsylvania for automatic brain segmentation.” Dr. Wadhwa estimated that adding automation will provide an accuracy rate of around 90%.

“We will train the computer accordingly,” Dr. Wadhwa said, “and then the computer will tell us, yes, this is ALK positive, this is EGFR positive.”

The investigators reported no external study funding and reported no conflicts of interest.

SOURCE: Wadhwa S et al. ELCC 2019, Abstract 55O.

GENEVA – Radiogenomic MRI signatures may be able to identify anaplastic lymphoma kinase (ALK)–positive brain metastases in non–small cell lung cancer (NSCLC), offering a minimally invasive option that could allow for initiation of treatment while waiting for molecular results, according to investigators.

Will Pass/MDedge News

In the future, artificial intelligence may be able to detect these imaging patterns, allowing for rapid and accurate mutation subtyping, reported lead author Shweta Wadhwa, MD, of Tata Memorial Centre in Mumbai, India, who presented the findings at the European Lung Cancer Conference.

“Radiogenomics is a concept used to associate genetic information with medical images,” Dr. Wadhwa explained at the meeting presented by the European Society for Medical Oncology. “It creates imaging biomarkers noninvasively without using biopsy. … The aim of my study was to analyze certain MRI data genomic parameters and correlate with the ALK mutation status.”

Dr. Wadhwa and her colleagues retrospectively analyzed data from 75 patients with ALK-positive NSCLC who underwent multiparametric MRI at the time of diagnosis. Univariate logistic regression analysis was conducted to look for associations between ALK mutation status and various clinical factors, including sex, age, smoking, histology, TNM stage, and imaging characteristics.

Out of 75 patients, 46 were ALK positive and 29 were ALK negative. Analysis showed that ALK positivity was associated with a variety of lesion morphology characteristics. ALK-positive lesions more often exhibited a fuzzy and infiltrative T2w border with hypointense peripheral solid rim, compared with ALK-negative lesions, which frequently had a well-defined T2w border with no solid rim (P less than .001). On T1w, most ALK-positive lesions were heterogeneous, whereas ALK-negative lesions were predominantly hypointense (P less than .001). Diffusion-weighted images showed that ALK-positive lesions often had peripheral restriction of the solid rim, compared with ALK-negative lesions, which were associated with central restriction (P = .001). MRI also revealed that about half of ALK-positive patients (54.3%) had meningeal involvement, compared with just 17.2% of ALK-negative patients (P = .02). ALK positivity was also associated with younger age and lack of smoking history. Considering these findings, Dr. Wadhwa concluded that “radiogenomics has a potential role in personalized management of ALK-positive NSCLC brain metastases.”

In an interview, Dr. Wadhwa provided more insight regarding the clinical need for this technology. “We have to wait for 10 days [for molecular diagnostic results], and ALK is usually aggressive disease, so if we wait for 10 days, patients can undergo rapid progression.”

Dr. Wadhwa noted that these results are similar to that of her colleague, Abhishek Mahajan, MD, who recently published results showing potential for radiogenomic detection of epidermal growth factor receptor (EGFR) status. According to Dr. Wadhwa, the two investigators plan to build on their collective findings in an effort to automate radiogenomic detection of NSCLC mutation subtypes.

“My upcoming project with my coinvestigator is to take a bigger sample,” Dr. Wadhwa said. “We will be further generalizing [this process] to all patients in a prospective study. We will also be sending this to the University of Pennsylvania for automatic brain segmentation.” Dr. Wadhwa estimated that adding automation will provide an accuracy rate of around 90%.

“We will train the computer accordingly,” Dr. Wadhwa said, “and then the computer will tell us, yes, this is ALK positive, this is EGFR positive.”

The investigators reported no external study funding and reported no conflicts of interest.

SOURCE: Wadhwa S et al. ELCC 2019, Abstract 55O.

GENEVA – Radiogenomic MRI signatures may be able to identify anaplastic lymphoma kinase (ALK)–positive brain metastases in non–small cell lung cancer (NSCLC), offering a minimally invasive option that could allow for initiation of treatment while waiting for molecular results, according to investigators.

Will Pass/MDedge News

In the future, artificial intelligence may be able to detect these imaging patterns, allowing for rapid and accurate mutation subtyping, reported lead author Shweta Wadhwa, MD, of Tata Memorial Centre in Mumbai, India, who presented the findings at the European Lung Cancer Conference.

“Radiogenomics is a concept used to associate genetic information with medical images,” Dr. Wadhwa explained at the meeting presented by the European Society for Medical Oncology. “It creates imaging biomarkers noninvasively without using biopsy. … The aim of my study was to analyze certain MRI data genomic parameters and correlate with the ALK mutation status.”

Dr. Wadhwa and her colleagues retrospectively analyzed data from 75 patients with ALK-positive NSCLC who underwent multiparametric MRI at the time of diagnosis. Univariate logistic regression analysis was conducted to look for associations between ALK mutation status and various clinical factors, including sex, age, smoking, histology, TNM stage, and imaging characteristics.

Out of 75 patients, 46 were ALK positive and 29 were ALK negative. Analysis showed that ALK positivity was associated with a variety of lesion morphology characteristics. ALK-positive lesions more often exhibited a fuzzy and infiltrative T2w border with hypointense peripheral solid rim, compared with ALK-negative lesions, which frequently had a well-defined T2w border with no solid rim (P less than .001). On T1w, most ALK-positive lesions were heterogeneous, whereas ALK-negative lesions were predominantly hypointense (P less than .001). Diffusion-weighted images showed that ALK-positive lesions often had peripheral restriction of the solid rim, compared with ALK-negative lesions, which were associated with central restriction (P = .001). MRI also revealed that about half of ALK-positive patients (54.3%) had meningeal involvement, compared with just 17.2% of ALK-negative patients (P = .02). ALK positivity was also associated with younger age and lack of smoking history. Considering these findings, Dr. Wadhwa concluded that “radiogenomics has a potential role in personalized management of ALK-positive NSCLC brain metastases.”

In an interview, Dr. Wadhwa provided more insight regarding the clinical need for this technology. “We have to wait for 10 days [for molecular diagnostic results], and ALK is usually aggressive disease, so if we wait for 10 days, patients can undergo rapid progression.”

Dr. Wadhwa noted that these results are similar to that of her colleague, Abhishek Mahajan, MD, who recently published results showing potential for radiogenomic detection of epidermal growth factor receptor (EGFR) status. According to Dr. Wadhwa, the two investigators plan to build on their collective findings in an effort to automate radiogenomic detection of NSCLC mutation subtypes.

“My upcoming project with my coinvestigator is to take a bigger sample,” Dr. Wadhwa said. “We will be further generalizing [this process] to all patients in a prospective study. We will also be sending this to the University of Pennsylvania for automatic brain segmentation.” Dr. Wadhwa estimated that adding automation will provide an accuracy rate of around 90%.

“We will train the computer accordingly,” Dr. Wadhwa said, “and then the computer will tell us, yes, this is ALK positive, this is EGFR positive.”

The investigators reported no external study funding and reported no conflicts of interest.

SOURCE: Wadhwa S et al. ELCC 2019, Abstract 55O.

GENEVA – For lung lesion biopsy, electromagnetic navigation bronchoscopy (ENB) offers high navigational success with a relatively low rate of pneumothorax, according to European data from the international NAVIGATE study.

Will Pass/MDedge News

In addition to lung lesion biopsy, ENB can facilitate concurrent lymph node sampling and fiducial placement during a single anesthetic event, reported lead author Kelvin Lau, MD, chief of thoracic surgery at Barts Thorax Centre in London, and his colleagues. According to Dr. Lau, who presented at the European Lung Cancer Conference, the findings from this European cohort add weight to previously published data from the NAVIGATE trial, which aims to demonstrate real-world use of ENB.

“The outcomes show that [ENB] is very safe in terms of pneumothorax rate, despite the fact that many of these patients were challenging and actually were turned down by the percutaneous radiologist before they came to us,” Dr. Lau said at the meeting, presented by the European Society for Medical Oncology.

Out of 1,200 patients enrolled in the NAVIGATE trial in the United States and Europe, the present 1-month interim analysis showed experiences with 175 patients treated at eight European centers. Anyone undergoing navigational bronchoscopy was eligible. The primary outcome was pneumothorax rate and the secondary outcome was diagnostic yield.

Data analysis showed that lesions were most frequently in the upper lobe (62.6%) and in the peripheral third of the lung (72.7%), the latter of which is beyond the reach of a conventional bronchoscope. In two out of three patients (66.8%), a bronchus sign was present, which “means that the bronchoscope runs straight into the lesion, and theoretically means it’s easier to access,” Dr. Lau said. Almost all patients had ENB for lung biopsy (99.4%), while in a small minority (8.0%), ENB was used for fiducial marking. The median total procedure time was 43.5 minutes, of which 32.9 minutes were spent navigating and sampling with ENB.

The ENB-related pneumothorax rate was 7.4%, although a slightly lower percentage, 5.1%, required intervention or hospitalization. According to the ENB-related Common Terminology Criteria for Adverse Events, 2.3% of patients had grade 2 or higher bronchopulmonary hemorrhage and 0.6% of patients had grade 4 or higher respiratory failure. Although the secondary endpoint, diagnostic yield, was not met because of inadequate follow-up time, the navigational success rate, defined as access to the intended lung lesion, was 96.6%, which offers some sense of efficacy.

“The purpose of this study is to show that [ENB] is very safe,” Dr. Lau said in an interview. “And the numbers are significantly better than historic CT-guided biopsy data.”

Considering the choice between ENB and CT-guided biopsy, invited discussant Anne-Marie Dingemans, MD, of Maastricht University, the Netherlands, offered a different viewpoint.

Will Pass/MDedge News

“CT-guided biopsies are low cost ... and the sensitivity is very, very high,” Dr. Dingemans said. “In good hands, with a good radiologist, you have a high chance that you will have a good diagnosis of the nodules.” She also noted that a bronchus sign does not impact efficacy.

“I’m very into CT-guided biopsies,” Dr. Dingemans continued, noting that the radiologist at her treatment center takes biopsies with a 10-gauge large-core needle. With this technique, Dr. Dingemans reported a 5.7% pneumothorax rate, which is comparable with the present NAVIGATE data.

However, Dr. Lau contested this figure.

“The pneumothorax rates [for CT-guided biopsy] in larger studies have always been about 20% to 40%,” Dr. Lau said. “You can’t compare large overall practice in a pragmatic study capturing everyone versus one single center. The truth is, most centers will have a 20% pneumothorax rate.”

Dr. Lau added that patient experiences are likely to be better with ENB than with CT-guided percutaneous biopsy.

“To me, patient comfort for biopsy is essential,” Dr. Lau said. “Having a needle stuck into your chest – it’s very uncomfortable. I’ve had patients who’ve come to me after they had a percutaneous biopsy and who for some reason needed a re-biopsy ... those patients almost always wish they had navigational bronchoscopy the first time because there would be no pain for them.”

When asked about capital cost concerns surrounding ENB, Dr. Lau suggested that the benefits outweigh the costs.

“The most expensive procedure is the one you have to do again,” Dr. Lau said. “So what we do is put a brush in, and a needle, and a biopsy, and hopefully, one of those three, if not all three, gets tissue, and we can do that with navigational bronchoscopy because there is one channel down. You can’t repeatedly stick needles into patients. By definition, you can’t throw three needle jabs, because you will get a 90% pneumothorax rate. And that’s the beauty of navigational bronchoscopy as well, because in the NAVIGATE series, a number of patients, about 10%, had multiple lesions biopsied.” Furthermore, Dr. Lau noted, percutaneous biopsy is “almost never” performed bilaterally, for fear of collapsing both lungs, but this is not the case with ENB. “We’ve done it on patients who have one lung,” he said.

Dr. Lau predicted that costs of ENB will come down with time. “Because of the number of products increasing, the price will drop,” he said.

Concluding the interview, Dr. Lau offered a summarizing message: “If you want to give the patient the safe option, you should do [ENB], and when it becomes more popular, the price will fall,” he said.

Medtronic funded the study. The investigators reported financial relationships with Olympus, Ambu, PulmonX, Boston Scientific, and others.

SOURCE: Lau et al. ELCC 2019. Abstract 68O.

GENEVA – For lung lesion biopsy, electromagnetic navigation bronchoscopy (ENB) offers high navigational success with a relatively low rate of pneumothorax, according to European data from the international NAVIGATE study.

Will Pass/MDedge News

In addition to lung lesion biopsy, ENB can facilitate concurrent lymph node sampling and fiducial placement during a single anesthetic event, reported lead author Kelvin Lau, MD, chief of thoracic surgery at Barts Thorax Centre in London, and his colleagues. According to Dr. Lau, who presented at the European Lung Cancer Conference, the findings from this European cohort add weight to previously published data from the NAVIGATE trial, which aims to demonstrate real-world use of ENB.

“The outcomes show that [ENB] is very safe in terms of pneumothorax rate, despite the fact that many of these patients were challenging and actually were turned down by the percutaneous radiologist before they came to us,” Dr. Lau said at the meeting, presented by the European Society for Medical Oncology.

Out of 1,200 patients enrolled in the NAVIGATE trial in the United States and Europe, the present 1-month interim analysis showed experiences with 175 patients treated at eight European centers. Anyone undergoing navigational bronchoscopy was eligible. The primary outcome was pneumothorax rate and the secondary outcome was diagnostic yield.

Data analysis showed that lesions were most frequently in the upper lobe (62.6%) and in the peripheral third of the lung (72.7%), the latter of which is beyond the reach of a conventional bronchoscope. In two out of three patients (66.8%), a bronchus sign was present, which “means that the bronchoscope runs straight into the lesion, and theoretically means it’s easier to access,” Dr. Lau said. Almost all patients had ENB for lung biopsy (99.4%), while in a small minority (8.0%), ENB was used for fiducial marking. The median total procedure time was 43.5 minutes, of which 32.9 minutes were spent navigating and sampling with ENB.

The ENB-related pneumothorax rate was 7.4%, although a slightly lower percentage, 5.1%, required intervention or hospitalization. According to the ENB-related Common Terminology Criteria for Adverse Events, 2.3% of patients had grade 2 or higher bronchopulmonary hemorrhage and 0.6% of patients had grade 4 or higher respiratory failure. Although the secondary endpoint, diagnostic yield, was not met because of inadequate follow-up time, the navigational success rate, defined as access to the intended lung lesion, was 96.6%, which offers some sense of efficacy.

“The purpose of this study is to show that [ENB] is very safe,” Dr. Lau said in an interview. “And the numbers are significantly better than historic CT-guided biopsy data.”

Considering the choice between ENB and CT-guided biopsy, invited discussant Anne-Marie Dingemans, MD, of Maastricht University, the Netherlands, offered a different viewpoint.

Will Pass/MDedge News

“CT-guided biopsies are low cost ... and the sensitivity is very, very high,” Dr. Dingemans said. “In good hands, with a good radiologist, you have a high chance that you will have a good diagnosis of the nodules.” She also noted that a bronchus sign does not impact efficacy.

“I’m very into CT-guided biopsies,” Dr. Dingemans continued, noting that the radiologist at her treatment center takes biopsies with a 10-gauge large-core needle. With this technique, Dr. Dingemans reported a 5.7% pneumothorax rate, which is comparable with the present NAVIGATE data.

However, Dr. Lau contested this figure.

“The pneumothorax rates [for CT-guided biopsy] in larger studies have always been about 20% to 40%,” Dr. Lau said. “You can’t compare large overall practice in a pragmatic study capturing everyone versus one single center. The truth is, most centers will have a 20% pneumothorax rate.”

Dr. Lau added that patient experiences are likely to be better with ENB than with CT-guided percutaneous biopsy.

“To me, patient comfort for biopsy is essential,” Dr. Lau said. “Having a needle stuck into your chest – it’s very uncomfortable. I’ve had patients who’ve come to me after they had a percutaneous biopsy and who for some reason needed a re-biopsy ... those patients almost always wish they had navigational bronchoscopy the first time because there would be no pain for them.”

When asked about capital cost concerns surrounding ENB, Dr. Lau suggested that the benefits outweigh the costs.

“The most expensive procedure is the one you have to do again,” Dr. Lau said. “So what we do is put a brush in, and a needle, and a biopsy, and hopefully, one of those three, if not all three, gets tissue, and we can do that with navigational bronchoscopy because there is one channel down. You can’t repeatedly stick needles into patients. By definition, you can’t throw three needle jabs, because you will get a 90% pneumothorax rate. And that’s the beauty of navigational bronchoscopy as well, because in the NAVIGATE series, a number of patients, about 10%, had multiple lesions biopsied.” Furthermore, Dr. Lau noted, percutaneous biopsy is “almost never” performed bilaterally, for fear of collapsing both lungs, but this is not the case with ENB. “We’ve done it on patients who have one lung,” he said.

Dr. Lau predicted that costs of ENB will come down with time. “Because of the number of products increasing, the price will drop,” he said.

Concluding the interview, Dr. Lau offered a summarizing message: “If you want to give the patient the safe option, you should do [ENB], and when it becomes more popular, the price will fall,” he said.

Medtronic funded the study. The investigators reported financial relationships with Olympus, Ambu, PulmonX, Boston Scientific, and others.

SOURCE: Lau et al. ELCC 2019. Abstract 68O.

GENEVA – For lung lesion biopsy, electromagnetic navigation bronchoscopy (ENB) offers high navigational success with a relatively low rate of pneumothorax, according to European data from the international NAVIGATE study.

Will Pass/MDedge News

In addition to lung lesion biopsy, ENB can facilitate concurrent lymph node sampling and fiducial placement during a single anesthetic event, reported lead author Kelvin Lau, MD, chief of thoracic surgery at Barts Thorax Centre in London, and his colleagues. According to Dr. Lau, who presented at the European Lung Cancer Conference, the findings from this European cohort add weight to previously published data from the NAVIGATE trial, which aims to demonstrate real-world use of ENB.

“The outcomes show that [ENB] is very safe in terms of pneumothorax rate, despite the fact that many of these patients were challenging and actually were turned down by the percutaneous radiologist before they came to us,” Dr. Lau said at the meeting, presented by the European Society for Medical Oncology.

Out of 1,200 patients enrolled in the NAVIGATE trial in the United States and Europe, the present 1-month interim analysis showed experiences with 175 patients treated at eight European centers. Anyone undergoing navigational bronchoscopy was eligible. The primary outcome was pneumothorax rate and the secondary outcome was diagnostic yield.

Data analysis showed that lesions were most frequently in the upper lobe (62.6%) and in the peripheral third of the lung (72.7%), the latter of which is beyond the reach of a conventional bronchoscope. In two out of three patients (66.8%), a bronchus sign was present, which “means that the bronchoscope runs straight into the lesion, and theoretically means it’s easier to access,” Dr. Lau said. Almost all patients had ENB for lung biopsy (99.4%), while in a small minority (8.0%), ENB was used for fiducial marking. The median total procedure time was 43.5 minutes, of which 32.9 minutes were spent navigating and sampling with ENB.

The ENB-related pneumothorax rate was 7.4%, although a slightly lower percentage, 5.1%, required intervention or hospitalization. According to the ENB-related Common Terminology Criteria for Adverse Events, 2.3% of patients had grade 2 or higher bronchopulmonary hemorrhage and 0.6% of patients had grade 4 or higher respiratory failure. Although the secondary endpoint, diagnostic yield, was not met because of inadequate follow-up time, the navigational success rate, defined as access to the intended lung lesion, was 96.6%, which offers some sense of efficacy.

“The purpose of this study is to show that [ENB] is very safe,” Dr. Lau said in an interview. “And the numbers are significantly better than historic CT-guided biopsy data.”

Considering the choice between ENB and CT-guided biopsy, invited discussant Anne-Marie Dingemans, MD, of Maastricht University, the Netherlands, offered a different viewpoint.

Will Pass/MDedge News

“CT-guided biopsies are low cost ... and the sensitivity is very, very high,” Dr. Dingemans said. “In good hands, with a good radiologist, you have a high chance that you will have a good diagnosis of the nodules.” She also noted that a bronchus sign does not impact efficacy.

“I’m very into CT-guided biopsies,” Dr. Dingemans continued, noting that the radiologist at her treatment center takes biopsies with a 10-gauge large-core needle. With this technique, Dr. Dingemans reported a 5.7% pneumothorax rate, which is comparable with the present NAVIGATE data.

However, Dr. Lau contested this figure.

“The pneumothorax rates [for CT-guided biopsy] in larger studies have always been about 20% to 40%,” Dr. Lau said. “You can’t compare large overall practice in a pragmatic study capturing everyone versus one single center. The truth is, most centers will have a 20% pneumothorax rate.”

Dr. Lau added that patient experiences are likely to be better with ENB than with CT-guided percutaneous biopsy.

“To me, patient comfort for biopsy is essential,” Dr. Lau said. “Having a needle stuck into your chest – it’s very uncomfortable. I’ve had patients who’ve come to me after they had a percutaneous biopsy and who for some reason needed a re-biopsy ... those patients almost always wish they had navigational bronchoscopy the first time because there would be no pain for them.”

When asked about capital cost concerns surrounding ENB, Dr. Lau suggested that the benefits outweigh the costs.

“The most expensive procedure is the one you have to do again,” Dr. Lau said. “So what we do is put a brush in, and a needle, and a biopsy, and hopefully, one of those three, if not all three, gets tissue, and we can do that with navigational bronchoscopy because there is one channel down. You can’t repeatedly stick needles into patients. By definition, you can’t throw three needle jabs, because you will get a 90% pneumothorax rate. And that’s the beauty of navigational bronchoscopy as well, because in the NAVIGATE series, a number of patients, about 10%, had multiple lesions biopsied.” Furthermore, Dr. Lau noted, percutaneous biopsy is “almost never” performed bilaterally, for fear of collapsing both lungs, but this is not the case with ENB. “We’ve done it on patients who have one lung,” he said.

Dr. Lau predicted that costs of ENB will come down with time. “Because of the number of products increasing, the price will drop,” he said.

Concluding the interview, Dr. Lau offered a summarizing message: “If you want to give the patient the safe option, you should do [ENB], and when it becomes more popular, the price will fall,” he said.

Medtronic funded the study. The investigators reported financial relationships with Olympus, Ambu, PulmonX, Boston Scientific, and others.

SOURCE: Lau et al. ELCC 2019. Abstract 68O.

ATLANTA – A combination of the epidermal growth factor receptor–targeted agent osimertinib (Tagrisso) with selumetinib, an investigational inhibitor of MEK1/2, was safe and associated with partial responses in about one-third of patients with non–small cell lung cancer in the phase 1b TATTON trial.

Neil Osterweil/MDedge News

In the dose-finding phase of the trial, the objective response rate was 42% for 36 patients treated with the combination either as a second- or third-line therapy, or following prior therapy for the epidermal growth factor receptor (EGFR) T70M mutation. In the dose-expansion phase of the trial, the ORR was 34% for 47 patients treated regardless of mutational status, reported Suresh S. Ramalingam, MD, from the Winship Cancer Institute at Emory University, Atlanta.

“We conclude that combining osimertinib with intermittent selumetinib is feasible with manageable toxicity and has already demonstrated promising preliminary anticancer activity,” he said at the annual meeting of the American Association for Cancer Research.

The EGFR T790M mutation is the most common cause of resistance in patients with non–small cell lung cancer (NSCLC) bearing EGFR mutations who are treated with first- or second-generation, EGFR-targeted tyrosine kinase inhibitors (TKI). Up-regulation of the RAS/RAF/MEK/ERK signaling pathway has also been implicated in NSCLC resistance to EGFR-targeted TKIs.

Selumetinib is an oral, potent, and selective inhibitor of MEK1/2 with a short half-life.

In the phase 3 SELECT-1 trial, selumetinib in combination with docetaxel did not significantly improve progression-free survival, compared with docetaxel alone as second-line therapy for patients with KRAS-mutated NSCLC.

Therapeutic rationale

Invited discussant Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Conn., said that there is sound rationale for combining osimertinib and selumetinib in EGFR-mutant NSCLC.

Neil Osterweil/MDedge News

In addition to the up-regulation of the RAS/RAF/MEK/ERK pathway noted before, resistance to osimertinib has been shown in models of EGFR-mutant NSCLC to develop from aberrant ERK signaling mediation in part by MEK1 amplification, and MEK kinase inhibitors can restore sensitivity to osimertinib in resistant cells, he said.

As previously reported, the TATTON investigators are evaluating in separate cohorts combinations of osimertinib with savolitinib, an investigational MET inhibitor for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents, or with selumetinib for patients with advanced EGFR-mutated NSCLC that had progressed on prior therapy, including EGFR-targeted TKIs, irrespective of T790M or KRAS status.

In part A, the dose-finding phase, patients received osimertinib 80 mg daily plus intermittent or continuous selumetinib. Asian patients received continuous selumetinib 25/50 mg twice daily, while other patients received continuous selumetinib 50/75 mg twice daily, or intermittent selumetinib 75 mg twice daily 4 days on, 3 days off or on days 1 and 4 of each week of treatment.

In part B, the dose-expansion phase, patients received osimertinib plus intermittent selumetinib 75 mg twice daily on the 4 days on/3 days off schedule.

An analysis of preliminary antitumor activity in part A showed an ORR in 15 of 36 patients (42%); all were partial responses (PR). In addition, 14 patients (39%) had stable disease at 6 weeks, 3 had progressive disease, 2 died, and 2 were not evaluable. The median duration of response was 16.6 months; 77% of the patients had responses lasting at least 12 months.

In part B, 16 of 47 patients enrolled (34%) had confirmed PR, and 16 had stable disease. Of the remaining patients, 11 had disease progression, 2 died, and 2 were not evaluable. The median duration of response in this group was 9.1 months, and 31% of patients remained in response at 12 months.

The most common treatment-related adverse events in the dose-finding phase were diarrhea in 75% of patients, nausea in 39% and fatigue in 33%. Dose-limiting toxicities occurred in six patients, all of whom had been treated with continuous selumetinib. These toxicities, all grade 3, include liver enzyme increases, diarrhea, asthenia, dizziness, nausea, and pneumonitis.

The most common treatment-related adverse events in the dose-expansion phase were diarrhea in 81%, stomatitis in 32%, and paronychia in 30% of patients.

Results ‘okay’

In his discussion, Dr. Herbst commented that the part A results “look okay, until you realize that the most of the activity is in those patients who are T790M-positive, who have not been exposed in this cohort to a third-generation T790M inhibitor.” Patients with the mutation who are treated with third-generation inhibitors would be expected to have a 78% response rate.

Part B included a few more patients with responses who were negative for T790M. “My thought here is that perhaps there is a biomarker” for selecting patients most likely to benefit from the combination, he said.

For MET-negative patients, the combination appears to have manageable toxicities with noncontinuous dosing of selumetinib, and there may be benefit to using it in the first-line setting in select patients, but that will require further trials and identification of suitable biomarkers, Dr. Herbst summarized.

TATTON was sponsored by AstraZeneca. Dr. Ramalingam reported receiving research support from the company and consulting/contracting with others. Dr. Herbst reported receiving research support from AstraZeneca, Eli Lilly, and Merck, and serving as a consultant for AstraZeneca, Eli Lilly, Genentech/Roche, Merck, NextCure, and Pfizer.

SOURCE: Ramalingam SS et al. AACR 2019, Abstract CT034.

ATLANTA – A combination of the epidermal growth factor receptor–targeted agent osimertinib (Tagrisso) with selumetinib, an investigational inhibitor of MEK1/2, was safe and associated with partial responses in about one-third of patients with non–small cell lung cancer in the phase 1b TATTON trial.

Neil Osterweil/MDedge News

In the dose-finding phase of the trial, the objective response rate was 42% for 36 patients treated with the combination either as a second- or third-line therapy, or following prior therapy for the epidermal growth factor receptor (EGFR) T70M mutation. In the dose-expansion phase of the trial, the ORR was 34% for 47 patients treated regardless of mutational status, reported Suresh S. Ramalingam, MD, from the Winship Cancer Institute at Emory University, Atlanta.

“We conclude that combining osimertinib with intermittent selumetinib is feasible with manageable toxicity and has already demonstrated promising preliminary anticancer activity,” he said at the annual meeting of the American Association for Cancer Research.

The EGFR T790M mutation is the most common cause of resistance in patients with non–small cell lung cancer (NSCLC) bearing EGFR mutations who are treated with first- or second-generation, EGFR-targeted tyrosine kinase inhibitors (TKI). Up-regulation of the RAS/RAF/MEK/ERK signaling pathway has also been implicated in NSCLC resistance to EGFR-targeted TKIs.

Selumetinib is an oral, potent, and selective inhibitor of MEK1/2 with a short half-life.

In the phase 3 SELECT-1 trial, selumetinib in combination with docetaxel did not significantly improve progression-free survival, compared with docetaxel alone as second-line therapy for patients with KRAS-mutated NSCLC.

Therapeutic rationale

Invited discussant Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Conn., said that there is sound rationale for combining osimertinib and selumetinib in EGFR-mutant NSCLC.

Neil Osterweil/MDedge News

In addition to the up-regulation of the RAS/RAF/MEK/ERK pathway noted before, resistance to osimertinib has been shown in models of EGFR-mutant NSCLC to develop from aberrant ERK signaling mediation in part by MEK1 amplification, and MEK kinase inhibitors can restore sensitivity to osimertinib in resistant cells, he said.

As previously reported, the TATTON investigators are evaluating in separate cohorts combinations of osimertinib with savolitinib, an investigational MET inhibitor for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents, or with selumetinib for patients with advanced EGFR-mutated NSCLC that had progressed on prior therapy, including EGFR-targeted TKIs, irrespective of T790M or KRAS status.

In part A, the dose-finding phase, patients received osimertinib 80 mg daily plus intermittent or continuous selumetinib. Asian patients received continuous selumetinib 25/50 mg twice daily, while other patients received continuous selumetinib 50/75 mg twice daily, or intermittent selumetinib 75 mg twice daily 4 days on, 3 days off or on days 1 and 4 of each week of treatment.

In part B, the dose-expansion phase, patients received osimertinib plus intermittent selumetinib 75 mg twice daily on the 4 days on/3 days off schedule.

An analysis of preliminary antitumor activity in part A showed an ORR in 15 of 36 patients (42%); all were partial responses (PR). In addition, 14 patients (39%) had stable disease at 6 weeks, 3 had progressive disease, 2 died, and 2 were not evaluable. The median duration of response was 16.6 months; 77% of the patients had responses lasting at least 12 months.

In part B, 16 of 47 patients enrolled (34%) had confirmed PR, and 16 had stable disease. Of the remaining patients, 11 had disease progression, 2 died, and 2 were not evaluable. The median duration of response in this group was 9.1 months, and 31% of patients remained in response at 12 months.

The most common treatment-related adverse events in the dose-finding phase were diarrhea in 75% of patients, nausea in 39% and fatigue in 33%. Dose-limiting toxicities occurred in six patients, all of whom had been treated with continuous selumetinib. These toxicities, all grade 3, include liver enzyme increases, diarrhea, asthenia, dizziness, nausea, and pneumonitis.

The most common treatment-related adverse events in the dose-expansion phase were diarrhea in 81%, stomatitis in 32%, and paronychia in 30% of patients.

Results ‘okay’

In his discussion, Dr. Herbst commented that the part A results “look okay, until you realize that the most of the activity is in those patients who are T790M-positive, who have not been exposed in this cohort to a third-generation T790M inhibitor.” Patients with the mutation who are treated with third-generation inhibitors would be expected to have a 78% response rate.

Part B included a few more patients with responses who were negative for T790M. “My thought here is that perhaps there is a biomarker” for selecting patients most likely to benefit from the combination, he said.

For MET-negative patients, the combination appears to have manageable toxicities with noncontinuous dosing of selumetinib, and there may be benefit to using it in the first-line setting in select patients, but that will require further trials and identification of suitable biomarkers, Dr. Herbst summarized.

TATTON was sponsored by AstraZeneca. Dr. Ramalingam reported receiving research support from the company and consulting/contracting with others. Dr. Herbst reported receiving research support from AstraZeneca, Eli Lilly, and Merck, and serving as a consultant for AstraZeneca, Eli Lilly, Genentech/Roche, Merck, NextCure, and Pfizer.

SOURCE: Ramalingam SS et al. AACR 2019, Abstract CT034.

ATLANTA – A combination of the epidermal growth factor receptor–targeted agent osimertinib (Tagrisso) with selumetinib, an investigational inhibitor of MEK1/2, was safe and associated with partial responses in about one-third of patients with non–small cell lung cancer in the phase 1b TATTON trial.

Neil Osterweil/MDedge News

In the dose-finding phase of the trial, the objective response rate was 42% for 36 patients treated with the combination either as a second- or third-line therapy, or following prior therapy for the epidermal growth factor receptor (EGFR) T70M mutation. In the dose-expansion phase of the trial, the ORR was 34% for 47 patients treated regardless of mutational status, reported Suresh S. Ramalingam, MD, from the Winship Cancer Institute at Emory University, Atlanta.

“We conclude that combining osimertinib with intermittent selumetinib is feasible with manageable toxicity and has already demonstrated promising preliminary anticancer activity,” he said at the annual meeting of the American Association for Cancer Research.

The EGFR T790M mutation is the most common cause of resistance in patients with non–small cell lung cancer (NSCLC) bearing EGFR mutations who are treated with first- or second-generation, EGFR-targeted tyrosine kinase inhibitors (TKI). Up-regulation of the RAS/RAF/MEK/ERK signaling pathway has also been implicated in NSCLC resistance to EGFR-targeted TKIs.

Selumetinib is an oral, potent, and selective inhibitor of MEK1/2 with a short half-life.

In the phase 3 SELECT-1 trial, selumetinib in combination with docetaxel did not significantly improve progression-free survival, compared with docetaxel alone as second-line therapy for patients with KRAS-mutated NSCLC.

Therapeutic rationale

Invited discussant Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Conn., said that there is sound rationale for combining osimertinib and selumetinib in EGFR-mutant NSCLC.

Neil Osterweil/MDedge News

In addition to the up-regulation of the RAS/RAF/MEK/ERK pathway noted before, resistance to osimertinib has been shown in models of EGFR-mutant NSCLC to develop from aberrant ERK signaling mediation in part by MEK1 amplification, and MEK kinase inhibitors can restore sensitivity to osimertinib in resistant cells, he said.

As previously reported, the TATTON investigators are evaluating in separate cohorts combinations of osimertinib with savolitinib, an investigational MET inhibitor for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents, or with selumetinib for patients with advanced EGFR-mutated NSCLC that had progressed on prior therapy, including EGFR-targeted TKIs, irrespective of T790M or KRAS status.

In part A, the dose-finding phase, patients received osimertinib 80 mg daily plus intermittent or continuous selumetinib. Asian patients received continuous selumetinib 25/50 mg twice daily, while other patients received continuous selumetinib 50/75 mg twice daily, or intermittent selumetinib 75 mg twice daily 4 days on, 3 days off or on days 1 and 4 of each week of treatment.

In part B, the dose-expansion phase, patients received osimertinib plus intermittent selumetinib 75 mg twice daily on the 4 days on/3 days off schedule.

An analysis of preliminary antitumor activity in part A showed an ORR in 15 of 36 patients (42%); all were partial responses (PR). In addition, 14 patients (39%) had stable disease at 6 weeks, 3 had progressive disease, 2 died, and 2 were not evaluable. The median duration of response was 16.6 months; 77% of the patients had responses lasting at least 12 months.

In part B, 16 of 47 patients enrolled (34%) had confirmed PR, and 16 had stable disease. Of the remaining patients, 11 had disease progression, 2 died, and 2 were not evaluable. The median duration of response in this group was 9.1 months, and 31% of patients remained in response at 12 months.

The most common treatment-related adverse events in the dose-finding phase were diarrhea in 75% of patients, nausea in 39% and fatigue in 33%. Dose-limiting toxicities occurred in six patients, all of whom had been treated with continuous selumetinib. These toxicities, all grade 3, include liver enzyme increases, diarrhea, asthenia, dizziness, nausea, and pneumonitis.

The most common treatment-related adverse events in the dose-expansion phase were diarrhea in 81%, stomatitis in 32%, and paronychia in 30% of patients.

Results ‘okay’

In his discussion, Dr. Herbst commented that the part A results “look okay, until you realize that the most of the activity is in those patients who are T790M-positive, who have not been exposed in this cohort to a third-generation T790M inhibitor.” Patients with the mutation who are treated with third-generation inhibitors would be expected to have a 78% response rate.

Part B included a few more patients with responses who were negative for T790M. “My thought here is that perhaps there is a biomarker” for selecting patients most likely to benefit from the combination, he said.

For MET-negative patients, the combination appears to have manageable toxicities with noncontinuous dosing of selumetinib, and there may be benefit to using it in the first-line setting in select patients, but that will require further trials and identification of suitable biomarkers, Dr. Herbst summarized.

TATTON was sponsored by AstraZeneca. Dr. Ramalingam reported receiving research support from the company and consulting/contracting with others. Dr. Herbst reported receiving research support from AstraZeneca, Eli Lilly, and Merck, and serving as a consultant for AstraZeneca, Eli Lilly, Genentech/Roche, Merck, NextCure, and Pfizer.

SOURCE: Ramalingam SS et al. AACR 2019, Abstract CT034.

For patients with centrally located lung cancers in a multicenter phase 1/2 trial, a specific five-fraction radiotherapy schedule was well tolerated and linked to fairly low rates of treatment-related toxicity, investigators say.

The 12-Gy/fraction schedule of stereotactic body radiotherapy (SBRT) had a 7.2% rate of dose-limiting toxicities and a high tumor-control rate in the NRG Oncology/RTOG 0813 trial, which enrolled 120 patients with medically inoperable stage T1/2 N0M0 non–small cell lung cancers at 43 centers in the United States and Canada.

This is an important study that has implications for clinical practice, according to the investigators, led by Andrea Bezjak, MD, of Princess Margaret Cancer Centre in Toronto.

“The ability to treat patients with centrally located node-negative tumors in multiple institutions across the United States and Canada while maintaining plan qualities and achieving good patient outcomes and relatively modest rates of toxicity is an important achievement,” Dr. Bezjak and coinvestigators said in the Journal of Clinical Oncology.

These patients are frequently at increased risk from surgery, because of advanced age and the comorbidities that come with it, they added.

The 12-Gy/fraction dose level was the highest of nine dose levels included in the study protocol. Doses were delivered in five fractions over the course of 1.5-2 weeks. Investigators sought to determine the maximum tolerated dose of SRBT, defined as the level at which the probability of dose-limiting toxicities (grade 3 or greater) within the first year was as close to 20% as possible, without going over.

Thus, the 7.2% rate of dose-limiting toxicities at this highest-allowed dose level was “well below” that protocol-specified threshold, investigators said, commenting on results of the study.

The rate of local control at 2 years was 89.4% for the 12-Gy/fraction dose level. The 2-year overall survival was 70%, which compared favorably to what has been seen previously with use of SBRT in similar patients with peripheral tumors, according to Dr. Bezjak and colleagues.

Most deaths in the study were attributable to causes other than lung cancer, according to investigators, who noted that all accrued patients were deemed medically inoperable by an experienced thoracic surgeon.

“Thus, this study provides robust data about the safety and efficacy of a five-fraction SBRT schedule that is well tolerated and associated with relatively low rates of serious treatment-related toxicity,” they concluded.

Dr. Bezjak reported disclosures related to AstraZeneca and Abbvie. Coauthors provided disclosures related to Varian Medical Systems, Elekta, Accuray, Seattle Genetics, Celgene, Exelixis, Gilead Sciences, Illumina, Ions Pharmaceuticals, and EMD Serono, among others.

SOURCE: Bezjak A et al. J Clin Oncol. 2019 Apr 3. doi: 10.1200/JCO.18.00622.

For patients with centrally located lung cancers in a multicenter phase 1/2 trial, a specific five-fraction radiotherapy schedule was well tolerated and linked to fairly low rates of treatment-related toxicity, investigators say.

The 12-Gy/fraction schedule of stereotactic body radiotherapy (SBRT) had a 7.2% rate of dose-limiting toxicities and a high tumor-control rate in the NRG Oncology/RTOG 0813 trial, which enrolled 120 patients with medically inoperable stage T1/2 N0M0 non–small cell lung cancers at 43 centers in the United States and Canada.

This is an important study that has implications for clinical practice, according to the investigators, led by Andrea Bezjak, MD, of Princess Margaret Cancer Centre in Toronto.

“The ability to treat patients with centrally located node-negative tumors in multiple institutions across the United States and Canada while maintaining plan qualities and achieving good patient outcomes and relatively modest rates of toxicity is an important achievement,” Dr. Bezjak and coinvestigators said in the Journal of Clinical Oncology.

These patients are frequently at increased risk from surgery, because of advanced age and the comorbidities that come with it, they added.

The 12-Gy/fraction dose level was the highest of nine dose levels included in the study protocol. Doses were delivered in five fractions over the course of 1.5-2 weeks. Investigators sought to determine the maximum tolerated dose of SRBT, defined as the level at which the probability of dose-limiting toxicities (grade 3 or greater) within the first year was as close to 20% as possible, without going over.

Thus, the 7.2% rate of dose-limiting toxicities at this highest-allowed dose level was “well below” that protocol-specified threshold, investigators said, commenting on results of the study.

The rate of local control at 2 years was 89.4% for the 12-Gy/fraction dose level. The 2-year overall survival was 70%, which compared favorably to what has been seen previously with use of SBRT in similar patients with peripheral tumors, according to Dr. Bezjak and colleagues.

Most deaths in the study were attributable to causes other than lung cancer, according to investigators, who noted that all accrued patients were deemed medically inoperable by an experienced thoracic surgeon.

“Thus, this study provides robust data about the safety and efficacy of a five-fraction SBRT schedule that is well tolerated and associated with relatively low rates of serious treatment-related toxicity,” they concluded.

Dr. Bezjak reported disclosures related to AstraZeneca and Abbvie. Coauthors provided disclosures related to Varian Medical Systems, Elekta, Accuray, Seattle Genetics, Celgene, Exelixis, Gilead Sciences, Illumina, Ions Pharmaceuticals, and EMD Serono, among others.

SOURCE: Bezjak A et al. J Clin Oncol. 2019 Apr 3. doi: 10.1200/JCO.18.00622.

For patients with centrally located lung cancers in a multicenter phase 1/2 trial, a specific five-fraction radiotherapy schedule was well tolerated and linked to fairly low rates of treatment-related toxicity, investigators say.

The 12-Gy/fraction schedule of stereotactic body radiotherapy (SBRT) had a 7.2% rate of dose-limiting toxicities and a high tumor-control rate in the NRG Oncology/RTOG 0813 trial, which enrolled 120 patients with medically inoperable stage T1/2 N0M0 non–small cell lung cancers at 43 centers in the United States and Canada.

This is an important study that has implications for clinical practice, according to the investigators, led by Andrea Bezjak, MD, of Princess Margaret Cancer Centre in Toronto.

“The ability to treat patients with centrally located node-negative tumors in multiple institutions across the United States and Canada while maintaining plan qualities and achieving good patient outcomes and relatively modest rates of toxicity is an important achievement,” Dr. Bezjak and coinvestigators said in the Journal of Clinical Oncology.

These patients are frequently at increased risk from surgery, because of advanced age and the comorbidities that come with it, they added.

The 12-Gy/fraction dose level was the highest of nine dose levels included in the study protocol. Doses were delivered in five fractions over the course of 1.5-2 weeks. Investigators sought to determine the maximum tolerated dose of SRBT, defined as the level at which the probability of dose-limiting toxicities (grade 3 or greater) within the first year was as close to 20% as possible, without going over.

Thus, the 7.2% rate of dose-limiting toxicities at this highest-allowed dose level was “well below” that protocol-specified threshold, investigators said, commenting on results of the study.

The rate of local control at 2 years was 89.4% for the 12-Gy/fraction dose level. The 2-year overall survival was 70%, which compared favorably to what has been seen previously with use of SBRT in similar patients with peripheral tumors, according to Dr. Bezjak and colleagues.

Most deaths in the study were attributable to causes other than lung cancer, according to investigators, who noted that all accrued patients were deemed medically inoperable by an experienced thoracic surgeon.

“Thus, this study provides robust data about the safety and efficacy of a five-fraction SBRT schedule that is well tolerated and associated with relatively low rates of serious treatment-related toxicity,” they concluded.

Dr. Bezjak reported disclosures related to AstraZeneca and Abbvie. Coauthors provided disclosures related to Varian Medical Systems, Elekta, Accuray, Seattle Genetics, Celgene, Exelixis, Gilead Sciences, Illumina, Ions Pharmaceuticals, and EMD Serono, among others.

SOURCE: Bezjak A et al. J Clin Oncol. 2019 Apr 3. doi: 10.1200/JCO.18.00622.

ATLANTA – About 10%-25% of patients with epithelial growth factor receptor–(EGFR) mutant non–small cell lung cancer (NSCLC) have tumors with either MET amplification or another MET-based mechanism that leads to drug resistance.

In the TATTON trial, investigators are evaluating a combination of the EGFR-targeted tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) with savolitinib, an investigational MET inhibitor, for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents.

In a video interview at the annual meeting of the American Association for Cancer Research, Lecia Sequist, MD, from the Massachusetts General Hospital Cancer Center in Boston, discusses early results with the osimertinib/savolitinib combination in patients with disease progression after a first and/or second-generation EGFR TKI, or after a third-generation agent.

Dr. Sequist said results of TATTON suggest that it may be possible to overcome MET-driven drug-resistance mechanisms.

The TATTON trial is sponsored by AstraZeneca. Dr. Sequist reported serving as an advisory board member and receiving research support and honoraria from the company.

ATLANTA – About 10%-25% of patients with epithelial growth factor receptor–(EGFR) mutant non–small cell lung cancer (NSCLC) have tumors with either MET amplification or another MET-based mechanism that leads to drug resistance.

In the TATTON trial, investigators are evaluating a combination of the EGFR-targeted tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) with savolitinib, an investigational MET inhibitor, for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents.

In a video interview at the annual meeting of the American Association for Cancer Research, Lecia Sequist, MD, from the Massachusetts General Hospital Cancer Center in Boston, discusses early results with the osimertinib/savolitinib combination in patients with disease progression after a first and/or second-generation EGFR TKI, or after a third-generation agent.

Dr. Sequist said results of TATTON suggest that it may be possible to overcome MET-driven drug-resistance mechanisms.

The TATTON trial is sponsored by AstraZeneca. Dr. Sequist reported serving as an advisory board member and receiving research support and honoraria from the company.

ATLANTA – About 10%-25% of patients with epithelial growth factor receptor–(EGFR) mutant non–small cell lung cancer (NSCLC) have tumors with either MET amplification or another MET-based mechanism that leads to drug resistance.

In the TATTON trial, investigators are evaluating a combination of the EGFR-targeted tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) with savolitinib, an investigational MET inhibitor, for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents.

In a video interview at the annual meeting of the American Association for Cancer Research, Lecia Sequist, MD, from the Massachusetts General Hospital Cancer Center in Boston, discusses early results with the osimertinib/savolitinib combination in patients with disease progression after a first and/or second-generation EGFR TKI, or after a third-generation agent.

Dr. Sequist said results of TATTON suggest that it may be possible to overcome MET-driven drug-resistance mechanisms.

The TATTON trial is sponsored by AstraZeneca. Dr. Sequist reported serving as an advisory board member and receiving research support and honoraria from the company.

Taking a deep dive into plasma cell-free DNA in patients with advanced non–small cell lung cancer may reveal targetable mutations and cancer resistance mechanisms in tumors, even when tissue biopsy samples are not adequate for genotyping, investigators say,

Noninvasive tumor genotyping of plasma cell-free DNA (cfDNA) with ultra-deep next generation sequencing (NGS) in plasma samples from 127 patients identified known oncogenic drivers with a sensitivity of 75% and ruled out the presence of driver mutations with a specificity of 100% in patients with tissue samples indicating no mutations, reported Bob T. Li, MD, MPH, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, and his colleagues.

“These results reveal the potential utility of NGS assays that use cfDNA as input for detecting actionable driver alterations and both de novo and emergent resistance mechanisms in the clinical setting,” they wrote. The report is in Annals of Oncology.

Although the researchers did not directly assess clinical utility, the results suggest that NGS-based analysis of cfDNA may help guide treatment selection, they added.

Ultra-deep NGS is a kind of obsessive-compulsive form of sequencing in which the same genomic region is read repeatedly – in this study, 50,000 times over – with filtering of somatic mutations attributable to clonal hematopoiesis. The technique allows for detection of rare genetic alterations that can be missed by other methods.

“More recent studies employing plasma cfDNA NGS have shown promise in detecting a broader variety of genetic alterations with similar sensitivity to that of digital PCR, with potential to change clinical practice,” Dr. Li and his colleagues wrote.

They conducted a systematic study of a novel cfDNA assay in patients whose cancers had oncogenic driver mutations, those who were driver negative on tissue-based NGS, and those whose tumors had unknown mutational status.

A total of 127 patients from three centers (MSKCC, the Dana-Farber Cancer Center in Boston, and the University of Texas MD Anderson Cancer Center in Houston) were available for assessment.

Ultra-deep NGS was performed on cfDNA and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50,000 times raw-target coverage filtering somatic mutations attributable to clonal hematopoiesis.

Plasma NGS was able to detect driver mutations with variant allele frequencies ranging from as low as 0.14% to as high as 52%.

In 21 of 22 patients, plasma digital drop polymerase chain reaction (ddPCR) results for EGFR or KRAS mutations were nearly identical to those of NGS, with high concordance for variant allele frequencies (r = .98).

In analyses blinded to tissue genotyping results in 91 patients, plasma NGS detected de novo known oncogenic driver alterations in 68 samples, for a sensitivity of 75%, and in 19 of 19 patients who were driver negative by tissue sequencing, plasma NGS also showed an absence of mutations, for a specificity of 100%.

Furthermore, plasma NGS identified four KRAS mutations in plasma from 17 patients for whom tissues samples were not adequate for genotyping, and the plasma-based technique was able to identify potential resistance mutations in samples from 23 patients with EGFR mutations whose tumors had required resistance to targeted therapy.

“The sensitivity of detection by NGS was comparable to that of established ddPCR methods. Its high concordance with tissue genotyping and the detection of drivers in settings where tissue biopsy had failed or was not feasible lend credence to the potential clinical use of plasma cfDNA NGS and the development of cfDNA-guided intervention studies,” the investigators wrote.

The study was supported by Illumina. Authors from MSKCC and MD Anderson were supported by National Institutes of Health grants. Dr. Li received consulting/advisory board fees from Genentech, Thermo-Fisher Scientific, and Guardant Health outside of the submitted work. Multiple coauthors reported similar relationships, and eight coauthors were current or former employees of Illumina.

SOURCE: Source: Li BT et al. Ann Oncol. doi: 10.1093/annonc/mdz046.

Taking a deep dive into plasma cell-free DNA in patients with advanced non–small cell lung cancer may reveal targetable mutations and cancer resistance mechanisms in tumors, even when tissue biopsy samples are not adequate for genotyping, investigators say,

Noninvasive tumor genotyping of plasma cell-free DNA (cfDNA) with ultra-deep next generation sequencing (NGS) in plasma samples from 127 patients identified known oncogenic drivers with a sensitivity of 75% and ruled out the presence of driver mutations with a specificity of 100% in patients with tissue samples indicating no mutations, reported Bob T. Li, MD, MPH, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, and his colleagues.

“These results reveal the potential utility of NGS assays that use cfDNA as input for detecting actionable driver alterations and both de novo and emergent resistance mechanisms in the clinical setting,” they wrote. The report is in Annals of Oncology.

Although the researchers did not directly assess clinical utility, the results suggest that NGS-based analysis of cfDNA may help guide treatment selection, they added.

Ultra-deep NGS is a kind of obsessive-compulsive form of sequencing in which the same genomic region is read repeatedly – in this study, 50,000 times over – with filtering of somatic mutations attributable to clonal hematopoiesis. The technique allows for detection of rare genetic alterations that can be missed by other methods.

“More recent studies employing plasma cfDNA NGS have shown promise in detecting a broader variety of genetic alterations with similar sensitivity to that of digital PCR, with potential to change clinical practice,” Dr. Li and his colleagues wrote.

They conducted a systematic study of a novel cfDNA assay in patients whose cancers had oncogenic driver mutations, those who were driver negative on tissue-based NGS, and those whose tumors had unknown mutational status.

A total of 127 patients from three centers (MSKCC, the Dana-Farber Cancer Center in Boston, and the University of Texas MD Anderson Cancer Center in Houston) were available for assessment.

Ultra-deep NGS was performed on cfDNA and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50,000 times raw-target coverage filtering somatic mutations attributable to clonal hematopoiesis.

Plasma NGS was able to detect driver mutations with variant allele frequencies ranging from as low as 0.14% to as high as 52%.

In 21 of 22 patients, plasma digital drop polymerase chain reaction (ddPCR) results for EGFR or KRAS mutations were nearly identical to those of NGS, with high concordance for variant allele frequencies (r = .98).

In analyses blinded to tissue genotyping results in 91 patients, plasma NGS detected de novo known oncogenic driver alterations in 68 samples, for a sensitivity of 75%, and in 19 of 19 patients who were driver negative by tissue sequencing, plasma NGS also showed an absence of mutations, for a specificity of 100%.

Furthermore, plasma NGS identified four KRAS mutations in plasma from 17 patients for whom tissues samples were not adequate for genotyping, and the plasma-based technique was able to identify potential resistance mutations in samples from 23 patients with EGFR mutations whose tumors had required resistance to targeted therapy.

“The sensitivity of detection by NGS was comparable to that of established ddPCR methods. Its high concordance with tissue genotyping and the detection of drivers in settings where tissue biopsy had failed or was not feasible lend credence to the potential clinical use of plasma cfDNA NGS and the development of cfDNA-guided intervention studies,” the investigators wrote.

The study was supported by Illumina. Authors from MSKCC and MD Anderson were supported by National Institutes of Health grants. Dr. Li received consulting/advisory board fees from Genentech, Thermo-Fisher Scientific, and Guardant Health outside of the submitted work. Multiple coauthors reported similar relationships, and eight coauthors were current or former employees of Illumina.

SOURCE: Source: Li BT et al. Ann Oncol. doi: 10.1093/annonc/mdz046.

Taking a deep dive into plasma cell-free DNA in patients with advanced non–small cell lung cancer may reveal targetable mutations and cancer resistance mechanisms in tumors, even when tissue biopsy samples are not adequate for genotyping, investigators say,

Noninvasive tumor genotyping of plasma cell-free DNA (cfDNA) with ultra-deep next generation sequencing (NGS) in plasma samples from 127 patients identified known oncogenic drivers with a sensitivity of 75% and ruled out the presence of driver mutations with a specificity of 100% in patients with tissue samples indicating no mutations, reported Bob T. Li, MD, MPH, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, and his colleagues.

“These results reveal the potential utility of NGS assays that use cfDNA as input for detecting actionable driver alterations and both de novo and emergent resistance mechanisms in the clinical setting,” they wrote. The report is in Annals of Oncology.

Although the researchers did not directly assess clinical utility, the results suggest that NGS-based analysis of cfDNA may help guide treatment selection, they added.

Ultra-deep NGS is a kind of obsessive-compulsive form of sequencing in which the same genomic region is read repeatedly – in this study, 50,000 times over – with filtering of somatic mutations attributable to clonal hematopoiesis. The technique allows for detection of rare genetic alterations that can be missed by other methods.

“More recent studies employing plasma cfDNA NGS have shown promise in detecting a broader variety of genetic alterations with similar sensitivity to that of digital PCR, with potential to change clinical practice,” Dr. Li and his colleagues wrote.

They conducted a systematic study of a novel cfDNA assay in patients whose cancers had oncogenic driver mutations, those who were driver negative on tissue-based NGS, and those whose tumors had unknown mutational status.

A total of 127 patients from three centers (MSKCC, the Dana-Farber Cancer Center in Boston, and the University of Texas MD Anderson Cancer Center in Houston) were available for assessment.

Ultra-deep NGS was performed on cfDNA and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50,000 times raw-target coverage filtering somatic mutations attributable to clonal hematopoiesis.

Plasma NGS was able to detect driver mutations with variant allele frequencies ranging from as low as 0.14% to as high as 52%.

In 21 of 22 patients, plasma digital drop polymerase chain reaction (ddPCR) results for EGFR or KRAS mutations were nearly identical to those of NGS, with high concordance for variant allele frequencies (r = .98).

In analyses blinded to tissue genotyping results in 91 patients, plasma NGS detected de novo known oncogenic driver alterations in 68 samples, for a sensitivity of 75%, and in 19 of 19 patients who were driver negative by tissue sequencing, plasma NGS also showed an absence of mutations, for a specificity of 100%.

Furthermore, plasma NGS identified four KRAS mutations in plasma from 17 patients for whom tissues samples were not adequate for genotyping, and the plasma-based technique was able to identify potential resistance mutations in samples from 23 patients with EGFR mutations whose tumors had required resistance to targeted therapy.

“The sensitivity of detection by NGS was comparable to that of established ddPCR methods. Its high concordance with tissue genotyping and the detection of drivers in settings where tissue biopsy had failed or was not feasible lend credence to the potential clinical use of plasma cfDNA NGS and the development of cfDNA-guided intervention studies,” the investigators wrote.

The study was supported by Illumina. Authors from MSKCC and MD Anderson were supported by National Institutes of Health grants. Dr. Li received consulting/advisory board fees from Genentech, Thermo-Fisher Scientific, and Guardant Health outside of the submitted work. Multiple coauthors reported similar relationships, and eight coauthors were current or former employees of Illumina.

SOURCE: Source: Li BT et al. Ann Oncol. doi: 10.1093/annonc/mdz046.

The Food and Drug Administration has approved atezolizumab (Tecentriq), in combination with carboplatin and etoposide, for the first-line treatment of adults with extensive-stage small cell lung cancer (ES-SCLC).

Approval was based on results from the phase 3 IMpower133 study, in which 403 treatment-naive patients with ES-SCLC received atezolizumab at 1,200 mg with carboplatin at 5 mg/mL per minute on day 1 and etoposide 100 mg/m² on days 1, 2, and 3 of a 21-day cycle for four cycles, followed by atezolizumab at 1,200 mg once every 3 weeks until disease progression or unacceptable toxicity; or received placebo with the same dosage of carboplatin and etoposide for a similar duration.

Overall survival was significantly better in patients who received atezolizumab, compared with placebo (12.3 vs. 10.3 months; hazard ratio, 0.70; 95% confidence interval, 0.54-0.91; P = .0069), as was progression-free survival (5.2 vs. 4.3 months; HR, 0.77; 95% CI, 0.62-0.96; P = .017).

The most common adverse events associated with atezolizumab in the study were fatigue/asthenia, nausea, alopecia, constipation, and decreased appetite.

According to the FDA, the recommended dose is 1,200 mg IV over 60 minutes every 3 weeks. When administered on the same day as chemotherapy, atezolizumab should be given first. If the first infusion is tolerated, all subsequent infusions can be delivered over 30 minutes.

Find the full press release on the FDA website.

lfranki@mdedge.com

The Food and Drug Administration has approved atezolizumab (Tecentriq), in combination with carboplatin and etoposide, for the first-line treatment of adults with extensive-stage small cell lung cancer (ES-SCLC).

Approval was based on results from the phase 3 IMpower133 study, in which 403 treatment-naive patients with ES-SCLC received atezolizumab at 1,200 mg with carboplatin at 5 mg/mL per minute on day 1 and etoposide 100 mg/m² on days 1, 2, and 3 of a 21-day cycle for four cycles, followed by atezolizumab at 1,200 mg once every 3 weeks until disease progression or unacceptable toxicity; or received placebo with the same dosage of carboplatin and etoposide for a similar duration.

Overall survival was significantly better in patients who received atezolizumab, compared with placebo (12.3 vs. 10.3 months; hazard ratio, 0.70; 95% confidence interval, 0.54-0.91; P = .0069), as was progression-free survival (5.2 vs. 4.3 months; HR, 0.77; 95% CI, 0.62-0.96; P = .017).

The most common adverse events associated with atezolizumab in the study were fatigue/asthenia, nausea, alopecia, constipation, and decreased appetite.

According to the FDA, the recommended dose is 1,200 mg IV over 60 minutes every 3 weeks. When administered on the same day as chemotherapy, atezolizumab should be given first. If the first infusion is tolerated, all subsequent infusions can be delivered over 30 minutes.

Find the full press release on the FDA website.

lfranki@mdedge.com

The Food and Drug Administration has approved atezolizumab (Tecentriq), in combination with carboplatin and etoposide, for the first-line treatment of adults with extensive-stage small cell lung cancer (ES-SCLC).

Approval was based on results from the phase 3 IMpower133 study, in which 403 treatment-naive patients with ES-SCLC received atezolizumab at 1,200 mg with carboplatin at 5 mg/mL per minute on day 1 and etoposide 100 mg/m² on days 1, 2, and 3 of a 21-day cycle for four cycles, followed by atezolizumab at 1,200 mg once every 3 weeks until disease progression or unacceptable toxicity; or received placebo with the same dosage of carboplatin and etoposide for a similar duration.

Overall survival was significantly better in patients who received atezolizumab, compared with placebo (12.3 vs. 10.3 months; hazard ratio, 0.70; 95% confidence interval, 0.54-0.91; P = .0069), as was progression-free survival (5.2 vs. 4.3 months; HR, 0.77; 95% CI, 0.62-0.96; P = .017).

The most common adverse events associated with atezolizumab in the study were fatigue/asthenia, nausea, alopecia, constipation, and decreased appetite.

According to the FDA, the recommended dose is 1,200 mg IV over 60 minutes every 3 weeks. When administered on the same day as chemotherapy, atezolizumab should be given first. If the first infusion is tolerated, all subsequent infusions can be delivered over 30 minutes.

Find the full press release on the FDA website.

lfranki@mdedge.com