Lung Cancer

CHICAGO – The oral tyrosine kinase inhibitor (TKI) repotrectinib is safe and has demonstrated encouraging activity in patients with advanced ROS1 fusion-positive non-small cell lung cancer, early results of a phase 1/2 study show.

Objective response rates of 82% in 11 TKI-naive patients and 39% in 22 TKI-pretreated patients were seen after treatment with repotrectinib, a next-generation inhibitor of ROS1/TRK/ALK with a 90-fold greater potency for ROS1 versus crizotinib, according to an investigator in the study.

“The TRIDENT-1 study supports repotrectinib as a potential best-in-class ROS1 agent in advanced non–small cell lung cancer,” said investigator ByoungChul Cho, MD, PhD, of Yonsei Cancer Center in Seoul, South Korea, in a podium presentation at the annual meeting of the American Society of Clinical Oncology.

For the 11 TKI-naive patients, no median duration of response had yet been reached over a median follow-up duration of nearly 17 months, with individual response durations that ranged from 10.9 to 17.7 or more months in the 5 of 9 patients remaining in response, Dr. Cho reported.

“This is exciting, because this is the most promising data presented so far with ROS1 TKI in TKI-naive patient population,” Dr. Cho said.

Repotrectinib also showed a potential to overcome TKI resistance mutations, notably G2032R, which is the most common ROS1 resistance mutation after crizotinib treatment.

All five patients with ROS1 G2032R mutation experienced tumor regression, with a confirmed response rate of 40%, Dr. Cho said.

The TKI was relatively well tolerated with four dose-limiting toxicity events including grade 2-3 dizziness in three cases and grade 3 dyspnea and hypoxia in one case.

Of four grade 5 treatment-emergent adverse events, only one case was possibly related to the treatment, Dr. Cho said.

Based on this tolerability and preliminary activity, the pivotal phase 2 portion of TRIDENT-1 is set to begin in the second half of 2019.

Benjamin Besse, MD, PhD, of Paris-Sud University, Orsay, and Institut Gustave Roussy said these preliminary results were very encouraging.

“If we look at the global picture, repotrectinib is probably today the most potent TKI against ROS1,” Dr. Besse said in a podium discussion of the results. “We don’t know yet if this will translate in an improved progression-free survival.”

Close follow-up of adverse events are warranted in further investigations because of the potency of the drug, he added.

Turning Point Therapeutics sponsored the study. Dr. Cho reported disclosures related to TheraCanVac, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Champions Oncology, Dizal Pharma, Dong-A ST, Eli Lilly, Janssen, Mogam Institute, MSD, Novartis, Ono, Pfizer, Roche, Takeda, and Yuhan.
 

SOURCE: Cho BC et al. ASCO 2019, Abstract 9011.

CHICAGO – The oral tyrosine kinase inhibitor (TKI) repotrectinib is safe and has demonstrated encouraging activity in patients with advanced ROS1 fusion-positive non-small cell lung cancer, early results of a phase 1/2 study show.

Objective response rates of 82% in 11 TKI-naive patients and 39% in 22 TKI-pretreated patients were seen after treatment with repotrectinib, a next-generation inhibitor of ROS1/TRK/ALK with a 90-fold greater potency for ROS1 versus crizotinib, according to an investigator in the study.

“The TRIDENT-1 study supports repotrectinib as a potential best-in-class ROS1 agent in advanced non–small cell lung cancer,” said investigator ByoungChul Cho, MD, PhD, of Yonsei Cancer Center in Seoul, South Korea, in a podium presentation at the annual meeting of the American Society of Clinical Oncology.

For the 11 TKI-naive patients, no median duration of response had yet been reached over a median follow-up duration of nearly 17 months, with individual response durations that ranged from 10.9 to 17.7 or more months in the 5 of 9 patients remaining in response, Dr. Cho reported.

“This is exciting, because this is the most promising data presented so far with ROS1 TKI in TKI-naive patient population,” Dr. Cho said.

Repotrectinib also showed a potential to overcome TKI resistance mutations, notably G2032R, which is the most common ROS1 resistance mutation after crizotinib treatment.

All five patients with ROS1 G2032R mutation experienced tumor regression, with a confirmed response rate of 40%, Dr. Cho said.

The TKI was relatively well tolerated with four dose-limiting toxicity events including grade 2-3 dizziness in three cases and grade 3 dyspnea and hypoxia in one case.

Of four grade 5 treatment-emergent adverse events, only one case was possibly related to the treatment, Dr. Cho said.

Based on this tolerability and preliminary activity, the pivotal phase 2 portion of TRIDENT-1 is set to begin in the second half of 2019.

Benjamin Besse, MD, PhD, of Paris-Sud University, Orsay, and Institut Gustave Roussy said these preliminary results were very encouraging.

“If we look at the global picture, repotrectinib is probably today the most potent TKI against ROS1,” Dr. Besse said in a podium discussion of the results. “We don’t know yet if this will translate in an improved progression-free survival.”

Close follow-up of adverse events are warranted in further investigations because of the potency of the drug, he added.

Turning Point Therapeutics sponsored the study. Dr. Cho reported disclosures related to TheraCanVac, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Champions Oncology, Dizal Pharma, Dong-A ST, Eli Lilly, Janssen, Mogam Institute, MSD, Novartis, Ono, Pfizer, Roche, Takeda, and Yuhan.
 

SOURCE: Cho BC et al. ASCO 2019, Abstract 9011.

CHICAGO – The oral tyrosine kinase inhibitor (TKI) repotrectinib is safe and has demonstrated encouraging activity in patients with advanced ROS1 fusion-positive non-small cell lung cancer, early results of a phase 1/2 study show.

Objective response rates of 82% in 11 TKI-naive patients and 39% in 22 TKI-pretreated patients were seen after treatment with repotrectinib, a next-generation inhibitor of ROS1/TRK/ALK with a 90-fold greater potency for ROS1 versus crizotinib, according to an investigator in the study.

“The TRIDENT-1 study supports repotrectinib as a potential best-in-class ROS1 agent in advanced non–small cell lung cancer,” said investigator ByoungChul Cho, MD, PhD, of Yonsei Cancer Center in Seoul, South Korea, in a podium presentation at the annual meeting of the American Society of Clinical Oncology.

For the 11 TKI-naive patients, no median duration of response had yet been reached over a median follow-up duration of nearly 17 months, with individual response durations that ranged from 10.9 to 17.7 or more months in the 5 of 9 patients remaining in response, Dr. Cho reported.

“This is exciting, because this is the most promising data presented so far with ROS1 TKI in TKI-naive patient population,” Dr. Cho said.

Repotrectinib also showed a potential to overcome TKI resistance mutations, notably G2032R, which is the most common ROS1 resistance mutation after crizotinib treatment.

All five patients with ROS1 G2032R mutation experienced tumor regression, with a confirmed response rate of 40%, Dr. Cho said.

The TKI was relatively well tolerated with four dose-limiting toxicity events including grade 2-3 dizziness in three cases and grade 3 dyspnea and hypoxia in one case.

Of four grade 5 treatment-emergent adverse events, only one case was possibly related to the treatment, Dr. Cho said.

Based on this tolerability and preliminary activity, the pivotal phase 2 portion of TRIDENT-1 is set to begin in the second half of 2019.

Benjamin Besse, MD, PhD, of Paris-Sud University, Orsay, and Institut Gustave Roussy said these preliminary results were very encouraging.

“If we look at the global picture, repotrectinib is probably today the most potent TKI against ROS1,” Dr. Besse said in a podium discussion of the results. “We don’t know yet if this will translate in an improved progression-free survival.”

Close follow-up of adverse events are warranted in further investigations because of the potency of the drug, he added.

Turning Point Therapeutics sponsored the study. Dr. Cho reported disclosures related to TheraCanVac, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Champions Oncology, Dizal Pharma, Dong-A ST, Eli Lilly, Janssen, Mogam Institute, MSD, Novartis, Ono, Pfizer, Roche, Takeda, and Yuhan.
 

SOURCE: Cho BC et al. ASCO 2019, Abstract 9011.

An immune-related adverse event during initial treatment with an immune checkpoint inhibitor does not necessarily preclude a rechallenge, based on a review of outcomes in 93 patients with a variety of cancers who were part of a cohort study.

Rechallenge resulted in the recurrence of a grade 2 or higher immune-related adverse event (irAE) in 55% of rechallenged patients, but no deaths occurred, according to Audrey Simonaggio, MD, of the department of drug development at Gustave Roussy, Villejuif, France, and colleagues.

In those rechallenged patients who had a second irAE, the second event was not more severe than the first. “The rechallenge should first be assessed in a multidisciplinary team meeting with regard to each patient’s individual risk-reward ratio. ... We recommend close monitoring,” the researchers wrote in a study published in JAMA Oncology.

As there are no specific recommendations to guide the decision to rechallenge, the usefulness of the rechallenge was considered. The readministration could be delayed if the patient was in complete or excellent partial response. The existence of other therapeutic alternatives was also important as was the patient’s clinical state. Rechallenge was considered possible only after the grade of the initial irAE returned to 0 or 1.

“Because of life-threatening risk, we did not support rechallenge for cardiac (myocarditis) and neurologic irAEs [such] as Guillain-Barré syndrome, encephalitis, and severe myositis,” they said. CT scans were used to guide the decision to rechallenge in those with initial lung adverse events.

The cohort study included 93 consecutive adult patients who were referred over an 18-month period to the ImmunoTOX assessment board at the Gustave Roussy cancer center and followed for at least 1 year. The cohort was balanced for gender and ranged in age from 33 to 85 years, with a median age of 62.5 years. Melanoma was the predominant tumor (33%), followed by lung (16%), colorectal (9%), and lymphoma (9%).

The initial immune-related adverse event was a grade 2 event in 46% of patients, grade 3 in 39%, and grade 4 in 15%. Events included hepatitis (18%), skin toxicity (15%), pneumonitis (14%), colitis (12%), and arthralgia (7.5%). A rechallenge with the same anti–PD-1 or anti–PD-L1 was conducted in 43% of patients.

When compared with patients who were not rechallenged, there was no difference in median patient age, time to initial immune-related adverse event (five vs. three treatment cycles), event severity, or steroid use. With a median follow-up period of 14 months, the same or a different immune-related adverse event occurred in 22 patients (55%). A shorter time to the initial event was linked to the occurrence of a second event (9 vs. 15 weeks; P = .04).

“However, we did observe a trend toward a higher recurrence rate after a more severe initial irAE and a trend toward more frequent recurrence in patients treated with corticosteroids after the initial irAE,” the researchers wrote. “An anti–PD-1or anti–PD-L1 rechallenge after a grade 4 irAE should always be considered with caution.” Three of the five patients with these events were being treated for lymphoma, they said.

“As long as patients are closely monitored, anti–PD-1 or anti–PD-L1 rechallenge appears to have an acceptable toxic effect profile. Myocarditis and neurologic toxic effect should remain a contraindication. Rechallenge conditions require further investigation in a prospective clinical trial. ... Well-powered, prospective studies with a larger number of patients would be required to generate information on putative risk factors for the recurrence of irAEs. Our results highlighted the value of a review board, like ImmunoTOX, with intention to build a large irAE database and then establish evidence-based guidelines on the safety of a rechallenge,” the researchers concluded.

The study was supported by the Gustave Roussy cancer center and the Gustave Roussy immunotherapy program. Dr. Simonaggio had no relevant disclosures; several coauthors reported consultancy fees and research support from multiple drug companies.

SOURCE: Simonaggio A et al. JAMA Oncol. 2019 Jun 6. doi:10.1001/jamaoncol.2019.1022.

An immune-related adverse event during initial treatment with an immune checkpoint inhibitor does not necessarily preclude a rechallenge, based on a review of outcomes in 93 patients with a variety of cancers who were part of a cohort study.

Rechallenge resulted in the recurrence of a grade 2 or higher immune-related adverse event (irAE) in 55% of rechallenged patients, but no deaths occurred, according to Audrey Simonaggio, MD, of the department of drug development at Gustave Roussy, Villejuif, France, and colleagues.

In those rechallenged patients who had a second irAE, the second event was not more severe than the first. “The rechallenge should first be assessed in a multidisciplinary team meeting with regard to each patient’s individual risk-reward ratio. ... We recommend close monitoring,” the researchers wrote in a study published in JAMA Oncology.

As there are no specific recommendations to guide the decision to rechallenge, the usefulness of the rechallenge was considered. The readministration could be delayed if the patient was in complete or excellent partial response. The existence of other therapeutic alternatives was also important as was the patient’s clinical state. Rechallenge was considered possible only after the grade of the initial irAE returned to 0 or 1.

“Because of life-threatening risk, we did not support rechallenge for cardiac (myocarditis) and neurologic irAEs [such] as Guillain-Barré syndrome, encephalitis, and severe myositis,” they said. CT scans were used to guide the decision to rechallenge in those with initial lung adverse events.

The cohort study included 93 consecutive adult patients who were referred over an 18-month period to the ImmunoTOX assessment board at the Gustave Roussy cancer center and followed for at least 1 year. The cohort was balanced for gender and ranged in age from 33 to 85 years, with a median age of 62.5 years. Melanoma was the predominant tumor (33%), followed by lung (16%), colorectal (9%), and lymphoma (9%).

The initial immune-related adverse event was a grade 2 event in 46% of patients, grade 3 in 39%, and grade 4 in 15%. Events included hepatitis (18%), skin toxicity (15%), pneumonitis (14%), colitis (12%), and arthralgia (7.5%). A rechallenge with the same anti–PD-1 or anti–PD-L1 was conducted in 43% of patients.

When compared with patients who were not rechallenged, there was no difference in median patient age, time to initial immune-related adverse event (five vs. three treatment cycles), event severity, or steroid use. With a median follow-up period of 14 months, the same or a different immune-related adverse event occurred in 22 patients (55%). A shorter time to the initial event was linked to the occurrence of a second event (9 vs. 15 weeks; P = .04).

“However, we did observe a trend toward a higher recurrence rate after a more severe initial irAE and a trend toward more frequent recurrence in patients treated with corticosteroids after the initial irAE,” the researchers wrote. “An anti–PD-1or anti–PD-L1 rechallenge after a grade 4 irAE should always be considered with caution.” Three of the five patients with these events were being treated for lymphoma, they said.

“As long as patients are closely monitored, anti–PD-1 or anti–PD-L1 rechallenge appears to have an acceptable toxic effect profile. Myocarditis and neurologic toxic effect should remain a contraindication. Rechallenge conditions require further investigation in a prospective clinical trial. ... Well-powered, prospective studies with a larger number of patients would be required to generate information on putative risk factors for the recurrence of irAEs. Our results highlighted the value of a review board, like ImmunoTOX, with intention to build a large irAE database and then establish evidence-based guidelines on the safety of a rechallenge,” the researchers concluded.

The study was supported by the Gustave Roussy cancer center and the Gustave Roussy immunotherapy program. Dr. Simonaggio had no relevant disclosures; several coauthors reported consultancy fees and research support from multiple drug companies.

SOURCE: Simonaggio A et al. JAMA Oncol. 2019 Jun 6. doi:10.1001/jamaoncol.2019.1022.

An immune-related adverse event during initial treatment with an immune checkpoint inhibitor does not necessarily preclude a rechallenge, based on a review of outcomes in 93 patients with a variety of cancers who were part of a cohort study.

Rechallenge resulted in the recurrence of a grade 2 or higher immune-related adverse event (irAE) in 55% of rechallenged patients, but no deaths occurred, according to Audrey Simonaggio, MD, of the department of drug development at Gustave Roussy, Villejuif, France, and colleagues.

In those rechallenged patients who had a second irAE, the second event was not more severe than the first. “The rechallenge should first be assessed in a multidisciplinary team meeting with regard to each patient’s individual risk-reward ratio. ... We recommend close monitoring,” the researchers wrote in a study published in JAMA Oncology.

As there are no specific recommendations to guide the decision to rechallenge, the usefulness of the rechallenge was considered. The readministration could be delayed if the patient was in complete or excellent partial response. The existence of other therapeutic alternatives was also important as was the patient’s clinical state. Rechallenge was considered possible only after the grade of the initial irAE returned to 0 or 1.

“Because of life-threatening risk, we did not support rechallenge for cardiac (myocarditis) and neurologic irAEs [such] as Guillain-Barré syndrome, encephalitis, and severe myositis,” they said. CT scans were used to guide the decision to rechallenge in those with initial lung adverse events.

The cohort study included 93 consecutive adult patients who were referred over an 18-month period to the ImmunoTOX assessment board at the Gustave Roussy cancer center and followed for at least 1 year. The cohort was balanced for gender and ranged in age from 33 to 85 years, with a median age of 62.5 years. Melanoma was the predominant tumor (33%), followed by lung (16%), colorectal (9%), and lymphoma (9%).

The initial immune-related adverse event was a grade 2 event in 46% of patients, grade 3 in 39%, and grade 4 in 15%. Events included hepatitis (18%), skin toxicity (15%), pneumonitis (14%), colitis (12%), and arthralgia (7.5%). A rechallenge with the same anti–PD-1 or anti–PD-L1 was conducted in 43% of patients.

When compared with patients who were not rechallenged, there was no difference in median patient age, time to initial immune-related adverse event (five vs. three treatment cycles), event severity, or steroid use. With a median follow-up period of 14 months, the same or a different immune-related adverse event occurred in 22 patients (55%). A shorter time to the initial event was linked to the occurrence of a second event (9 vs. 15 weeks; P = .04).

“However, we did observe a trend toward a higher recurrence rate after a more severe initial irAE and a trend toward more frequent recurrence in patients treated with corticosteroids after the initial irAE,” the researchers wrote. “An anti–PD-1or anti–PD-L1 rechallenge after a grade 4 irAE should always be considered with caution.” Three of the five patients with these events were being treated for lymphoma, they said.

“As long as patients are closely monitored, anti–PD-1 or anti–PD-L1 rechallenge appears to have an acceptable toxic effect profile. Myocarditis and neurologic toxic effect should remain a contraindication. Rechallenge conditions require further investigation in a prospective clinical trial. ... Well-powered, prospective studies with a larger number of patients would be required to generate information on putative risk factors for the recurrence of irAEs. Our results highlighted the value of a review board, like ImmunoTOX, with intention to build a large irAE database and then establish evidence-based guidelines on the safety of a rechallenge,” the researchers concluded.

The study was supported by the Gustave Roussy cancer center and the Gustave Roussy immunotherapy program. Dr. Simonaggio had no relevant disclosures; several coauthors reported consultancy fees and research support from multiple drug companies.

SOURCE: Simonaggio A et al. JAMA Oncol. 2019 Jun 6. doi:10.1001/jamaoncol.2019.1022.

CHICAGO – New data suggest pembrolizumab can increase 5-year overall survival (OS) for patients with advanced non–small cell lung cancer (NSCLC).

Jennifer Smith/MDedge News

In the phase 1b KEYNOTE-001 trial, the 5-year OS rate was 23.2% in treatment-naive patients and 15.5% in previously treated patients. This is in comparison to the 5.5% average 5-year OS rate observed in NSCLC patients who receive standard chemotherapy (Noone AM et al. SEER Cancer Statistics Review, 1975-2015).

“In total, the data confirm that pembrolizumab has the potential to improve long-term outcomes for both treatment-naive and previously treated patients with advanced non–small cell lung cancer,” said Edward B. Garon, MD, of the University of California, Los Angeles.

Dr. Garon and colleagues presented these results in a poster at the annual meeting of the American Society for Clinical Oncology, and the data were simultaneously published in the Journal of Clinical Oncology.

KEYNOTE-001 (NCT01295827) enrolled 550 patients with advanced NSCLC who had received no prior therapy (n = 101) or at least one prior line of therapy (n = 449). Initially, patients received pembrolizumab at varying doses depending on body weight, but the protocol was changed to a single dose of pembrolizumab at 200 mg every 3 weeks.

At a median follow-up of 60.6 months, 100 patients were still alive. Sixty patients had received at least 2 years of pembrolizumab, 14 of whom were treatment-naive at baseline, and 46 of whom were previously treated at baseline.

Five-year OS rates were best among patients who had high PD-L1 expression, which was defined as 50% or greater.

Among treatment-naive patients, the 5-year OS rate was 29.6% in PD-L1–high patients and 15.7% in PD-L1–low patients (expression of 1% to 49%). The median OS was 35.4 months and 19.5 months, respectively.

Among previously treated patients, the 5-year OS rate was 25.0% in PD-L1–high patients, 12.6% in patients with PD-L1 expression of 1%-49%, and 3.5% in patients with PD-L1 expression less than 1%. The median OS was 15.4 months, 8.5 months, and 8.6 months, respectively.

Among patients who received at least 2 years of pembrolizumab, the 5-year OS rate was 78.6% in the treatment-naive group and 75.8% in the previously treated group. The objective response rate was 86% and 91%, respectively. The rate of ongoing response at the data cutoff was 58% and 71%, respectively.

“The safety data did not show any unanticipated late toxicity, which I consider encouraging,” Dr. Garon noted.

He said rates of immune-mediated adverse events were similar at 3 years and 5 years of follow-up. At 5 years, 17% of patients (n = 92) had experienced an immune-related adverse event, the most common of which were hypothyroidism (9%), pneumonitis (5%), and hyperthyroidism (2%).

Dr. Garon disclosed relationships with AstraZeneca, Bristol-Myers Squibb, Dracen, Dynavax, Genentech, Iovance Biotherapeutics, Lilly, Merck, Mirati Therapeutics, Neon Therapeutics, and Novartis. KEYNOTE-001 was sponsored by Merck Sharp & Dohme Corp.

jensmith@mdedge.com

SOURCES: Garon E. et al. ASCO 2019, Abstract LBA9015; J Clin Oncol. 2019 June 2. doi: 10.1200/JCO.19.00934
 

CHICAGO – New data suggest pembrolizumab can increase 5-year overall survival (OS) for patients with advanced non–small cell lung cancer (NSCLC).

Jennifer Smith/MDedge News

In the phase 1b KEYNOTE-001 trial, the 5-year OS rate was 23.2% in treatment-naive patients and 15.5% in previously treated patients. This is in comparison to the 5.5% average 5-year OS rate observed in NSCLC patients who receive standard chemotherapy (Noone AM et al. SEER Cancer Statistics Review, 1975-2015).

“In total, the data confirm that pembrolizumab has the potential to improve long-term outcomes for both treatment-naive and previously treated patients with advanced non–small cell lung cancer,” said Edward B. Garon, MD, of the University of California, Los Angeles.

Dr. Garon and colleagues presented these results in a poster at the annual meeting of the American Society for Clinical Oncology, and the data were simultaneously published in the Journal of Clinical Oncology.

KEYNOTE-001 (NCT01295827) enrolled 550 patients with advanced NSCLC who had received no prior therapy (n = 101) or at least one prior line of therapy (n = 449). Initially, patients received pembrolizumab at varying doses depending on body weight, but the protocol was changed to a single dose of pembrolizumab at 200 mg every 3 weeks.

At a median follow-up of 60.6 months, 100 patients were still alive. Sixty patients had received at least 2 years of pembrolizumab, 14 of whom were treatment-naive at baseline, and 46 of whom were previously treated at baseline.

Five-year OS rates were best among patients who had high PD-L1 expression, which was defined as 50% or greater.

Among treatment-naive patients, the 5-year OS rate was 29.6% in PD-L1–high patients and 15.7% in PD-L1–low patients (expression of 1% to 49%). The median OS was 35.4 months and 19.5 months, respectively.

Among previously treated patients, the 5-year OS rate was 25.0% in PD-L1–high patients, 12.6% in patients with PD-L1 expression of 1%-49%, and 3.5% in patients with PD-L1 expression less than 1%. The median OS was 15.4 months, 8.5 months, and 8.6 months, respectively.

Among patients who received at least 2 years of pembrolizumab, the 5-year OS rate was 78.6% in the treatment-naive group and 75.8% in the previously treated group. The objective response rate was 86% and 91%, respectively. The rate of ongoing response at the data cutoff was 58% and 71%, respectively.

“The safety data did not show any unanticipated late toxicity, which I consider encouraging,” Dr. Garon noted.

He said rates of immune-mediated adverse events were similar at 3 years and 5 years of follow-up. At 5 years, 17% of patients (n = 92) had experienced an immune-related adverse event, the most common of which were hypothyroidism (9%), pneumonitis (5%), and hyperthyroidism (2%).

Dr. Garon disclosed relationships with AstraZeneca, Bristol-Myers Squibb, Dracen, Dynavax, Genentech, Iovance Biotherapeutics, Lilly, Merck, Mirati Therapeutics, Neon Therapeutics, and Novartis. KEYNOTE-001 was sponsored by Merck Sharp & Dohme Corp.

jensmith@mdedge.com

SOURCES: Garon E. et al. ASCO 2019, Abstract LBA9015; J Clin Oncol. 2019 June 2. doi: 10.1200/JCO.19.00934
 

CHICAGO – New data suggest pembrolizumab can increase 5-year overall survival (OS) for patients with advanced non–small cell lung cancer (NSCLC).

Jennifer Smith/MDedge News

In the phase 1b KEYNOTE-001 trial, the 5-year OS rate was 23.2% in treatment-naive patients and 15.5% in previously treated patients. This is in comparison to the 5.5% average 5-year OS rate observed in NSCLC patients who receive standard chemotherapy (Noone AM et al. SEER Cancer Statistics Review, 1975-2015).

“In total, the data confirm that pembrolizumab has the potential to improve long-term outcomes for both treatment-naive and previously treated patients with advanced non–small cell lung cancer,” said Edward B. Garon, MD, of the University of California, Los Angeles.

Dr. Garon and colleagues presented these results in a poster at the annual meeting of the American Society for Clinical Oncology, and the data were simultaneously published in the Journal of Clinical Oncology.

KEYNOTE-001 (NCT01295827) enrolled 550 patients with advanced NSCLC who had received no prior therapy (n = 101) or at least one prior line of therapy (n = 449). Initially, patients received pembrolizumab at varying doses depending on body weight, but the protocol was changed to a single dose of pembrolizumab at 200 mg every 3 weeks.

At a median follow-up of 60.6 months, 100 patients were still alive. Sixty patients had received at least 2 years of pembrolizumab, 14 of whom were treatment-naive at baseline, and 46 of whom were previously treated at baseline.

Five-year OS rates were best among patients who had high PD-L1 expression, which was defined as 50% or greater.

Among treatment-naive patients, the 5-year OS rate was 29.6% in PD-L1–high patients and 15.7% in PD-L1–low patients (expression of 1% to 49%). The median OS was 35.4 months and 19.5 months, respectively.

Among previously treated patients, the 5-year OS rate was 25.0% in PD-L1–high patients, 12.6% in patients with PD-L1 expression of 1%-49%, and 3.5% in patients with PD-L1 expression less than 1%. The median OS was 15.4 months, 8.5 months, and 8.6 months, respectively.

Among patients who received at least 2 years of pembrolizumab, the 5-year OS rate was 78.6% in the treatment-naive group and 75.8% in the previously treated group. The objective response rate was 86% and 91%, respectively. The rate of ongoing response at the data cutoff was 58% and 71%, respectively.

“The safety data did not show any unanticipated late toxicity, which I consider encouraging,” Dr. Garon noted.

He said rates of immune-mediated adverse events were similar at 3 years and 5 years of follow-up. At 5 years, 17% of patients (n = 92) had experienced an immune-related adverse event, the most common of which were hypothyroidism (9%), pneumonitis (5%), and hyperthyroidism (2%).

Dr. Garon disclosed relationships with AstraZeneca, Bristol-Myers Squibb, Dracen, Dynavax, Genentech, Iovance Biotherapeutics, Lilly, Merck, Mirati Therapeutics, Neon Therapeutics, and Novartis. KEYNOTE-001 was sponsored by Merck Sharp & Dohme Corp.

jensmith@mdedge.com

SOURCES: Garon E. et al. ASCO 2019, Abstract LBA9015; J Clin Oncol. 2019 June 2. doi: 10.1200/JCO.19.00934
 

Implementation of low-dose CT screening for lung cancer in community settings is successfully detecting the disease at an early, more treatable stage, suggests a survey of U.S. lung cancer screening centers.

Such screening led to a 20% reduction in lung cancer mortality in the National Lung Screening Trial (N Engl J Med. 2011;365:395-409), prompting the Centers for Medicare & Medicaid Services to start covering it in 2015. However, fewer than a third of trial practices were community based, and questions lingered regarding applicability of this screening in nonacademic settings.

Investigators working under senior author Jennifer C. King, PhD, senior director of science and research at the GO2 Foundation for Lung Cancer, Washington, administered a 21-question survey to 165 lung cancer screening centers designated as Screening Centers of Excellence asking about their 2016 program data and practices. Overall, 62% of the centers were community based, having no university or other academic affiliation.

Results reported in the Journal of Oncology Practice showed that more than half of 529 lung cancer diagnoses the centers made in 2016 were made at stage I or limited stage, with the same pattern seen for community and academic centers. Findings were similar when analyses instead considered Lung Imaging Reporting and Data System results for 40,000 low-dose CT scans performed that year.

Community and academic centers differed in how they addressed the CMS requirement for a prescreening shared decision making visit led by a health practitioner, with the former more commonly relying on only primary care providers (52% vs. 40%). The centers were similar in how they addressed the CMS requirement for smoking cessation services, with both using referral to a quitline, cessation counseling within the screening facility, and printed educational materials; however, academic centers more commonly followed up with current smokers (52% vs. 36%).

The main barriers to implementing screening were insurance and billing issues, lack of provider referral, lack of patient awareness, and internal work flow challenges, cited by more than half of centers overall. Community centers less often cited staffing and time limitations (35% vs. 53%) and insurance and billing issues (64% vs. 74%), but percentages were similar for other barriers.

“There has been concern about the ability of nonacademic centers to implement lung cancer screening as safely and effectively as academic medical centers,” Dr. King and coauthors wrote. “In this study, we not only demonstrate that lung cancer screening is happening in the community setting, but also that nonacademic screening programs are using similar protocols and are seeing similar findings as academic medical centers.

“These data indicate that responsible implementation is possible in the community and results in a meaningful stage shift for lung cancer diagnoses, and providers should support ongoing implementation of lung cancer screening efforts,” they concluded.

Dr. King reported that she receives honoraria from MedImmune, AstraZeneca, and Genentech; has a consulting or advisory role with GRAIL, Tesaro, AbbVie, and Foundation Medicine; and receives research funding from AstraZeneca. The study was supported by the GO2 Foundation for Lung Cancer.

SOURCE: King JC et al. J Oncol Pract. 2019 May 31. doi: 10.1200/JOP.18.00788.

Implementation of low-dose CT screening for lung cancer in community settings is successfully detecting the disease at an early, more treatable stage, suggests a survey of U.S. lung cancer screening centers.

Such screening led to a 20% reduction in lung cancer mortality in the National Lung Screening Trial (N Engl J Med. 2011;365:395-409), prompting the Centers for Medicare & Medicaid Services to start covering it in 2015. However, fewer than a third of trial practices were community based, and questions lingered regarding applicability of this screening in nonacademic settings.

Investigators working under senior author Jennifer C. King, PhD, senior director of science and research at the GO2 Foundation for Lung Cancer, Washington, administered a 21-question survey to 165 lung cancer screening centers designated as Screening Centers of Excellence asking about their 2016 program data and practices. Overall, 62% of the centers were community based, having no university or other academic affiliation.

Results reported in the Journal of Oncology Practice showed that more than half of 529 lung cancer diagnoses the centers made in 2016 were made at stage I or limited stage, with the same pattern seen for community and academic centers. Findings were similar when analyses instead considered Lung Imaging Reporting and Data System results for 40,000 low-dose CT scans performed that year.

Community and academic centers differed in how they addressed the CMS requirement for a prescreening shared decision making visit led by a health practitioner, with the former more commonly relying on only primary care providers (52% vs. 40%). The centers were similar in how they addressed the CMS requirement for smoking cessation services, with both using referral to a quitline, cessation counseling within the screening facility, and printed educational materials; however, academic centers more commonly followed up with current smokers (52% vs. 36%).

The main barriers to implementing screening were insurance and billing issues, lack of provider referral, lack of patient awareness, and internal work flow challenges, cited by more than half of centers overall. Community centers less often cited staffing and time limitations (35% vs. 53%) and insurance and billing issues (64% vs. 74%), but percentages were similar for other barriers.

“There has been concern about the ability of nonacademic centers to implement lung cancer screening as safely and effectively as academic medical centers,” Dr. King and coauthors wrote. “In this study, we not only demonstrate that lung cancer screening is happening in the community setting, but also that nonacademic screening programs are using similar protocols and are seeing similar findings as academic medical centers.

“These data indicate that responsible implementation is possible in the community and results in a meaningful stage shift for lung cancer diagnoses, and providers should support ongoing implementation of lung cancer screening efforts,” they concluded.

Dr. King reported that she receives honoraria from MedImmune, AstraZeneca, and Genentech; has a consulting or advisory role with GRAIL, Tesaro, AbbVie, and Foundation Medicine; and receives research funding from AstraZeneca. The study was supported by the GO2 Foundation for Lung Cancer.

SOURCE: King JC et al. J Oncol Pract. 2019 May 31. doi: 10.1200/JOP.18.00788.

Implementation of low-dose CT screening for lung cancer in community settings is successfully detecting the disease at an early, more treatable stage, suggests a survey of U.S. lung cancer screening centers.

Such screening led to a 20% reduction in lung cancer mortality in the National Lung Screening Trial (N Engl J Med. 2011;365:395-409), prompting the Centers for Medicare & Medicaid Services to start covering it in 2015. However, fewer than a third of trial practices were community based, and questions lingered regarding applicability of this screening in nonacademic settings.

Investigators working under senior author Jennifer C. King, PhD, senior director of science and research at the GO2 Foundation for Lung Cancer, Washington, administered a 21-question survey to 165 lung cancer screening centers designated as Screening Centers of Excellence asking about their 2016 program data and practices. Overall, 62% of the centers were community based, having no university or other academic affiliation.

Results reported in the Journal of Oncology Practice showed that more than half of 529 lung cancer diagnoses the centers made in 2016 were made at stage I or limited stage, with the same pattern seen for community and academic centers. Findings were similar when analyses instead considered Lung Imaging Reporting and Data System results for 40,000 low-dose CT scans performed that year.

Community and academic centers differed in how they addressed the CMS requirement for a prescreening shared decision making visit led by a health practitioner, with the former more commonly relying on only primary care providers (52% vs. 40%). The centers were similar in how they addressed the CMS requirement for smoking cessation services, with both using referral to a quitline, cessation counseling within the screening facility, and printed educational materials; however, academic centers more commonly followed up with current smokers (52% vs. 36%).

The main barriers to implementing screening were insurance and billing issues, lack of provider referral, lack of patient awareness, and internal work flow challenges, cited by more than half of centers overall. Community centers less often cited staffing and time limitations (35% vs. 53%) and insurance and billing issues (64% vs. 74%), but percentages were similar for other barriers.

“There has been concern about the ability of nonacademic centers to implement lung cancer screening as safely and effectively as academic medical centers,” Dr. King and coauthors wrote. “In this study, we not only demonstrate that lung cancer screening is happening in the community setting, but also that nonacademic screening programs are using similar protocols and are seeing similar findings as academic medical centers.

“These data indicate that responsible implementation is possible in the community and results in a meaningful stage shift for lung cancer diagnoses, and providers should support ongoing implementation of lung cancer screening efforts,” they concluded.

Dr. King reported that she receives honoraria from MedImmune, AstraZeneca, and Genentech; has a consulting or advisory role with GRAIL, Tesaro, AbbVie, and Foundation Medicine; and receives research funding from AstraZeneca. The study was supported by the GO2 Foundation for Lung Cancer.

SOURCE: King JC et al. J Oncol Pract. 2019 May 31. doi: 10.1200/JOP.18.00788.

CHICAGO – Fewer than 1 in 20 adults with cancer enroll in clinical trials, and even when cancer patients are willing to participate in a trial, they are often excluded because of comorbidities, prior therapies, or a host of other factors that could confound results.

But as a team of investigators shows in a proof-of-concept study, more generous exclusion criteria in some trials could nearly double the number of participants. Using retrospective, deidentified electronic health record data from the American Society of Clinical Oncology CancerLinQ Discovery database, R. Donald Harvey, PharmD and colleagues found that when they applied broader inclusion criteria for patients with advanced non–small cell lung cancer (NSCLC), the number of patients who would be eligible for clinical trials nearly doubled from 5,495 to 10,349.

In this video interview from the ASCO annual meeting, Dr. Harvey of the Winship Cancer Institute of Emory University in Atlanta discusses collaborations between the oncology community, federal agencies, and the pharmaceutical industry that could improve clinical trials by safely increasing sample sizes.

The study received funding from ASCO. Dr. Harvey disclosed consulting or advisory roles with and institutional research funding from multiple entities.

CHICAGO – Fewer than 1 in 20 adults with cancer enroll in clinical trials, and even when cancer patients are willing to participate in a trial, they are often excluded because of comorbidities, prior therapies, or a host of other factors that could confound results.

But as a team of investigators shows in a proof-of-concept study, more generous exclusion criteria in some trials could nearly double the number of participants. Using retrospective, deidentified electronic health record data from the American Society of Clinical Oncology CancerLinQ Discovery database, R. Donald Harvey, PharmD and colleagues found that when they applied broader inclusion criteria for patients with advanced non–small cell lung cancer (NSCLC), the number of patients who would be eligible for clinical trials nearly doubled from 5,495 to 10,349.

In this video interview from the ASCO annual meeting, Dr. Harvey of the Winship Cancer Institute of Emory University in Atlanta discusses collaborations between the oncology community, federal agencies, and the pharmaceutical industry that could improve clinical trials by safely increasing sample sizes.

The study received funding from ASCO. Dr. Harvey disclosed consulting or advisory roles with and institutional research funding from multiple entities.

CHICAGO – Fewer than 1 in 20 adults with cancer enroll in clinical trials, and even when cancer patients are willing to participate in a trial, they are often excluded because of comorbidities, prior therapies, or a host of other factors that could confound results.

But as a team of investigators shows in a proof-of-concept study, more generous exclusion criteria in some trials could nearly double the number of participants. Using retrospective, deidentified electronic health record data from the American Society of Clinical Oncology CancerLinQ Discovery database, R. Donald Harvey, PharmD and colleagues found that when they applied broader inclusion criteria for patients with advanced non–small cell lung cancer (NSCLC), the number of patients who would be eligible for clinical trials nearly doubled from 5,495 to 10,349.

In this video interview from the ASCO annual meeting, Dr. Harvey of the Winship Cancer Institute of Emory University in Atlanta discusses collaborations between the oncology community, federal agencies, and the pharmaceutical industry that could improve clinical trials by safely increasing sample sizes.

The study received funding from ASCO. Dr. Harvey disclosed consulting or advisory roles with and institutional research funding from multiple entities.

CHICAGO – While tyrosine kinase inhibitors (TKIs) have long dominated treatment approaches for EGFR-driven advanced non-small cell lung cancer, a few newer antibodies are showing early promise as potential new strategies to use after progression, recent reports show.

Both JNJ-372, an EGFR and MET bispecific antibody, and U3-1402, a HER3-directed antibody-drug conjugate (ADC), demonstrated manageable safety profiles and preliminary antitumor activity in phase 1 study results presented here at the annual meeting of the American Society of Clinical Oncology.

“There is definitely a role to play for antibodies in the TKI world,” said Jessica Ruth Bauman, MD, of Fox Chase Cancer Center, Philadelphia, Pa., a discussant on both abstracts.

These two antibodies harness new mechanisms of action that are not specific to a resistance mechanism, which may lead to broad applicability, according to Dr. Bauman.

“Mechanisms of acquired resistance have been the Achilles heel of EGFR TKI treatment,” she said.

The JNJ-372 bispecific antibody has preclinical data consistent with several proposed mechanisms of action, including inhibition of EGFR and cMet signaling, receptor degradation, and antibody-dependent cellular cytotoxicity, said investigator Eric B. Haura, MD, of H. Lee Moffitt Cancer Center & Research Institute, Tampa, Fla.

In the phase 1 study, which included patients with diverse EGFR mutations, 32 out of 108 patients (30%) had a best response of partial response (PR) after treatment with JNJ-372, Dr. Haura reported in an oral abstract presentation.

Responses were seen in patients with mutations that represent areas of high unmet need, including those with EGFR C797S-mediated or cMet-mediated resistance to the third-generation TKI osimertinib, and those with TKI-naïve EGFR exon 20 insertions, he emphasized in his presentation.

The safety profile was “manageable” and consistent with EGFR inhibition, he said, with a low (9%) rate of grade 3 or greater toxicities and frequent infusion-related reactions, mostly after the first dose.

Enrollment of patients with high unmet need is ongoing, according to Dr. Haura.

U3-1402, the antibody-drug conjugate that may have a place in the TKI world, consists of a fully human HER3-targeted antibody linked to a topoisomerase I inhibitor payload.

“Targeting HER3 with U3-1402 may be a practical approach to treat EGFR-mutant NSCLC with diverse mechanisms of resistance to EGFR TKIs,” said investigator Pasi A. Jänne, MD, PhD, of Dana-Farber Cancer Institute, Boston, Mass.

That’s because mechanisms of resistance to TKIs in EGFR-mutant NSCLC are turning out to be so diverse, that trying to combat each individual resistance mechanism is likely “impractical,” Dr. Jänne said.

Targeting HER3, the perhaps lesser-known of the four members of the EGFR tyrosine kinase family, may address multiple resistance mechanisms, and 57% to 67% of EGFR-mutant NSCLCs have at least some level of HER3 expression, according to the presenter.

In the phase 1 study data reported at the meeting, the response rate following U3-1402 treatment was about 31%, or 5 out of 16 patients, including 4 confirmed partial responses. Most treatment-emergent adverse events were grade 1 or 2, and only one patient discontinued due to an adverse event, according to Dr. Jänne, who said the study is ongoing.

Taken together, findings for U3-1402 and JNJ-372 show that there may be room for other approaches beyond TKIs to address the need for new therapies to overcome resistance, Dr. Bauman said in her commentary on these studies.

“Additional research will enable us to determine who will benefit from these compounds, what biomarkers are predictive, and novel combinations to consider,” she added.

Dr. Bauman reported a consulting or advisory role with Pfizer. Dr. Haura provided disclosures related to Bristol-Myers Squibb; Janssen Oncology, Boehringer Ingelheim, FORMA Therapeutics, Ignyta, Janssen, Lilly, and Ventana, plus a patent pending on technology related to kinase inhibitor sensitivity biomarkers. Dr. Jänne reported disclosures related to Gatekeeper Pharmaceuticals, Loxo, Araxes Pharma, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Lilly, and others.

SOURCE: Haura EB, et al. ASCO 2019. Abstract 9009, Jänne PA, et al. ASCO 2019. Abstract 9010.

CHICAGO – While tyrosine kinase inhibitors (TKIs) have long dominated treatment approaches for EGFR-driven advanced non-small cell lung cancer, a few newer antibodies are showing early promise as potential new strategies to use after progression, recent reports show.

Both JNJ-372, an EGFR and MET bispecific antibody, and U3-1402, a HER3-directed antibody-drug conjugate (ADC), demonstrated manageable safety profiles and preliminary antitumor activity in phase 1 study results presented here at the annual meeting of the American Society of Clinical Oncology.

“There is definitely a role to play for antibodies in the TKI world,” said Jessica Ruth Bauman, MD, of Fox Chase Cancer Center, Philadelphia, Pa., a discussant on both abstracts.

These two antibodies harness new mechanisms of action that are not specific to a resistance mechanism, which may lead to broad applicability, according to Dr. Bauman.

“Mechanisms of acquired resistance have been the Achilles heel of EGFR TKI treatment,” she said.

The JNJ-372 bispecific antibody has preclinical data consistent with several proposed mechanisms of action, including inhibition of EGFR and cMet signaling, receptor degradation, and antibody-dependent cellular cytotoxicity, said investigator Eric B. Haura, MD, of H. Lee Moffitt Cancer Center & Research Institute, Tampa, Fla.

In the phase 1 study, which included patients with diverse EGFR mutations, 32 out of 108 patients (30%) had a best response of partial response (PR) after treatment with JNJ-372, Dr. Haura reported in an oral abstract presentation.

Responses were seen in patients with mutations that represent areas of high unmet need, including those with EGFR C797S-mediated or cMet-mediated resistance to the third-generation TKI osimertinib, and those with TKI-naïve EGFR exon 20 insertions, he emphasized in his presentation.

The safety profile was “manageable” and consistent with EGFR inhibition, he said, with a low (9%) rate of grade 3 or greater toxicities and frequent infusion-related reactions, mostly after the first dose.

Enrollment of patients with high unmet need is ongoing, according to Dr. Haura.

U3-1402, the antibody-drug conjugate that may have a place in the TKI world, consists of a fully human HER3-targeted antibody linked to a topoisomerase I inhibitor payload.

“Targeting HER3 with U3-1402 may be a practical approach to treat EGFR-mutant NSCLC with diverse mechanisms of resistance to EGFR TKIs,” said investigator Pasi A. Jänne, MD, PhD, of Dana-Farber Cancer Institute, Boston, Mass.

That’s because mechanisms of resistance to TKIs in EGFR-mutant NSCLC are turning out to be so diverse, that trying to combat each individual resistance mechanism is likely “impractical,” Dr. Jänne said.

Targeting HER3, the perhaps lesser-known of the four members of the EGFR tyrosine kinase family, may address multiple resistance mechanisms, and 57% to 67% of EGFR-mutant NSCLCs have at least some level of HER3 expression, according to the presenter.

In the phase 1 study data reported at the meeting, the response rate following U3-1402 treatment was about 31%, or 5 out of 16 patients, including 4 confirmed partial responses. Most treatment-emergent adverse events were grade 1 or 2, and only one patient discontinued due to an adverse event, according to Dr. Jänne, who said the study is ongoing.

Taken together, findings for U3-1402 and JNJ-372 show that there may be room for other approaches beyond TKIs to address the need for new therapies to overcome resistance, Dr. Bauman said in her commentary on these studies.

“Additional research will enable us to determine who will benefit from these compounds, what biomarkers are predictive, and novel combinations to consider,” she added.

Dr. Bauman reported a consulting or advisory role with Pfizer. Dr. Haura provided disclosures related to Bristol-Myers Squibb; Janssen Oncology, Boehringer Ingelheim, FORMA Therapeutics, Ignyta, Janssen, Lilly, and Ventana, plus a patent pending on technology related to kinase inhibitor sensitivity biomarkers. Dr. Jänne reported disclosures related to Gatekeeper Pharmaceuticals, Loxo, Araxes Pharma, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Lilly, and others.

SOURCE: Haura EB, et al. ASCO 2019. Abstract 9009, Jänne PA, et al. ASCO 2019. Abstract 9010.

CHICAGO – While tyrosine kinase inhibitors (TKIs) have long dominated treatment approaches for EGFR-driven advanced non-small cell lung cancer, a few newer antibodies are showing early promise as potential new strategies to use after progression, recent reports show.

Both JNJ-372, an EGFR and MET bispecific antibody, and U3-1402, a HER3-directed antibody-drug conjugate (ADC), demonstrated manageable safety profiles and preliminary antitumor activity in phase 1 study results presented here at the annual meeting of the American Society of Clinical Oncology.

“There is definitely a role to play for antibodies in the TKI world,” said Jessica Ruth Bauman, MD, of Fox Chase Cancer Center, Philadelphia, Pa., a discussant on both abstracts.

These two antibodies harness new mechanisms of action that are not specific to a resistance mechanism, which may lead to broad applicability, according to Dr. Bauman.

“Mechanisms of acquired resistance have been the Achilles heel of EGFR TKI treatment,” she said.

The JNJ-372 bispecific antibody has preclinical data consistent with several proposed mechanisms of action, including inhibition of EGFR and cMet signaling, receptor degradation, and antibody-dependent cellular cytotoxicity, said investigator Eric B. Haura, MD, of H. Lee Moffitt Cancer Center & Research Institute, Tampa, Fla.

In the phase 1 study, which included patients with diverse EGFR mutations, 32 out of 108 patients (30%) had a best response of partial response (PR) after treatment with JNJ-372, Dr. Haura reported in an oral abstract presentation.

Responses were seen in patients with mutations that represent areas of high unmet need, including those with EGFR C797S-mediated or cMet-mediated resistance to the third-generation TKI osimertinib, and those with TKI-naïve EGFR exon 20 insertions, he emphasized in his presentation.

The safety profile was “manageable” and consistent with EGFR inhibition, he said, with a low (9%) rate of grade 3 or greater toxicities and frequent infusion-related reactions, mostly after the first dose.

Enrollment of patients with high unmet need is ongoing, according to Dr. Haura.

U3-1402, the antibody-drug conjugate that may have a place in the TKI world, consists of a fully human HER3-targeted antibody linked to a topoisomerase I inhibitor payload.

“Targeting HER3 with U3-1402 may be a practical approach to treat EGFR-mutant NSCLC with diverse mechanisms of resistance to EGFR TKIs,” said investigator Pasi A. Jänne, MD, PhD, of Dana-Farber Cancer Institute, Boston, Mass.

That’s because mechanisms of resistance to TKIs in EGFR-mutant NSCLC are turning out to be so diverse, that trying to combat each individual resistance mechanism is likely “impractical,” Dr. Jänne said.

Targeting HER3, the perhaps lesser-known of the four members of the EGFR tyrosine kinase family, may address multiple resistance mechanisms, and 57% to 67% of EGFR-mutant NSCLCs have at least some level of HER3 expression, according to the presenter.

In the phase 1 study data reported at the meeting, the response rate following U3-1402 treatment was about 31%, or 5 out of 16 patients, including 4 confirmed partial responses. Most treatment-emergent adverse events were grade 1 or 2, and only one patient discontinued due to an adverse event, according to Dr. Jänne, who said the study is ongoing.

Taken together, findings for U3-1402 and JNJ-372 show that there may be room for other approaches beyond TKIs to address the need for new therapies to overcome resistance, Dr. Bauman said in her commentary on these studies.

“Additional research will enable us to determine who will benefit from these compounds, what biomarkers are predictive, and novel combinations to consider,” she added.

Dr. Bauman reported a consulting or advisory role with Pfizer. Dr. Haura provided disclosures related to Bristol-Myers Squibb; Janssen Oncology, Boehringer Ingelheim, FORMA Therapeutics, Ignyta, Janssen, Lilly, and Ventana, plus a patent pending on technology related to kinase inhibitor sensitivity biomarkers. Dr. Jänne reported disclosures related to Gatekeeper Pharmaceuticals, Loxo, Araxes Pharma, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Lilly, and others.

SOURCE: Haura EB, et al. ASCO 2019. Abstract 9009, Jänne PA, et al. ASCO 2019. Abstract 9010.

The Food and Drug Administration has approved the NovoTTF-100L System in combination with pemetrexed plus platinum-based chemotherapy for the first-line treatment of unresectable, locally advanced or metastatic, malignant pleural mesothelioma (MPM).

The NovoTTF-100L System uses electric fields tuned to specific frequencies to disrupt solid tumor cancer cell division, Novocure, makers of NovoTTF-100L, said in a press release.

FDA approval was based on the single-arm STELLAR registration trial, which included 80 patients with unresectable and previously untreated MPM who were candidates for treatment with pemetrexed and cisplatin or carboplatin.

Median overall survival among all patients treated with NovoTTF-100L plus chemotherapy was 18.2 months (95% confidence interval, 12.1-25.8). The disease control rate in the 72 patients with at least one follow-up CT scan performed was 97%; 40% of patients had a partial response, 57% had stable disease, and 3% had progressive disease. The median progression free survival was 7.6 months.

The most common adverse events observed with the NovoTTF-100L System in combination with chemotherapy in patients with MPM were anemia, constipation, nausea, asthenia, chest pain, fatigue, device skin reaction, pruritus, and cough.

Other potential adverse effects associated with the use of the NovoTTF-100L System include: treatment related skin toxicity, allergic reaction to the plaster or to the gel, electrode overheating leading to pain and/or local skin burns, infections at sites of electrode contact with the skin, local warmth and tingling sensation beneath the electrodes, muscle twitching, medical site reaction, and skin breakdown/skin ulcer.

The NovoTTF-100L System can be prescribed only by a health care provider who has completed the required certification training provided by Novocure, the company said in the press release.

The Food and Drug Administration has approved the NovoTTF-100L System in combination with pemetrexed plus platinum-based chemotherapy for the first-line treatment of unresectable, locally advanced or metastatic, malignant pleural mesothelioma (MPM).

The NovoTTF-100L System uses electric fields tuned to specific frequencies to disrupt solid tumor cancer cell division, Novocure, makers of NovoTTF-100L, said in a press release.

FDA approval was based on the single-arm STELLAR registration trial, which included 80 patients with unresectable and previously untreated MPM who were candidates for treatment with pemetrexed and cisplatin or carboplatin.

Median overall survival among all patients treated with NovoTTF-100L plus chemotherapy was 18.2 months (95% confidence interval, 12.1-25.8). The disease control rate in the 72 patients with at least one follow-up CT scan performed was 97%; 40% of patients had a partial response, 57% had stable disease, and 3% had progressive disease. The median progression free survival was 7.6 months.

The most common adverse events observed with the NovoTTF-100L System in combination with chemotherapy in patients with MPM were anemia, constipation, nausea, asthenia, chest pain, fatigue, device skin reaction, pruritus, and cough.

Other potential adverse effects associated with the use of the NovoTTF-100L System include: treatment related skin toxicity, allergic reaction to the plaster or to the gel, electrode overheating leading to pain and/or local skin burns, infections at sites of electrode contact with the skin, local warmth and tingling sensation beneath the electrodes, muscle twitching, medical site reaction, and skin breakdown/skin ulcer.

The NovoTTF-100L System can be prescribed only by a health care provider who has completed the required certification training provided by Novocure, the company said in the press release.

The Food and Drug Administration has approved the NovoTTF-100L System in combination with pemetrexed plus platinum-based chemotherapy for the first-line treatment of unresectable, locally advanced or metastatic, malignant pleural mesothelioma (MPM).

The NovoTTF-100L System uses electric fields tuned to specific frequencies to disrupt solid tumor cancer cell division, Novocure, makers of NovoTTF-100L, said in a press release.

FDA approval was based on the single-arm STELLAR registration trial, which included 80 patients with unresectable and previously untreated MPM who were candidates for treatment with pemetrexed and cisplatin or carboplatin.

Median overall survival among all patients treated with NovoTTF-100L plus chemotherapy was 18.2 months (95% confidence interval, 12.1-25.8). The disease control rate in the 72 patients with at least one follow-up CT scan performed was 97%; 40% of patients had a partial response, 57% had stable disease, and 3% had progressive disease. The median progression free survival was 7.6 months.

The most common adverse events observed with the NovoTTF-100L System in combination with chemotherapy in patients with MPM were anemia, constipation, nausea, asthenia, chest pain, fatigue, device skin reaction, pruritus, and cough.

Other potential adverse effects associated with the use of the NovoTTF-100L System include: treatment related skin toxicity, allergic reaction to the plaster or to the gel, electrode overheating leading to pain and/or local skin burns, infections at sites of electrode contact with the skin, local warmth and tingling sensation beneath the electrodes, muscle twitching, medical site reaction, and skin breakdown/skin ulcer.

The NovoTTF-100L System can be prescribed only by a health care provider who has completed the required certification training provided by Novocure, the company said in the press release.

Patients with oligometastatic non–small cell lung cancer (NSCLC) have better outcomes when treated with local consolidative therapy than with maintenance therapy or observation, based on updated results from a phase 2 trial.

The randomized study showed that both median progression-free and overall survival were better in patients who received radiotherapy or surgery instead of maintenance therapy or observation, reported lead author Daniel R. Gomez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues. These findings build on earlier results that showed the positive impact of local consolidative therapy (LCT), the investigators noted.

“The trial was closed early after it demonstrated an observed 8-month benefit in [progression-free survival] for patients who received LCT relative to patients who received maintenance therapy or observation,” the investigators wrote in Journal of Clinical Oncology.

After early closure, 49 patients remained in the dataset. All had metastatic NSCLC with three or fewer metastases that did not progress for at least 3 months after first-line systemic therapy. Most patients had adenocarcinoma (80%). Patients were randomly divided in a 1:1 ratio between radiotherapy or surgery (LCT) for all active disease sites or maintenance therapy/observation (MT/O). Progression-free survival was the primary endpoint. Overall survival and several other secondary endpoints were also evaluated.

Data analysis showed a clear benefit of LCT. Continuing the previously reported trend, median progression-free survival was extended in the LCT group, compared with the MT/O group (14.2 vs. 4.4 months; P = .022). Similarly, median overall survival showed a significant improvement (41.2 vs. 17.0 months; P = .017). Median time to appearance of new lesions also supported the advantage of LCT over MT/O, albeit with less statistical significance (14.2 vs. 6.0 months; P = .11).

The investigators suggested several mechanisms behind the efficacy of LCT, including elimination of treatment-resistant cells, potentiation of systemic therapy, and elimination of the residual tumor as a driver of distant micrometastatic disease. “Notably,” the investigators wrote, “these mechanisms are not mutually exclusive, and more than one could contribute to the benefits of LCT.”

“[A]lthough these data are compelling ... we emphasize that future studies should be supported to definitively assess the role of LCT in larger populations (e.g., phase III trials such as NRG-LU002) and in the context of novel systemic therapies,” the investigators concluded.

The study was funded by MD Anderson Cancer Center, The Mohaymen Sahebzadah Family Philanthropic Grant, and the National Cancer Institute, National Institutes of Health. The authors disclosed relationships with Merck, Bristol-Myers Squibb, AstraZeneca, and others.

SOURCE: Gomez et al. J Clin Oncol. 8 May 2019. doi:10.1200/JCO.19.00201.

Patients with oligometastatic non–small cell lung cancer (NSCLC) have better outcomes when treated with local consolidative therapy than with maintenance therapy or observation, based on updated results from a phase 2 trial.

The randomized study showed that both median progression-free and overall survival were better in patients who received radiotherapy or surgery instead of maintenance therapy or observation, reported lead author Daniel R. Gomez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues. These findings build on earlier results that showed the positive impact of local consolidative therapy (LCT), the investigators noted.

“The trial was closed early after it demonstrated an observed 8-month benefit in [progression-free survival] for patients who received LCT relative to patients who received maintenance therapy or observation,” the investigators wrote in Journal of Clinical Oncology.

After early closure, 49 patients remained in the dataset. All had metastatic NSCLC with three or fewer metastases that did not progress for at least 3 months after first-line systemic therapy. Most patients had adenocarcinoma (80%). Patients were randomly divided in a 1:1 ratio between radiotherapy or surgery (LCT) for all active disease sites or maintenance therapy/observation (MT/O). Progression-free survival was the primary endpoint. Overall survival and several other secondary endpoints were also evaluated.

Data analysis showed a clear benefit of LCT. Continuing the previously reported trend, median progression-free survival was extended in the LCT group, compared with the MT/O group (14.2 vs. 4.4 months; P = .022). Similarly, median overall survival showed a significant improvement (41.2 vs. 17.0 months; P = .017). Median time to appearance of new lesions also supported the advantage of LCT over MT/O, albeit with less statistical significance (14.2 vs. 6.0 months; P = .11).

The investigators suggested several mechanisms behind the efficacy of LCT, including elimination of treatment-resistant cells, potentiation of systemic therapy, and elimination of the residual tumor as a driver of distant micrometastatic disease. “Notably,” the investigators wrote, “these mechanisms are not mutually exclusive, and more than one could contribute to the benefits of LCT.”

“[A]lthough these data are compelling ... we emphasize that future studies should be supported to definitively assess the role of LCT in larger populations (e.g., phase III trials such as NRG-LU002) and in the context of novel systemic therapies,” the investigators concluded.

The study was funded by MD Anderson Cancer Center, The Mohaymen Sahebzadah Family Philanthropic Grant, and the National Cancer Institute, National Institutes of Health. The authors disclosed relationships with Merck, Bristol-Myers Squibb, AstraZeneca, and others.

SOURCE: Gomez et al. J Clin Oncol. 8 May 2019. doi:10.1200/JCO.19.00201.

Patients with oligometastatic non–small cell lung cancer (NSCLC) have better outcomes when treated with local consolidative therapy than with maintenance therapy or observation, based on updated results from a phase 2 trial.

The randomized study showed that both median progression-free and overall survival were better in patients who received radiotherapy or surgery instead of maintenance therapy or observation, reported lead author Daniel R. Gomez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues. These findings build on earlier results that showed the positive impact of local consolidative therapy (LCT), the investigators noted.

“The trial was closed early after it demonstrated an observed 8-month benefit in [progression-free survival] for patients who received LCT relative to patients who received maintenance therapy or observation,” the investigators wrote in Journal of Clinical Oncology.

After early closure, 49 patients remained in the dataset. All had metastatic NSCLC with three or fewer metastases that did not progress for at least 3 months after first-line systemic therapy. Most patients had adenocarcinoma (80%). Patients were randomly divided in a 1:1 ratio between radiotherapy or surgery (LCT) for all active disease sites or maintenance therapy/observation (MT/O). Progression-free survival was the primary endpoint. Overall survival and several other secondary endpoints were also evaluated.

Data analysis showed a clear benefit of LCT. Continuing the previously reported trend, median progression-free survival was extended in the LCT group, compared with the MT/O group (14.2 vs. 4.4 months; P = .022). Similarly, median overall survival showed a significant improvement (41.2 vs. 17.0 months; P = .017). Median time to appearance of new lesions also supported the advantage of LCT over MT/O, albeit with less statistical significance (14.2 vs. 6.0 months; P = .11).

The investigators suggested several mechanisms behind the efficacy of LCT, including elimination of treatment-resistant cells, potentiation of systemic therapy, and elimination of the residual tumor as a driver of distant micrometastatic disease. “Notably,” the investigators wrote, “these mechanisms are not mutually exclusive, and more than one could contribute to the benefits of LCT.”

“[A]lthough these data are compelling ... we emphasize that future studies should be supported to definitively assess the role of LCT in larger populations (e.g., phase III trials such as NRG-LU002) and in the context of novel systemic therapies,” the investigators concluded.

The study was funded by MD Anderson Cancer Center, The Mohaymen Sahebzadah Family Philanthropic Grant, and the National Cancer Institute, National Institutes of Health. The authors disclosed relationships with Merck, Bristol-Myers Squibb, AstraZeneca, and others.

SOURCE: Gomez et al. J Clin Oncol. 8 May 2019. doi:10.1200/JCO.19.00201.

In patients with tumors bordering the central airway, use of antiangiogenic agents has been linked to fatal hemorrhage after radiation treatment, according to investigators reporting a large, retrospective case series.

Most hemorrhagic events in these patients with so-called “ultracentral” lung tumors occurred in those who received bevacizumab or pazopanib within 30 days of stereotactic body radiation therapy (SBRT), according to radiation oncologist Abraham J. Wu, MD, and coinvestigators at Memorial Sloan Kettering Cancer Center in New York.

Based on these new data, the combination of antiangiogenic agents (AAAs) and SBRT should be avoided in patients with ultracentral lung tumors, the researchers wrote.

“Although this report is limited by its retrospective nature, these findings strongly suggest that AAAs potentiate severe SBRT-related toxic effects,” Dr. Wu and coinvestigators wrote in a report on the study in JAMA Oncology. While AAAs are not indicated for treatment of patients with early-stage lung cancer, they may be used to treat oligometastatic disease, which may also be treated with SBRT.

The study included 88 patients with a median age of 74 years who had a lung tumor abutting the proximal bronchial tree, a planned target volume overlapping the esophagus, or both. There were lung metastases in 35 patients.

Nine patients had received bevacizumab, pazopanib, or ramucirumab, stopping a median of 30 days prior to SBRT and resuming a median of 29 days after the end of the radiation treatment.

There were six fatal pulmonary hemorrhages in 19.6 months of follow-up, Dr. Wu and coinvestigators reported. Of those six patients, four had received an antiangiogenic agent (three bevacizumab, one pazopanib) within 30 days of SBRT.

The probability of fatal pulmonary hemorrhage was significantly higher in the patients receiving AAAs versus those who did not (hazard ratio, 16.9; 95% confidence interval, 3.2-88.8; P less than .001).

Another six patients received AAAs more than 90 days before or after SBRT, and none of them had fatal hemorrhages.

A high rate of fatal hemorrhage was reported in another recent study of patients with ultracentral lung tumors, but that study did not identify any risk factors related to this toxic effect, Dr. Wu and coauthors wrote.

The research was partly supported by the National Institutes of Health, the China Scholarship Council, and the Joanne & John Dallepezze Foundation. The investigators reported disclosures related to AstraZeneca, CivaTech Oncology, Alpha Tau Medical, Varian Medical Systems, Boehringer Ingelheim, Pfizer, Merck, and Elekta.

SOURCE: Wu AJ et al. JAMA Oncol. 2019 Apr 4. doi: 10.1001/jamaoncol.2019.0205.

In patients with tumors bordering the central airway, use of antiangiogenic agents has been linked to fatal hemorrhage after radiation treatment, according to investigators reporting a large, retrospective case series.

Most hemorrhagic events in these patients with so-called “ultracentral” lung tumors occurred in those who received bevacizumab or pazopanib within 30 days of stereotactic body radiation therapy (SBRT), according to radiation oncologist Abraham J. Wu, MD, and coinvestigators at Memorial Sloan Kettering Cancer Center in New York.

Based on these new data, the combination of antiangiogenic agents (AAAs) and SBRT should be avoided in patients with ultracentral lung tumors, the researchers wrote.

“Although this report is limited by its retrospective nature, these findings strongly suggest that AAAs potentiate severe SBRT-related toxic effects,” Dr. Wu and coinvestigators wrote in a report on the study in JAMA Oncology. While AAAs are not indicated for treatment of patients with early-stage lung cancer, they may be used to treat oligometastatic disease, which may also be treated with SBRT.

The study included 88 patients with a median age of 74 years who had a lung tumor abutting the proximal bronchial tree, a planned target volume overlapping the esophagus, or both. There were lung metastases in 35 patients.

Nine patients had received bevacizumab, pazopanib, or ramucirumab, stopping a median of 30 days prior to SBRT and resuming a median of 29 days after the end of the radiation treatment.

There were six fatal pulmonary hemorrhages in 19.6 months of follow-up, Dr. Wu and coinvestigators reported. Of those six patients, four had received an antiangiogenic agent (three bevacizumab, one pazopanib) within 30 days of SBRT.

The probability of fatal pulmonary hemorrhage was significantly higher in the patients receiving AAAs versus those who did not (hazard ratio, 16.9; 95% confidence interval, 3.2-88.8; P less than .001).

Another six patients received AAAs more than 90 days before or after SBRT, and none of them had fatal hemorrhages.

A high rate of fatal hemorrhage was reported in another recent study of patients with ultracentral lung tumors, but that study did not identify any risk factors related to this toxic effect, Dr. Wu and coauthors wrote.

The research was partly supported by the National Institutes of Health, the China Scholarship Council, and the Joanne & John Dallepezze Foundation. The investigators reported disclosures related to AstraZeneca, CivaTech Oncology, Alpha Tau Medical, Varian Medical Systems, Boehringer Ingelheim, Pfizer, Merck, and Elekta.

SOURCE: Wu AJ et al. JAMA Oncol. 2019 Apr 4. doi: 10.1001/jamaoncol.2019.0205.

In patients with tumors bordering the central airway, use of antiangiogenic agents has been linked to fatal hemorrhage after radiation treatment, according to investigators reporting a large, retrospective case series.

Most hemorrhagic events in these patients with so-called “ultracentral” lung tumors occurred in those who received bevacizumab or pazopanib within 30 days of stereotactic body radiation therapy (SBRT), according to radiation oncologist Abraham J. Wu, MD, and coinvestigators at Memorial Sloan Kettering Cancer Center in New York.

Based on these new data, the combination of antiangiogenic agents (AAAs) and SBRT should be avoided in patients with ultracentral lung tumors, the researchers wrote.

“Although this report is limited by its retrospective nature, these findings strongly suggest that AAAs potentiate severe SBRT-related toxic effects,” Dr. Wu and coinvestigators wrote in a report on the study in JAMA Oncology. While AAAs are not indicated for treatment of patients with early-stage lung cancer, they may be used to treat oligometastatic disease, which may also be treated with SBRT.

The study included 88 patients with a median age of 74 years who had a lung tumor abutting the proximal bronchial tree, a planned target volume overlapping the esophagus, or both. There were lung metastases in 35 patients.

Nine patients had received bevacizumab, pazopanib, or ramucirumab, stopping a median of 30 days prior to SBRT and resuming a median of 29 days after the end of the radiation treatment.

There were six fatal pulmonary hemorrhages in 19.6 months of follow-up, Dr. Wu and coinvestigators reported. Of those six patients, four had received an antiangiogenic agent (three bevacizumab, one pazopanib) within 30 days of SBRT.

The probability of fatal pulmonary hemorrhage was significantly higher in the patients receiving AAAs versus those who did not (hazard ratio, 16.9; 95% confidence interval, 3.2-88.8; P less than .001).

Another six patients received AAAs more than 90 days before or after SBRT, and none of them had fatal hemorrhages.

A high rate of fatal hemorrhage was reported in another recent study of patients with ultracentral lung tumors, but that study did not identify any risk factors related to this toxic effect, Dr. Wu and coauthors wrote.

The research was partly supported by the National Institutes of Health, the China Scholarship Council, and the Joanne & John Dallepezze Foundation. The investigators reported disclosures related to AstraZeneca, CivaTech Oncology, Alpha Tau Medical, Varian Medical Systems, Boehringer Ingelheim, Pfizer, Merck, and Elekta.

SOURCE: Wu AJ et al. JAMA Oncol. 2019 Apr 4. doi: 10.1001/jamaoncol.2019.0205.

Although epidermal growth factor receptor–mutant lung cancers generally don’t benefit from checkpoint inhibitors, there may be some subtypes that do respond, results of a large, multi-institution analysis suggest.

Compared with wild-type lung cancer cases, tumors with epidermal growth factor receptor (EGFR) exon 19 deletion did indeed have worse outcomes after progressive death-1/progressive death–ligand 1 (PD-1/PD-L1) blockade; however, tumors harboring EGFR L858R mutations had comparable response rates and overall survival.

These findings don’t change clinical practice, but do serve as a “foundation” for more research into which patients with EGFR-mutant disease might benefit from immunotherapy, according to Katherine Hastings, PhD, of Yale University, New Haven, Conn., and associates.

“We unequivocally support the guidance that EGFR TKIs should be the preferred first-line treatment option for patients with EGFR-mutant lung cancer,” Dr. Hastings and coauthors wrote in Annals of Oncology.

To date, clinical investigations of immune checkpoint inhibitors in patients with EGFR-mutant lung cancers have largely been discouraging, the authors wrote. However, there have been some exceptions, including a phase 2 study where third-line durvalumab showed activity in some patients with EGFR-positive, PD-L1-expressing advanced non–small cell lung cancer (NSCLC).

Accordingly, the investigators sought to determine whether specific molecular features made a difference. They looked at a total of 171 EGFR-mutant lung cancers that had been treated with PD-1/PD-L1 inhibitors, alone or in combination with a cytotoxic T-lymphocyte antigen 4 inhibitor.

In their analysis, they drilled down on the most common EGFR tyrosine kinase inhibitor–sensitizing alleles: EGFR exon 19 deletions, which represented 76 cases, and EGFR L858R, which represented 44 cases. For comparison, they looked at a cohort of 212 patients with EGFR wild-type NSCLC who had also been treated with immune checkpoint inhibitors.

EGFR exon 19 deletion cases had a significantly lower overall response rate versus EGFR wild-type tumors, at 7% versus 22%, respectively (P = .002), the investigators found. Likewise, overall survival was significantly reduced, with a hazard ratio of 0.69 (95% confidence interval, 0.493-0.965; P = .03).

By contrast, EGFR L858R tumors had similar response rates versus EGFR wild type, at 16% and 22%, respectively (P = .42); overall survival also was similar, with a hazard ratio of 0.917 (95% CI, 0.597-1.409; P = .69).

Of note, progression-free survival was reduced in both EGFR L858R and EGFR exon 19 deletion cases as compared with EGFR wild-type cases, though the investigators wrote that discrepancy might be related to variations in scanning intervals between different institutions that contributed cases to the study.

“Overall, these data suggest that patients with EGFR exon 19–mutant tumors, in particular, have a significantly reduced benefit upon treatment with immune checkpoint inhibitors,” the authors noted.

In a separate but related analysis of 383 patients with EGFR-mutant lung cancer, tumor mutation burden was lower in EGFR exon 19 deletion cases as compared with the EGFR L858R cases. That finding lined up with the immunotherapy response data, the investigators wrote, though it’s unclear what might be driving the differences in tumor burden between these two groups.

There were no differences in response to immune checkpoint blockade based on whether or not tumors harbored the EGFR T790M mutation, the investigators added. Similarly, PD-L1 expression did not impact response.

The study authors reported disclosures related to Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Calithera Biosciences, Daiichi, Eli Lilly, Merck, Mirati Therapeutics, Novartis, Pfizer, Roche, and Takeda, among others.

SOURCE: Hastings K et al. Ann Oncol. 2019 May 14. doi: 10.1093/annonc/mdz141.

Although epidermal growth factor receptor–mutant lung cancers generally don’t benefit from checkpoint inhibitors, there may be some subtypes that do respond, results of a large, multi-institution analysis suggest.

Compared with wild-type lung cancer cases, tumors with epidermal growth factor receptor (EGFR) exon 19 deletion did indeed have worse outcomes after progressive death-1/progressive death–ligand 1 (PD-1/PD-L1) blockade; however, tumors harboring EGFR L858R mutations had comparable response rates and overall survival.

These findings don’t change clinical practice, but do serve as a “foundation” for more research into which patients with EGFR-mutant disease might benefit from immunotherapy, according to Katherine Hastings, PhD, of Yale University, New Haven, Conn., and associates.

“We unequivocally support the guidance that EGFR TKIs should be the preferred first-line treatment option for patients with EGFR-mutant lung cancer,” Dr. Hastings and coauthors wrote in Annals of Oncology.

To date, clinical investigations of immune checkpoint inhibitors in patients with EGFR-mutant lung cancers have largely been discouraging, the authors wrote. However, there have been some exceptions, including a phase 2 study where third-line durvalumab showed activity in some patients with EGFR-positive, PD-L1-expressing advanced non–small cell lung cancer (NSCLC).

Accordingly, the investigators sought to determine whether specific molecular features made a difference. They looked at a total of 171 EGFR-mutant lung cancers that had been treated with PD-1/PD-L1 inhibitors, alone or in combination with a cytotoxic T-lymphocyte antigen 4 inhibitor.

In their analysis, they drilled down on the most common EGFR tyrosine kinase inhibitor–sensitizing alleles: EGFR exon 19 deletions, which represented 76 cases, and EGFR L858R, which represented 44 cases. For comparison, they looked at a cohort of 212 patients with EGFR wild-type NSCLC who had also been treated with immune checkpoint inhibitors.

EGFR exon 19 deletion cases had a significantly lower overall response rate versus EGFR wild-type tumors, at 7% versus 22%, respectively (P = .002), the investigators found. Likewise, overall survival was significantly reduced, with a hazard ratio of 0.69 (95% confidence interval, 0.493-0.965; P = .03).

By contrast, EGFR L858R tumors had similar response rates versus EGFR wild type, at 16% and 22%, respectively (P = .42); overall survival also was similar, with a hazard ratio of 0.917 (95% CI, 0.597-1.409; P = .69).

Of note, progression-free survival was reduced in both EGFR L858R and EGFR exon 19 deletion cases as compared with EGFR wild-type cases, though the investigators wrote that discrepancy might be related to variations in scanning intervals between different institutions that contributed cases to the study.

“Overall, these data suggest that patients with EGFR exon 19–mutant tumors, in particular, have a significantly reduced benefit upon treatment with immune checkpoint inhibitors,” the authors noted.

In a separate but related analysis of 383 patients with EGFR-mutant lung cancer, tumor mutation burden was lower in EGFR exon 19 deletion cases as compared with the EGFR L858R cases. That finding lined up with the immunotherapy response data, the investigators wrote, though it’s unclear what might be driving the differences in tumor burden between these two groups.

There were no differences in response to immune checkpoint blockade based on whether or not tumors harbored the EGFR T790M mutation, the investigators added. Similarly, PD-L1 expression did not impact response.

The study authors reported disclosures related to Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Calithera Biosciences, Daiichi, Eli Lilly, Merck, Mirati Therapeutics, Novartis, Pfizer, Roche, and Takeda, among others.

SOURCE: Hastings K et al. Ann Oncol. 2019 May 14. doi: 10.1093/annonc/mdz141.

Although epidermal growth factor receptor–mutant lung cancers generally don’t benefit from checkpoint inhibitors, there may be some subtypes that do respond, results of a large, multi-institution analysis suggest.

Compared with wild-type lung cancer cases, tumors with epidermal growth factor receptor (EGFR) exon 19 deletion did indeed have worse outcomes after progressive death-1/progressive death–ligand 1 (PD-1/PD-L1) blockade; however, tumors harboring EGFR L858R mutations had comparable response rates and overall survival.

These findings don’t change clinical practice, but do serve as a “foundation” for more research into which patients with EGFR-mutant disease might benefit from immunotherapy, according to Katherine Hastings, PhD, of Yale University, New Haven, Conn., and associates.

“We unequivocally support the guidance that EGFR TKIs should be the preferred first-line treatment option for patients with EGFR-mutant lung cancer,” Dr. Hastings and coauthors wrote in Annals of Oncology.

To date, clinical investigations of immune checkpoint inhibitors in patients with EGFR-mutant lung cancers have largely been discouraging, the authors wrote. However, there have been some exceptions, including a phase 2 study where third-line durvalumab showed activity in some patients with EGFR-positive, PD-L1-expressing advanced non–small cell lung cancer (NSCLC).

Accordingly, the investigators sought to determine whether specific molecular features made a difference. They looked at a total of 171 EGFR-mutant lung cancers that had been treated with PD-1/PD-L1 inhibitors, alone or in combination with a cytotoxic T-lymphocyte antigen 4 inhibitor.

In their analysis, they drilled down on the most common EGFR tyrosine kinase inhibitor–sensitizing alleles: EGFR exon 19 deletions, which represented 76 cases, and EGFR L858R, which represented 44 cases. For comparison, they looked at a cohort of 212 patients with EGFR wild-type NSCLC who had also been treated with immune checkpoint inhibitors.

EGFR exon 19 deletion cases had a significantly lower overall response rate versus EGFR wild-type tumors, at 7% versus 22%, respectively (P = .002), the investigators found. Likewise, overall survival was significantly reduced, with a hazard ratio of 0.69 (95% confidence interval, 0.493-0.965; P = .03).

By contrast, EGFR L858R tumors had similar response rates versus EGFR wild type, at 16% and 22%, respectively (P = .42); overall survival also was similar, with a hazard ratio of 0.917 (95% CI, 0.597-1.409; P = .69).

Of note, progression-free survival was reduced in both EGFR L858R and EGFR exon 19 deletion cases as compared with EGFR wild-type cases, though the investigators wrote that discrepancy might be related to variations in scanning intervals between different institutions that contributed cases to the study.

“Overall, these data suggest that patients with EGFR exon 19–mutant tumors, in particular, have a significantly reduced benefit upon treatment with immune checkpoint inhibitors,” the authors noted.

In a separate but related analysis of 383 patients with EGFR-mutant lung cancer, tumor mutation burden was lower in EGFR exon 19 deletion cases as compared with the EGFR L858R cases. That finding lined up with the immunotherapy response data, the investigators wrote, though it’s unclear what might be driving the differences in tumor burden between these two groups.

There were no differences in response to immune checkpoint blockade based on whether or not tumors harbored the EGFR T790M mutation, the investigators added. Similarly, PD-L1 expression did not impact response.

The study authors reported disclosures related to Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Calithera Biosciences, Daiichi, Eli Lilly, Merck, Mirati Therapeutics, Novartis, Pfizer, Roche, and Takeda, among others.

SOURCE: Hastings K et al. Ann Oncol. 2019 May 14. doi: 10.1093/annonc/mdz141.