In the Journals

Improved biomarker-integrated strategies needed for KRAS-mutated NSCLC

Previously treated patients with advanced KRAS–mutated non–small cell lung cancer achieved longer PFS on regimens that did not contain erlotinib, according to data from the randomized BATTLE-2 study.

However, improved biomarker-driven treatment strategies are needed for this patient population.

Lung cancers are biologically and molecularly diverse and have various responses to both traditional chemotherapy and targeted therapy designed to address molecular alterations that drive cancer progression,” Vassiliki Papadimitrakopoulou, MD, professor of medicine in the department of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center, and colleagues wrote. “The rapid evolution of genomic profiling has dramatically accelerated our knowledge of the diversity of lung cancer and has generated the impetus for using genotyping as a guide for clinical care of patients with lung cancer and for creating novel design paradigms in genomics-driven clinical trials.”

The Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination 2 (BATTLE-2) trial aimed to examine the effects of targeted therapies on KRAS–mutated cancers.

The analysis included 200 patients with advanced NSCLC, of whom 27% had KRAS–mutated tumors. Researchers randomly assigned patients to one of four treatment arms: erlotinib (Tarceva; Genentech, Astellas Oncology; n = 22), erlotinib plus MK-2206 (Merck; n = 42), MK-2206 plus AZD6244 (AstraZeneca; n = 75) and sorafenib (Nexavar, Bayer; n = 61). After randomization, 186 patients were eligible for analysis.

Disease control rate at 8 weeks served as the primary endpoint.

The 8-week disease control rate was 48% overall; 32% among patients assigned erlotinib alone; 50% among those assigned erlotinib plus MK-2206; 53% among those assigned MK-2206 plus AZD6244; and 46% among those assigned sorafenib.

Among patients with KRAS–mutated tumors, the disease control rates were 20% among those assigned erlotinib alone; 25% among those assigned erlotinib plus MK-2206; 62% among those assigned MK-2206 plus AZD6244; and 44% among those assigned sorafenib.

Among patients with KRAS wild-type tumors, disease control rates were 36% among those assigned erlotinib; 57% among those assigned erlotinib plus MK-2206; 49% among those assigned MK-2206 plus AZD6244; and 47% among those assigned sorafenib.

Researchers reported no difference in PFS or OS between patients with KRAS–mutated and KRAS wild-type tumors.

Among patients with KRAS wild-type tumors, researchers reported no difference in PFS between treatment with erlotinib or without (HR = 0.76; 95% CI, 0.54-1.09). However, these patients experienced improved OS when treated with therapies that contained erlotinib (HR = 0.66; 95% CI, 0.45-0.97).

Patients with KRAS–mutated tumors achieved significantly longer PFS when treated with therapies that did not contain erlotinib (HR = 1.95; 95% CI, 1-3.77). However, there was no difference in OS in this group when comparing regimens that included erlotinib and regimens that did not include erlotinib (HR = 0.26; 95% CI, 0.65-2.46).

“Although the [BATTLE-2] design theoretically provided advantages because clear predictive markers did not exist for any of the treatment arms, activity was modest, yielding no new predictive markers and not warranting further exploration,” Papadimitrakopoulou and colleagues wrote.

Aside from the “relatively unconventional” primary endpoint of an 8-week disease control rate, “BATTLE-2 should be recognized as a valuable contribution to the field, despite it failing to demonstrate encouraging efficacy in any of the treatment arms or patient subsets,” Howard West, MD, of Swedish Cancer Institute in Seattle, wrote in an accompanying editorial. “The authors deserve to be lauded for prospectively testing an array of targeted therapies in previously treated patients that were based on molecular marker findings from repeat biopsies. In the coming years, the true test of whether we deliver on the promise of precision medicine in cancer care will require us to prospectively define clear and clinically meaningful endpoints, and then demonstrate that we can achieve them.” – by Andy Polhamus

 

Disclosure: Papadimitrakopoulou reports consultant or advisory roles with Ariad, AstraZeneca, Biothera, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, Genentech, Gensignia Life Sciences, Janssen and Merck. Please see the full study for a full list of all other researchers’ relevant financial disclosures. West reports consultant or advisory roles with Ariad, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech, Guardant Health, Novartis and Trovagene, as well as speakers bureau fees from Ariad, Eli Lilly and Genentech.

Previously treated patients with advanced KRAS–mutated non–small cell lung cancer achieved longer PFS on regimens that did not contain erlotinib, according to data from the randomized BATTLE-2 study.

However, improved biomarker-driven treatment strategies are needed for this patient population.

Lung cancers are biologically and molecularly diverse and have various responses to both traditional chemotherapy and targeted therapy designed to address molecular alterations that drive cancer progression,” Vassiliki Papadimitrakopoulou, MD, professor of medicine in the department of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center, and colleagues wrote. “The rapid evolution of genomic profiling has dramatically accelerated our knowledge of the diversity of lung cancer and has generated the impetus for using genotyping as a guide for clinical care of patients with lung cancer and for creating novel design paradigms in genomics-driven clinical trials.”

The Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination 2 (BATTLE-2) trial aimed to examine the effects of targeted therapies on KRAS–mutated cancers.

The analysis included 200 patients with advanced NSCLC, of whom 27% had KRAS–mutated tumors. Researchers randomly assigned patients to one of four treatment arms: erlotinib (Tarceva; Genentech, Astellas Oncology; n = 22), erlotinib plus MK-2206 (Merck; n = 42), MK-2206 plus AZD6244 (AstraZeneca; n = 75) and sorafenib (Nexavar, Bayer; n = 61). After randomization, 186 patients were eligible for analysis.

Disease control rate at 8 weeks served as the primary endpoint.

The 8-week disease control rate was 48% overall; 32% among patients assigned erlotinib alone; 50% among those assigned erlotinib plus MK-2206; 53% among those assigned MK-2206 plus AZD6244; and 46% among those assigned sorafenib.

Among patients with KRAS–mutated tumors, the disease control rates were 20% among those assigned erlotinib alone; 25% among those assigned erlotinib plus MK-2206; 62% among those assigned MK-2206 plus AZD6244; and 44% among those assigned sorafenib.

Among patients with KRAS wild-type tumors, disease control rates were 36% among those assigned erlotinib; 57% among those assigned erlotinib plus MK-2206; 49% among those assigned MK-2206 plus AZD6244; and 47% among those assigned sorafenib.

Researchers reported no difference in PFS or OS between patients with KRAS–mutated and KRAS wild-type tumors.

Among patients with KRAS wild-type tumors, researchers reported no difference in PFS between treatment with erlotinib or without (HR = 0.76; 95% CI, 0.54-1.09). However, these patients experienced improved OS when treated with therapies that contained erlotinib (HR = 0.66; 95% CI, 0.45-0.97).

Patients with KRAS–mutated tumors achieved significantly longer PFS when treated with therapies that did not contain erlotinib (HR = 1.95; 95% CI, 1-3.77). However, there was no difference in OS in this group when comparing regimens that included erlotinib and regimens that did not include erlotinib (HR = 0.26; 95% CI, 0.65-2.46).

“Although the [BATTLE-2] design theoretically provided advantages because clear predictive markers did not exist for any of the treatment arms, activity was modest, yielding no new predictive markers and not warranting further exploration,” Papadimitrakopoulou and colleagues wrote.

Aside from the “relatively unconventional” primary endpoint of an 8-week disease control rate, “BATTLE-2 should be recognized as a valuable contribution to the field, despite it failing to demonstrate encouraging efficacy in any of the treatment arms or patient subsets,” Howard West, MD, of Swedish Cancer Institute in Seattle, wrote in an accompanying editorial. “The authors deserve to be lauded for prospectively testing an array of targeted therapies in previously treated patients that were based on molecular marker findings from repeat biopsies. In the coming years, the true test of whether we deliver on the promise of precision medicine in cancer care will require us to prospectively define clear and clinically meaningful endpoints, and then demonstrate that we can achieve them.” – by Andy Polhamus

 

Disclosure: Papadimitrakopoulou reports consultant or advisory roles with Ariad, AstraZeneca, Biothera, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, Genentech, Gensignia Life Sciences, Janssen and Merck. Please see the full study for a full list of all other researchers’ relevant financial disclosures. West reports consultant or advisory roles with Ariad, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech, Guardant Health, Novartis and Trovagene, as well as speakers bureau fees from Ariad, Eli Lilly and Genentech.