ARCHER 1050: Hitting an Important Mark in EGFR-Mutant Lung Cancer?

Small molecule inhibitors that target the epidermal growth factor receptor (EGFR) are cornerstones of therapy for non–small-cell lung cancers (NSCLCs) that harbor activating EGFR mutations. To date, three distinct generations of EGFR tyrosine kinase inhibitors (TKIs) have been developed, and at least one agent from each generation is now approved in the United States for front-line use. Despite some similarities, key differences distinguish these drugs. These include mode of drug binding (reversible v irreversible inhibition of EGFR), toxicity profiles (that stem from each drug’s activity against wild-type EGFR), activity against other HER/ErbB2 family members, CNS penetration, and the ability to overcome T790M-mediated resistance in the clinic. Taken together, such differences across EGFR inhibitors translate into distinct efficacy and safety profiles; thus, head-to-head comparisons between these drugs are essential to select optimal therapy.

In the article that accompanies this editorial, Mok et al1 report the overall survival (OS) results from the randomized, phase III ARCHER 1050 trial, which compared the second-generation EGFR inhibitor dacomitinib with the first-generation inhibitor gefitinib in treatment-naïve patients with EGFR-mutant NSCLC. As previously reported, the study met its primary endpoint by demonstrating an improvement in progression-free survival (PFS) among patients who received dacomitinib compared with gefitinib (14.7 v 9.2 months, respectively; hazard ratio [HR], 0.59; 95% CI, 0.47 to 0.74; P < .001).2 After additional follow-up, the ARCHER 1050 investigators now report the study’s final OS analysis, which identified a significant improvement in OS with dacomitinib versus gefitinib (median OS, 34.1 v 26.8 months, respectively; HR, 0.76; 95% CI, 0.582 to 0.993; P = .0438).1 These findings are noteworthy, because ARCHER 1050 represents the first randomized, phase III study that directly compared EGFR inhibitors to demonstrate an OS benefit. Nonetheless, this trial must be analyzed in the context of the evolving landscape of EGFR-mutant NSCLC.

In the initial phase III studies to establish EGFR inhibition as standard therapy for newly diagnosed EGFR-mutant NSCLC, including key trials such as iPASS and EURTAC,3,4 patients were randomly assigned to receive either first-generation EGFR inhibitors or platinum-doublet chemotherapy. In each trial, EGFR TKIs improved PFS compared with chemotherapy, but none demonstrated an OS benefit, presumably because of receipt of targeted therapy in subsequent lines of treatment. Importantly, all such studies were performed in an era in when EGFR TKIs were readily available, and it was neither possible nor desirable to prohibit crossover, given the marked activity of these agents. However, after extrapolation of results from a retrospective analysis in ALK-rearranged NSCLC,5 we suspected that such a trial, had it been done, would have likely shown a survival advantage that favored the genotype-directed therapy.

We are now in the midst of a second wave of pivotal studies for EGFR-mutant NSCLC that is centered upon head-to-head comparisons of different targeted therapies in the front-line setting. The paradigm of upfront genotype-directed therapy is firmly established in EGFR-mutant NSCLC, yet practitioners are now faced with questions about the optimal sequencing of multiple available targeted therapies. LUX-Lung 7, a phase IIB study in which patients were randomly assigned to first-line afatinib (a second-generation EGFR inhibitor) or gefitinib, was the first of these head-to-head comparisons.6 Although LUX-Lung 7 demonstrated a statistically significant PFS improvement (HR, 0.73; 95% CI, 0.57 to 0.95; P = .017), the degree of benefit was marginal and not particularly clinically meaningful (median PFS, 11.0 v 10.9 months, respectively). Furthermore, there was no difference in OS—a coprimary end point of the study.7

Journal of Clinical Oncology , éditorial en libre accès, 2017

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