“The success of the ARCHER trial makes it certain there will be more first-line trials to come in EGFR-mutant NSCLC.”— Geoffrey R. Oxnard, MD
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THE RESULTS FROM the ARCHER 1050 study—reported by Wu et al1 and reviewed in this issue of The ASCO Post—highlight the recent optimism about improved outcomes in metastatic non–small cell lung cancer (NSCLC) harboring mutations in the epidermal growth factor receptor (EGFR) gene. This trial convincingly shows us that first-line treatment with a second-generation EGFR tyrosine kinase inhibitor (TKI), dacomitinib, significantly prolongs progression-free survival, with increased toxicity, as compared with gefitinib (Iressa) in advanced NSCLC without brain metastases.
The key finding in this study is the demonstration that, despite the dramatic effectiveness of established EGFR TKIs such as erlotinib (Tarceva) and gefitinib, it is possible to improve outcomes even further. This is the first randomized phase III trial in this disease that has convincingly improved upon an established first-line targeted therapy. Although phase II data have suggested benefits from first-line treatment with afatinib (Gilotrif) or erlotinib with bevacizumab (Avastin), the dacomitinib data are more definitive. The success of the ARCHER trial makes it certain there will be more first-line trials to come in EGFR-mutant NSCLC.
Outcomes in Asian vs Non-Asian Patients
ONE INTERESTING FINDING from the ARCHER study was that a subgroup analysis suggested a more dramatic progression-free survival benefit in Asian patients (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.36–0.66) than in non-Asian patients (HR = 0.89, 95% CI = 0.57–1.39), although this difference was not statistically significant. In fact, the authors noted a prior single-arm phase II study showed the reverse, with better progression-free survival in non-Asian patients; they concluded that collectively, there is likely no difference between these two subgroups of patients. Although prevailing wisdom suggests tumor genotype trumps clinical features such as race when selecting targeted therapy, there is a possibility that Asian patients metabolize some EGFR TKIs differently. Further details on whether Asian patients experienced a different spectrum of toxicities or had different rates of dose adjustment might provide greater clarity.
Balancing Toxicity and Efficacy
THE CHALLENGE FROM the ARCHER trial is that the improvement in progression-free survival, from a median of 9 months to 15 months, comes with a clear increase in toxicity. This balance between toxicity and efficacy is something we are still perfecting with EGFR TKIs. With cytotoxic chemotherapy, we have historically waited for severe (grade 3) toxicity before reducing the dose. In contrast, my patients treated with EGFR TKIs commonly have lower-grade (grade 2) cutaneous and gastrointestinal toxicity, which requires daily management. Although these toxicities may be less dramatic, these patients often require dose adjustment to chronically tolerate the drug. It is notable that in the ARCHER study, 66% of patients who received dacomitinib required dose reduction, and 28% required multiple dose reductions. Despite the improved progression-free survival and the duration of response with dacomitinib, global quality of life significantly favored the gefitinib arm.
The pressing need in this disease is for treatments with increased effectiveness without the increased toxicity. Recent results suggest a third-generation EGFR TKI, osimertinib (Tagrisso), may offer this combination. An initial report from the phase III FLAURA trial showed improved progression-free survival with osimertinib over gefitinib or erlotinib in the first-line treatment of NSCLC (with or without brain metastases) and without increased toxicity.2 One crucial advantage of a tolerable drug such as osimertinib is that it could be the backbone for further improvements as first-line combination therapies are developed. A more complete report of the FLAURA trial, with greater details regarding tolerability, is eagerly awaited. For now, patients and clinicians can take heart at the persistent progress in achieving more durable control of this disease. ■
DISCLOSURE: Dr. Oxnard has received consulting fees from AstraZeneca, Boehringer-Ingelheim, Genentech, and Novartis.
1. Wu YL, Cheng Y, Zhou X, et al: Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): A randomised, open-label, phase 3 trial. Lancet Oncol. September 25, 2017 (early release online).
2. Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al: Osimertinib vs standard of care EGFR-TKI as first-line therapy in patients with EGFRm advanced NSCLC: FLAURA. ESMO 2017 Congress. Abstract LBA2_PR. Presented September 9, 2017.