Phase III study results in advanced EGFR-mutated lung cancer showed improved progression-free survival with afatinib compared with standard chemotherapy. J. Clin. Oncol. 2013 Jul 01;[EPub Ahead of Print], LV Sequist, J Chih-Hsin Yang, N Yamamoto, K O’Byrne, V Hirsh, T Mok, SL Geater, S Orlov, C-M Tsai, M Boyer, W-C Su, J Bennouna, T Kato, V Gorbunova, KH Lee, R Shah, D Massey, V Zazulina, M Shahidi, M Schuler ABSTRACT Purpose: The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation–positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS). Patients and Methods: In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs). Results: A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatment-related adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain. Conclusion: Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations. Commentary by Lee S. Schwartzberg, MD, FACP Evolution of therapy in the treatment of advanced non–small cell lung cancer (NSCLC) has been nothing short of remarkable over the past few years. We now know that EGFR mutations are common and predict for response to small molecular EGFR tyrosine kinase inhibitors (TKIs). In prior head-to-head studies, done in European or Asian populations, patients fared better with gefitinib or erlotinib than platinum doublets. Now comes a new kid on the block, afatinib, which is a pan-ErbB inhibitor targeting EGFR, HER2, and HER4. It has potential advantages over the older TKIs, particularly activity against the T790M mutation. In this trial published in the Journal of Clinical Oncology, the largest molecularly defined first-line lung cancer study to date, afatinib improved progression-free survival over the current best chemotherapy regimen, platinum/pemetrexed, by more than 4 months and 42% in a diverse population. Lung cancer symptoms improved more with afatinib than chemo; but, there is still a comparable grade 3 toxicity level associated with this drug and class consisting of diarrhea, rash, and fatigue. Nonetheless, it is likely that afatinib will soon be approved for use in the US, and it will expand the opportunities for patients with any EGFR mutation. As noted by the authors, all NSCLC patients should undergo testing for EGFR (and, if negative, ALK) as soon as they are diagnosed with advanced disease. The appropriate treatment decision depends on this testing.
Posted on: Sun, 07 Jul 2013 15:20:27 +0000
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