Phase III randomized controlled trial of gefitinib versus chemotherapy in EGFR-positive treatment-naïve metastatic lung cancer: Long-term outcome after eight years

Background: This was the first Phase III randomized study comparing an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), gefitinib, to standard-of-care chemotherapy (pemetrexed + carboplatin followed by pemetrexed maintenance) in advanced EGFR-mutated lung cancer. The initial interim analysis showed the superiority of gefitinib over chemotherapy in terms of progression-free survival (PFS), objective response rate (ORR), and safety. Objectives: We aimed to evaluate the long-term outcomes. Our primary endpoint was to evaluate the overall survival (OS) and the secondary endpoints were progression-free survival 2 (PFS2) and duration of response (DOR). Materials and Methods: This was a Phase III open-label, randomized, parallel-group study conducted in the Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India, in patients with EGFR mutation-positive treatment-naïve Stage IIIB or IV lung adenocarcinoma. Patients were randomized to gefitinib (250 mg orally daily) or carboplatin (area under the curve 5) and pemetrexed (500 mg/m2) chemotherapy, followed by maintenance pemetrexed (500 mg/m2). Results: Between February 2012 and April 2016, 290 patients were randomized:145 to each arm. At a median follow-up of 104 months, all 290 (100%) patients had progressed, and 287 (99%) deaths had occurred. The median OS in the gefitinib arm was 19.5 months (95% confidence interval [CI], 16.7-24.8) compared to 22.6 months (95% CI, 19.2-25.2) in the chemotherapy arm; hazard ratio [HR], 1.11; 95% CI, 0.87-1.39; P, 0.423. The median PFS2 in the gefitinib arm was 15.5 months (95% CI, 13.5-18.1) compared to 12.5 months (95% CI, 11.1-14.5) in the chemotherapy arm; HR, 0.86 (95% CI, 0.66-1.13); P, 0.270. The median DOR was improved in the gefitinib arm (7.6 months; 95% CI, 5.45-9.88) compared to 3.9 months (95% CI, 3.49-6.35) in the chemotherapy arm; HR, 0.59; 95% CI, 0.42-0.82; P, 0.002. The 5-year survival was 4.1% in the gefitinib arm versus 6.8% in the chemotherapy arm. Conclusions: This study establishes the advantages of first-line EGFR TKI therapy over chemotherapy in terms of a durable response and numerically superior PFS2. Due to crossover post-progression, there was is no significant difference in OS (Clinical Trials Registry of India number: CTRI/2015/08/006113).