Phase III randomized trial comparing gefitinib to gefitinib with pemetrexed-carboplatin chemotherapy in patients with advanced untreated EGFR mutant non-small cell lung cancer (gef vs gef+C).

Abstract

9001 Background: Standard first-line therapy for EGFR mutant advanced non-small cell lung cancer (NSCLC) is an EGFR-directed oral TKI. We evaluated whether adding pemetrexed-carboplatin to oral TKI would improve outcomes. Methods: Phase III randomized trial in advanced chemotherapy-naïve NSCLC harboring EGFR sensitizing mutation (exon 19, 21 or 18) with performance status (PS) 0 to 2 planned for palliative therapy. Patients were stratified for PS and EGFR mutation and randomly assigned (computer-generated randomization by independent biostatistician) 1:1 to gefitinib 250 mg orally daily (gef) or gefitinib 250 mg orally daily with pemetrexed 500 mg/m2 IV and carboplatin AUC 5 IV every 3 weeks for 4 cycles, followed by maintenance pemetrexed 500 mg/m2 IV every 3 weeks (gef+C). Restaging was every 2 to 3 mths; therapy continued until progression or intolerable toxicity. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), toxicity and response rate. Survival endpoints were assessed in the intention-to-treat population. Results: Between Aug 2016 and Aug 2018, 350 patients were randomly assigned to gef (n = 177) and gef+C (n = 173). Median age was 54 yrs, 48% were females, 84% never-smokers, 21% were PS 2 and 18% had brain metastases. Median follow-up in surviving patients was 17 months (range, 7 to 30). Radiologic response rates were 81% and 69% in gef+C and gef respectively, P = 0.012. 234 patients (67%) have had events for PFS, 98 in gef+C and 136 in gef. Estimated median PFS was significantly longer with gef+C than gef (16 months, [95% CI, 13.7 to 18.3] vs. 8 months [95% CI, 7.1 to 8.9]; hazard ratio for disease progression or death, 0.5; 95% CI, 0.39 to 0.65; P < 0.001). 120 patients (34%) have died, 42 in gef+C and 78 in gef. Estimated median OS was significantly longer with gef+C than gef (not reached vs. 18 months [95% CI, 14.28 to 21.72]; hazard ratio for death, 0.45; 95% CI, 0.31 to 0.66; P < 0.001). Clinically relevant ≥ grade 3 toxicities occurred in 51% and 25% of patients in gef+C and gef arms respectively, P < 0.001. Conclusion: Adding pemetrexed-carboplatin chemotherapy to gefitinib significantly prolonged progression free and overall survival but also increased toxicity. Pemetrexed-carboplatin-gefitinib represents a new standard first-line therapy for EGFR mutant NSCLC. Clinical trial information: CTRI/2016/08/007149.