Final overall survival analysis for a phase 3 randomized trial comparing afatinib to chemotherapy in treatment-naïve non-small cell lung cancer with a sensitizing uncommon epidermal growth factor receptor mutation (ACHILLES/TORG1834).

Abstract

8623 Background: The phase 3 randomized trial comparing afatinib to chemotherapy in treatment-naïve non-small cell lung cancer (NSCLC) with a sensitizing uncommon epidermal growth factor receptor mutation ( EGFR ) (ACHILLES) met its primary endpoint at the interim analysis. This trial demonstrated statistically significant improvement in progression-free survival (PFS)with hazard ratio 0.421; 95% confidence interval (CI), 0.251–0.706; p = 0.0010). Here, we report the final updated survival data. Methods: In this open-label phase 3 study, treatment-naïve patients (n=109) with sensitizing uncommon EGFR mutant NSCLC were randomized 2:1 to receive oral afatinib (30 mg or 40 mg daily) or a combination of platinum (cisplatin 75 mg/m 2 or carboplatin AUC 5 or 6) and pemetrexed (500 mg/m 2 ), followed by pemetrexed maintenance therapy every 3 weeks. The primary endpoint was PFS according to RECIST 1.1 criteria. Overall survival (OS) was a secondary endpoint. Post-protocol treatment was administered at the physician's discretion. Results: As of the 2 December 2024 database lock, the median follow-up time was 33.6 months. Afatinib continued to improve PFS compared with chemotherapy (median, 10.8 months vs 7.0 months; HR [95% CI], 0.528 [0.338–0.827], p = 0.0052). The updated OS HR for afatinib compared to chemotherapy was 0.645 (95% CI, 0.359–1.160; p = 0.1433; 49/109 events, 44.9% maturity). The median OS was 45.0 months (range, 27.0–not estimated) in the afatinib group and 27.0 months (range, 15.9–50.4) in the chemotherapy group. The crossover rate to EGFR-TKI was 90.6% in the chemotherapy arm. Notably, the subgroup receiving a starting dose of 40mg afatinib and the subgroup of younger patients (< 75 years) showed a favorable OS HR (HR 0.371, 95%CI, 0.140–0.986; HR 0.422, 95%CI, 0.201–0.886). No new safety signals were observed in this update analysis. Conclusions: This final survival analysis confirmed the superiority of afatinib compared to chemotherapy for uncommon or compound EGFR mutation-positive advanced NSCLC. Clinical trial information: jRCTs 031180175 . Treatment arm n Median PFS, mo[95%CI] PFS HR[95%CI] Median OS, mo[95%CI] OS HR[95%CI] Afatinib All 73 10.8[8.6–13.2] 0.528[0.338–0.827] 45.0[27.0–NE] 0.645[0.359–1.160] Major uncommon(G719X, L861X, S768I/V) 44 10.0[7.2–11.4] 0.630[0.385–1.030] 42.0[17.8–NE] 0.878[0.470–1.639] Other uncommon 5 8.6[6.1–NR] 1.006[0.384–2.635] 37.8[27.0–NE] 0.814[0.237–2.794] Compound 24 15.5[9.1–21.0] 0.414[0.230–0.748] NR[30.2–NE] 0.358[0.132–0.972] Chemotherapy Platinum+Pemetrexed 36 7.0[4.7–8.3] - 27.0[15.9–50.4] -