Resistance mechanisms and efficacy of first-line alectinib and sequential treatments in advanced <i>ALK</i> + NSCLC: Real-world outcomes from a multicenter, observational study in Japan (ALCURE).

Abstract

8604 Background: First-line (1L) alectinib has shown superior progression-free survival (PFS) vs crizotinib in advanced ALK + non-small cell lung cancer (NSCLC). We present final data from ALCURE (UMIN000038934), a real-world study exploring resistance mechanisms to 1L alectinib and treatment sequencing in Japanese patients (pts) with advanced ALK + NSCLC. Methods: Eligible pts, aged ≥20 years with ALK+ NSCLC, were enrolled into 2 cohorts: pts already receiving 1L alectinib before enrollment (cohort A) or treatment-naïve pts starting alectinib (cohort B). Results were reported separately by cohort to address the potential immortal time bias introduced by cohort A (pooled analyses were reported for second-line [2L] treatment since the bias did not apply and the sample size was limited). Clinical samples were collected and analyzed using next-generation sequencing. Results: From Jan–Nov 2020, 249 pts were enrolled (cohort A/B, n=200/49). Demographics in cohort A/B were: age ≥75 years, 21%/18%; female, 60%/57%; never smokers, 65%/67%; brain metastases, 22%/31%; TP53 mutations, 9%/41%. EML4-ALK variant 1 was the most common ALK variant (50% cohort A, 42% cohort B). Secondary ALK mutations at disease progression (PD) or end of 1L treatment were detected in 14/60 pts (23%) in cohort A and 3/25 pts (12%) in cohort B (primarily G1202R or I1171N). Median duration of 1L alectinib before enrolment in cohort A was 24 months (range 1–111). At data cutoff (Nov 6, 2024), median follow-up was 74.1 months (95% CI 11.8‒163.3) in cohort A and 48.7 months (95% CI 0.6‒56.7) in cohort B. Median PFS (mPFS) was not reached (NR) (95% CI 83.7‒NR) in cohort A and 32.9 months (95% CI 11.8‒38.5) in cohort B. In pts whose tumors were TP53 wildtype vs mutant prior to alectinib, mPFS was NR vs NR (HR 0.47, 95% CI 0.15–1.50) in cohort A and 33.6 vs 14.1 months (HR 0.96, 95% CI 0.46–2.00) in cohort B. mPFS in pts with secondary ALK mutations detected vs not detected at PD or end of 1L treatment was 14.6 vs 37.1 months (HR 1.68, 95% CI 0.84–3.34) in cohort A and 9.0 vs 11.8 months (HR 1.56, 95% CI 0.35–6.95) in cohort B. Median OS was NR (95% CI NR–NR) in cohort A and 54.7 months (95% CI 54.7–NR) in cohort B. Of the 118/249 pts who discontinued 1L alectinib, 84 received 2L treatment (including 18 who received non-ALK TKIs); mPFS for 2L treatment was 9.9 months (95% CI 7.4–12.1) in the overall cohort. Among these pts, 40 received lorlatinib and had the longest mPFS of all pts receiving 2L treatment (17.2 months). Conclusions: The use of 1L alectinib in clinical practice demonstrated efficacy consistent with that seen in clinical trials in pts with ALK+ NSCLC and confirms the existence of long-term responders. Lorlatinib may be an effective treatment following 1L alectinib; further research is needed to identify factors that may predict response and inform optimal treatment sequencing strategies. Clinical trial information: UMIN000038934.