Overall survival of first-line amivantamab plus lazertinib in atypical EGFR -mutated advanced non-small cell lung cancer (NSCLC): Updated results from the CHRYSALIS-2 study.

8501 Background: Patients with atypical EGFR -mutated advanced NSCLC have worse long-term outcomes with EGFR-targeted therapies than classical exon 19 deletion/L858R mutations (c EGFR ). Afatinib, approved for atypical EGFR -mutated NSCLC, showed a median overall survival (OS) of 19.4 months among 38 participants (pts) with atypical EGFR- mutations globally (Yang Lancet Oncol 2015). Amivantamab (ami)-based regimens are approved across multiple lines of therapy in different settings for c EGFR and exon 20 insertion (Ex20ins)-mutated advanced NSCLC. In MARIPOSA, first-line (1L) ami plus lazertinib (ami-laz) significantly prolonged OS vs osimertinib (HR, 0.75; P =0.005) in c EGFR -mutated NSCLC. In an earlier report of 49 pts with atypical EGFR -mutated advanced NSCLC who received 1L ami-laz, objective response rate (ORR) was 57%, median response duration was 20.7 months, median progression-free survival (PFS) was 19.5 months, and OS was still immature (Tomasini JCO 2025). Here we report OS data with longer follow-up for pts with atypical EGFR -mutated NSCLC who received 1L ami-laz. Methods: Cohort C of the global, phase I/Ib CHRYSALIS-2 study (NCT04077463) enrolled pts with atypical EGFR mutations, excluding Ex20ins and co-mutations with c EGFR , who were previously untreated or had ≤2 prior lines of therapy, which may have included a 1 st /2 nd -generation EGFR TKI. All enrolled pts received intravenous ami-laz. The primary endpoint was ORR by investigator per RECIST v1.1, which has been previously reported. Here we report OS, a key secondary endpoint, in the treatment-naïve population (n=49). Results: As of Oct 31, 2025, the median follow-up was 31.3 months (range, 0.1–53.2). The median OS was 41.0 months (95% CI, 27.7–not estimable), with 55% alive at 3 years and 46% alive at 4 years. As of data cutoff, 20% (10/49; 6 were confirmed responders and 4 had stable disease) of pts were still ongoing 1L treatment (range, 2.5–4.4 years), with 7 pts receiving ami treatment for >3 years. Safety profile was consistent with prior reports; no additional safety signals were identified with longer-term follow-up. Among pts whose disease had progressed and discontinued 1L treatment, 71% (20/28) received subsequent therapy. The most common subsequent regimens included platinum-based chemotherapy agents (55%). Conclusions: 1L treatment of atypical EGFR -mutated advanced NSCLC with ami-laz resulted in a clinically meaningful median OS of nearly 3.5 years. Many pts were able to stay on 1L treatment long term, with 20% still ongoing. Ami-laz has now shown substantial survival benefit in both 1L c EGFR- and atypical EGFR- mutated disease. The recently FDA-approved subcutaneous formulation of ami may further simplify the overall treatment experience for this regimen. Clinical trial information: NCT04077463 .