Amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer (NSCLC): Results from CHRYSALIS-2.

8516 Background: Afatinib is the only EGFR tyrosine kinase inhibitor (TKI) approved to treat patients (pts) with EGFR-mutated advanced NSCLC harboring atypical mutations (eg, S768I, L861Q, G719X), excluding exon 20 insertion mutations (Ex20ins). In a retrospective analysis of 38 TKI-naïve pts, 27 had a response to afatinib, with a median duration of response (mDoR) of 11.1 months (mo) and median progression-free survival (mPFS) of 10.7 mo (Yang Lancet Oncol 2015;16(7):830-8). Amivantamab (ami) is an EGFR- MET bispecific antibody with immune-cell directing activity. Lazertinib (laz) is a CNS-penetrant, 3 rd -generation EGFR TKI. This combination was evaluated among pts with atypical EGFR-mutated advanced NSCLC. Methods: Cohort C of the CHRYSALIS-2 study (NCT04077463) enrolled pts with atypical EGFR mutations, excluding Ex20ins, who were treatment-naïve or had ≤2 prior lines, which may have included a 1 st /2 nd -generation EGFR TKI. Pts with Ex19del or L858R co-mutations were excluded. Ami was intravenously administered at 1050 mg (1400 mg, ≥80 kg) weekly for the first 4 weeks and then biweekly. Laz was given orally at 240 mg daily. Response was assessed by the investigator per RECIST v1.1. Results: As of 4 Dec 2023, 105 pts received ami+laz, with a median follow-up of 13.8 mo (range, 0.1–30.2). The median age was 64 years, 50% were female, 68% Asian, 30% White, and 35% had CNS lesions at baseline. The most common mutations were G719X (54%), L861Q (24%), and S768I (22%). The ORR was 51% (95% CI, 41–61). In the treatment-naïve subset (n = 49), ORR was 55% (95% CI, 40–69), with mDoR not estimable (NE; 95% CI, 9.9 mo–NE) and mPFS of 19.5 mo (95% CI, 11.0–NE). Among responders, 78% (21/27) had DoR ≥6 mo. The ORR for pts harboring solitary mutations at G719 (n = 13), L861 (n = 8), and S768 (n = 2) was 54%, 63%, and 100%, respectively. The ORR for pts with compound atypical mutations (n = 17) was 41%, with DoR ≥6 mo for all 7 responders. Among pts treated with prior afatinib (n = 40), ORR was 45% (95% CI, 29–62), with mDoR of 8.9 mo (95% CI, 2.8–NE) and mPFS of 5.7 mo (95% CI, 4.2–10.7). Among the 18 responders, 56% had DoR ≥6 mo. The most common AEs were primarily EGFR- and MET-related toxicities, primarily grade 1-2. Discontinuations of both ami and laz due to treatment-related AEs occurred in 9% of pts. The incidence of VTE was 30% (31/105), with the majority of events, 71% (22/31), occurring in the first 4 mo of treatment. The vast majority of pts, 97% (30/31), were not on anticoagulation at time of first VTE. The rate of pneumonitis/interstitial lung disease was 6%. Biomarker analyses are ongoing; updated results will be presented at time of meeting. Conclusions: In the largest, single-cohort, prospective study of atypical EGFR-mutated advanced NSCLC, ami+laz demonstrated clinically meaningful and durable antitumor activity in pts who were treatment-naïve or had disease progression on afatinib. Clinical trial information: NCT04077463 .