Among 81 patients, the overall response rate was 40% with a median duration of response of 11.1 months.

  • Major Finding: Among 81 patients, the overall response rate was 40% with a median duration of response of 11.1 months.

  • Concept: Amivantamab binds to the extracellular domains of EGFR and MET and bypasses kinase site mutations.

  • Impact: A bispecific antibody approach can benefit a population that does not respond well to tyrosine kinase inhibitors.

Unlike other patients with EGFR-mutant non–small cell lung cancer (NSCLC), the standard first-line therapy for patients with EGFR exon 20 (ex20) insertion–mutant tumors remains platinum-based chemotherapy because these mutations limit the effectiveness of approved EGFR tyrosine kinase inhibitors (TKI) due to steric hindrance at the EGFR active site. Amivantamab is a bispecific antibody targeting EGFR and MET that binds to each receptor's extracellular domain, blocking ligand binding and directing immune cell activity through a mechanism of action that is independent of the EGFR active site. CHRYSALIS is a first-in-human, phase I dose-escalation and dose-expansion study to evaluate the efficacy, safety, and pharmacokinetics of amivantamab monotherapy in patients with advanced NSCLC; Park and colleagues report results from the cohort of patients with EGFR ex20-mutant disease who had previously received platinum-based chemotherapy. The primary objective of the dose escalation was to determine the maximum tolerated dose and recommended phase II dose (RP2D), and the primary endpoint was the incidence of dose-limiting toxicity. The primary objective of the dose expansion was to evaluate safety, tolerability, and antitumor activity at the RP2D, and the primary endpoint was overall response rate. Secondary endpoints of the dose expansion included duration of response (DOR) and progression-free survival (PFS). In the 81 patients included in the efficacy analysis, the overall response rate was 40%, including 3 complete responses, with a median PFS of 8.3 months and a median DOR of 11.1 months. In the 114 patients included in the safety analysis, amivantamab was generally well tolerated and the safety profile was consistent with on-target anti-EGFR and anti-MET activity, with the most common adverse events being rash, infusion-related reactions, and paronychia. Based on the results of this trial, the FDA granted accelerated approval to amivantamab for patients with locally advanced or metastatic EGFR ex20-mutant NSCLC that progressed on or after platinum-based chemotherapy.

Park K, Haura EB, Leighl NB, Mitchell P, Shu CA, Girard N, et al. Amivantamab in EGFR exon 20 insertion–mutated non–small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study. J Clin Oncol 2021 Aug 2 [Epub ahead of print].

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