Amivantamab, a novel, fully human bispecific antibody targeting both the epidermal growth factor receptor (EGFR) and MET, is currently being explored as a monotherapy in non-small cell lung cancer (NSCLC). The MET-2 cohort of the CHRYSALIS study now provides the first evidence of amivantamab activity in MET-driven NSCLC, in addition to its previously reported anti-EGFR activity, consistent with its bispecific mechanism of action.
Amivantamab is an EGFR-MET bispecific antibody with a unique mechanism of action, including immune cell-directing activity. Amivantamab has demonstrated monotherapy activity (objective response rate of 40%, median duration of response of 11.1 months) in EGFR Exon 20 insertion non-small cell lung cancer (NSCLC) that progressed after platinum-based chemotherapy and was recently approved for this indication in the United States. Given the bispecific nature of amivantamab, its role in patients with MET exon 14 skipping (METex14) mutations is now being explored (MET-2 cohort) in patients both naïve to and refractory to other available MET therapy. At the 2021 World Conference on Lung cancer, early results demonstrating amivantamab activity in MET-driven NSCLC from the CHRYSALIS study were presented.
CHRYSALIS study design
CHRYSALIS is an ongoing phase I dose escalation/dose expansion study of amivantamab (140 - 1,750 mg) in patients with advanced NSCLC. In the METex14 cohort, patients with METex14 NSCLC whose disease progressed on or who declined current standard of care were treated at the recommended phase II dose of 1,050 mg (1,400 mg ≥80 kg) weekly in cycle 1 and biweekly thereafter. The expansion cohort accrued 19 METex14 patients in total, with up to 100 patients planned. Response was assessed by the investigator using RECIST v1.1 criteria. Median age of study participants was 70 years with slightly more women (63%). In total, 58% of patients were non-smokers. Median prior lines of therapy were 2 (range, 0–10), including prior treatment with crizotinib (N= 5), capmatinib (N= 2), tepotinib (N= 2), and anti-MET antibody (N= 1). Four patients were treatment-naïve.
In this early METex14 experience, safety of amivantamab is consistent with that observed previously. Treatment-related grade ≥ 3 adverse events were reported in three patients (16%) and included dyspnoea, hypoalbuminaemia and rash (N= 1, each). Treatment-related discontinuations, dose reductions and dose interruptions were observed in 5%, 11% and 32% of patients, respectively.
Of the fourteen response-evaluable patients, partial responses were observed in 9 patients (64%), with 5 confirmed and 4 pending confirmation. Activity of amivantamab was observed in both treatment-naïve and previously treated patients, including 4 partial responses in 7 patients previously treated with MET tyrosine kinase inhibitors. Of note, of these 7 patients, 2 had potential resistance mechanisms identified (PIK3CA in one patient and CDK4/EGFR amplification and MET A1251V in the other). The median time to first confirmed response was 4.1 months (range, 1.6-9.9 months). Responses were durable and no patient demonstrated an increase in tumour assessment as defined by change in sum of diameters of target lesions. Median treatment duration was 6.5 months and median duration of response was not reached. Eight out of nine patients who responded are still in response. In total, 11 out of 14 response-evaluable patients remain on treatment.
In the CHRYSALIS study, amivantamab demonstrated antitumour activity in METex14 NSCLC. In addition, the safety profile of amivantamab in this subgroup of patients with METex14 is consistent with previously reported experience of patients with EGFR-mutated NSCLC. This first report of amivantamab activity in METex14 NSCLC confirms the bispecific targeting action of amivantamab, with monotherapy activity now demonstrated in both EGFR-driven (Exon20ins) and MET-driven NSCLC. Enrolment in the METex14 cohort of the CHRYSALIS study is ongoing.
Spira A, Krebs MG, Cho BC, et al. Amivantamab in Non-small Cell Lung Cancer (NSCLC) with MET Exon 14 Skipping (METex14) Mutation: Initial Results from CHRYSALIS. Presented at the 2021 World Conference on Lung Cancer; Abstract OA15.03.