Amivantamab Generates Activity With Manageable Toxicity in EGFR Exon 20-Mutant NSCLC

Amivantamab (JNJ-61186372) induced durable responses and demonstrated a manageable safety profile in patients with EGFR exon 20-mutant non–small cell lung cancer (NSCLC), according to results from the phase I CHRYSALIS study (NCT02609776) presented during the 2020 American Society of Clinical Oncology Virtual Scientific Program.

“Approximately 49% of EGFR-mutant [tumors] harbor exon 20 insertion mutations, which, to date, has no approved therapies and is an area of high unmet need. Amivantamab is a fully-human, EGFR/MET bispecific antibody with immune-cell directing activity and targets activating and the resistance in the upper mutations, as well as MET mutations and/or amplifications,” said the primary investigator Keunchil Park, MD, PhD, during his presentation.

Results from this study ultimately led to the allocation of a Breakthrough Therapy Designation from the FDA for amivantamab as treatment of patients with EGFR exon 20-mutant NSCLC who progressed on or after receiving platinum-base chemotherapy.

Amivantamab is an EGFR/MET bispecific antibody that targets EGFR mutations as well as MET mutations and amplifications. When evaluated as monotherapy in patients with NSCLC who harbored EGFR exon 19 deletions, L858R, T790M, C797S, exon 20 insertions, and MET amplifications, the drug demonstrated activity, which warranted further assessment of the amivantamab in a phase 1 study.

Fifty patients were enrolled in the CHRYSALIS study, of which 39 were evaluable for response. Thirteen distinct EGFR exon20 insertions were identified in the evaluable patients. In terms of prior treatment, 29 of the response-evaluable subjects received prior platinum-based chemotherapy for metastatic disease, 6 patients were treatment-naïve, and 4 received other prior therapies like immunotherapy, EGFR tyrosine kinase inhibitors (TKIs) and/or VEGF inhibitors.

Tumor response including a reduction in target lesion and objective responses were seen in both patients who received prior platinum-based chemotherapy and those who were treatment naïve. The activity spanned across all distinct EGFR exon 20 insertion alterations.

The confirmed overall response rate (ORR) was 36% (95% CI, 21%-53%), of which 14 out of 39 were partial responses (PRs). In the subset of post-platinum patients, the ORR was 41% (95% CI, 24%-61%). Clinical benefit for the overall study population was defined by PRs minimally, or by stable disease (SD). The clinical benefit rate was 67% (95% CI, 50%-81%) in the overall population and was 72% (95% CI, 53%-87%) in patients who received prior platinum.

Most responses were observed within 2 months of treatment with amivantamab. At a median follow-up 4 months (range, 1-26), the median duration of response (DOR) was 10 months (range, 1-16) overall. The post-platinum population had a median DOR of 7 months (range, 1-16). Sixty-four percent of patients in the overall population had continuing responses at the time of data cutoff, as did 58% of patients who received prior platinum.

Overall, the median progression-free survival overall was 8.3 months (95% CI, 3.0-14.8). The post-platinum group had a median PFS of 8.6 months (95% CI, 3.7-14.8).

Most patients (96%) in the study experienced adverse events (AEs), which were mainly grades 1 and 2. The most common AEs of any grade were rash (72%), infusion-related reaction (60%), and paronychia (34%). Grade 3 AEs were observed in 36% of patients, and serious treatment-related AEs were observed in 28%. Five patients (10%) required dose reductions dues to AEs, and 3 patients (6%) discontinued treatment altogether. Dose interruptions or modifications were not needed because no severe toxicity patterns were observed in the study. AEs led to death in 4 patients (8%), but these were not considered treatment-related.

CHRYSALIS is an ongoing 2-part study. In the dose-escalation phase of the trial, the dose of amivantamab first administered is 140 mg, which is increased to 1750 mg to determine the recommended dose for the phase 1 study. Treatment in part 1 is continued for a 28-day cycle.

In part 2, there are 2 EGFR-positive cohorts and 3 MET-positive cohorts. The EGFR cohorts include patients with post EGFR TKI treatment and C797S mutations, and EGFR exon20 insertions. The MET cohorts include post EGFR TKI individuals with MET amplification in 1 cohort and patients with MET exon 14 skipping mutation in another cohort. The primary end points of part 2 are safety and preliminary efficacy, as well as, pharmacokinetics and immunogenicity. Patients in part 2 were treated with the recommended tolerated dose range of 1050 mg to 1400 mg.

Patients were eligible for enrollment is they had metastatic/unresectable NSCLC and progressed on prior therapy and are ineligible for or opted not to take current therapies. Participants were required to have an ECOG performance status of 1 or lower, evaluable or measurable disease, EGFR or MET mutations or amplifications, and prior progression on the standard of care treatment. Individuals with brain metastases were allowed if they were definitively treated prior to the study.

At baseline, the median age for the study population was reported as 61 years (range 40-79 years). Most subjects were female (51%), and Asian (64%). Other racial groups including in the study were White (28%, Black (3%), and no racial group was reported for 5% of patients. The majority of patients had an ECOG performance status of 1 (62%), and 0 (36%). There was 1 patient with an ECOG performance status of 2, which was above the ECOG eligibility criteria of 1 or lower.

EGFR exon 20 insertions in patients with NSCLC is usually resistant to EGFR TKIs and often correlates with poor prognosis. The study of amivantamab continues to potentially offer a new option for this in-need patient population.

_Reference:

_{Park K, John T, Kim SW, et al. Amivantamab (JNJ-61186372), an anti-EGFR-MET bispecific antibody, in patients with EGFR exon 20 insertion (exon20ins)-mutated non-small cell lung cancer (NSCLC). J Clin Oncol. 2020: 38 (suppl; abstr 9512). doi: 10.1200/JCO.2020.38.15_suppl.9512}