Amivantamab in EGFR Exon 20 Insertion–Mutated Non–Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study

Abstract

PURPOSE Non–small-cell lung cancer (NSCLC) with epidermal growth factor receptor ( EGFR) exon 20 insertion (Exon20ins) mutations exhibits inherent resistance to approved tyrosine kinase inhibitors. Amivantamab, an EGFR-MET bispecific antibody with immune cell–directing activity, binds to each receptor's extracellular domain, bypassing resistance at the tyrosine kinase inhibitor binding site. METHODS CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion study, which included a population with EGFR Exon20ins NSCLC. The primary end points were dose-limiting toxicity and overall response rate. We report findings from the postplatinum EGFR Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab (1,400 mg, ≥ 80 kg) given once weekly for the first 4 weeks and then once every 2 weeks starting at week 5. RESULTS In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years); 40 patients (49%) were Asian, and the median number of previous lines of therapy was two (range, 1-7). The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months (95% CI, 6.9 to not reached). The median progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety population (n = 114), the most common adverse events were rash in 98 patients (86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The most common grade 3-4 adverse events were hypokalemia in six patients (5%) and rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients, respectively. CONCLUSION Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with EGFR Exon20ins mutations after progression on platinum-based chemotherapy.

Spotlight on Amivantamab (JNJ-61186372) for EGFR Exon 20 Insertions Positive Non-Small Cell Lung Cancer

“…These findings are clinically meaningful considering the 136 population of interest is relapsed metastatic or unresectable NSCLC with a 5-year survival rate of less than 10%. 25 For full approval, the FDA will require results of a Phase III trial. The phase III PAPILLON trial (NCT04538664) is currently investigating amivantamab in combination with carboplatin-pemetrexed chemotherapy compared to chemotherapy alone in the first line treatment setting of metastatic NSCLC with exon 20 insertion mutations.…”

“…In vitro studies showed saturation of circulating free EGFR began after a single dose of 350 mg and saturation of MET at a single dose of 140 mg. Complete and durable saturation of both EGFR and MET was reliably achieved at doses ≥700 mg. 25 …”

“…Amivantamab concentration increased rapidly during Cycle 1, gradually decreasing in subsequent cycles to reach a steady state by Cycle 4. 25 The half-life of amivantamab is 11.3 (± 4.53) days.…”

“…Accelerated FDA approval was based on CHRYSALIS, a Phase I, multicenter, open label, dose-escalation clinical trial assessing the safety and efficacy of amivantamab (NCT02609776). 25 Patients received amivantamab 140 mg IV weekly for four weeks then every two weeks until disease progression or toxicity. The main efficacy outcome measure was overall response rate (ORR) with secondary outcomes of interest including clinical benefit rate, duration of response, progression-free survival, and overall survival.…”

Case Report: Osimertinib Followed by Osimertinib Plus Bevacizumab, Personalized Treatment Strategy for a Lung Cancer Patient With a Novel EGFR Exon 20 Insertion D770_N771insGT and Multiple Brain Metastases

“…Interestingly, amivantamab, an EGFR-MET bispecific antibody, was recently approved to treat EGFR ex20ins NSCLC patients ( 30 ). This approval was based on the results of a phase 1 trial CHRYSALIS (NCT02609776) in which amivantamab achieved an ORR of 40% (95% CI: 29%, 51%) and a median response duration of 11.1 months (95% CI: 6.9, not evaluable) ( 31 ).…”