Amivantamab demonstrated robust and durable responses in patients with epidermal growth factor receptor Exon 20 insertion (EGFR Exon20ins)-mutated non-small cell lung cancer (NSCLC) after progression on standard-of-care platinum-based chemotherapy. Amivantamab exhibited a tolerable safety profile consistent with on-target inhibition of EGFR and MET pathways. The findings from the CHRYSALIS study are published by Prof. Byoung Chul Cho of the Yonsei Cancer Center, Yonsei University College of Medicine in Seoul, South Korea and colleagues on 2 August 2021 in the Journal of Clinical Oncology.
Activating EGFR mutations are a major oncogenic driver in NSCLC with 85% of cases arising from an Exon 19 deletion or Exon 21 L858R point substitution. The third most frequently occurring Exon20ins mutations are characterised by in-frame insertions and duplications near the C-helix of the EGFR kinase domain. EGFR Exon20ins mutations are molecularly heterogeneous with more than 100 variants identified by next-generation sequencing.
With some geographical variation, EGFR Exon20ins mutations are detected in up to 4% of all advanced NSCLC and in 4-12% of EGFR–mutated NSCLC. EGFR Exon20ins are more common in tumours among never smokers. Most of the Exon20ins mutations exhibit de novo resistance to the currently approved first-line EGFR tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, afatinib, and osimertinib. Mechanisms of TKI resistance are multifactorial.
Amivantamab, an EGFR-MET bispecific antibody with immune cell–directing activity, binds to each receptor’s extracellular domain, bypassing resistance at the TKI binding site.
CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion study, which included patients with EGFR Exon20ins NSCLC. The primary endpoints were dose-limiting toxicity and overall response rate (ORR). In the Journal of Clinical Oncology article, the study team reported findings from the post-platinum 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.
In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years). Almost half, 40 patients (49%) were Asian. The median number of previous lines of therapy was 2 (range, 1-7).
The ORR was 40% (95% confidence interval [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 hypokalaemia in six patients (5%) and rash, pulmonary embolism, diarrhoea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients.
The authors wrote that their results provide proof of concept that the EGFR can be effectively targeted through the extracellular domain for mutations that are resistant to EGFR TKIs, including EGFR Exon20ins mutations. Amivantamab is the first bispecific antibody to demonstrate clinically meaningful efficacy in patients with EGFR Exon20ins-mutated NSCLC. Amivantamab has the potential to target other EGFR-driven and/or MET-driven tumours, as monotherapy or in combination. Combined approaches are under investigation.
Jens Köhler and Pasi Jänne of the Dana-Farber Cancer Institute, Harvard Medical School in Boston, MA, US wrote in an article about understanding the pathway that for moving amivantamab into the first-line, either as a single agent or in combination with chemotherapy (currently under investigation in the PAPILLON study), a comprehensive analysis of the impact of EGFR Exon20ins on baseline EGFR and MET expression and the subsequent validation of treatment predictors will be essential.
There is some initial evidence that a high combined EGFR/MET immunohistochemistry score enriches for amivantamab responders after progression with osimertinib. Drs Köhler and Jänne wrote that systematic molecular analyses using on-treatment biopsies, cell-free DNA, or circulating tumour cells at progression are warranted to better understand the biology of efficacy and resistance.
The study was funded by Janssen R&D LLC.
Park K, Haura EB, Leighl NB, 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: JCO; Published online 2 August 2021. DOI: 10.1200/JCO.21.00662
Köhler J, Jänne P. Amivantamab: Treating EGFR Exon 20–Mutant Cancers With Bispecific Antibody-Mediated Receptor Degradation. JCO; Published online 2 August 2021. DOI: 10.1200/JCO.21.01494