Amivantamab in the Treatment of Metastatic NSCLC: Patient Selection and Special Considerations

Abstract

Amivantamab is a bispecific antibody that recognizes epidermal growth factor receptor (EGFR) and MET proto-oncogene (MET). In May 2021, the Food and Drug Administration gave an accelerated approval of amivantamab for the treatment of non-small cell lung cancer (NSCLC) patients with EGFR exon 20 insertions (Exon20ins) who progressed after platinum-based chemotherapy. Amivantamab prevents ligand binding to EGFR and MET and the dimerization of the receptors suppressing the downstream signal transduction. Moreover, amivantamab determines antibody dependent cellular cytotoxicity and down regulation of cell surface proteins through internalization of the receptor and trogocytosis. Preliminary results of the Phase I/IB CHRYSALIS trial demonstrated an objective response rate of 40% with a median duration of response of 11.1 months (95% CI 9.6-not reached) in 81 patients treated with amivantamab with pretreated NSCLC with Exon20ins EGFR mutations. In a different cohort of the CHRYSALIS trial, patients with Ex19del and L858R EGFR mutations were enrolled after progression on osimertinib. 121 and 45 patients received amivantamab or a combination with lazertinib, a third-generation tyrosine kinase inhibitor, respectively. The objective response rate was 19% and 36% in patients treated with amivantamab alone or in combination with lazertinib, with a median progression-free survival of 6.9 (95% CI: 3.2-5.3) and 11.1 (95% CI: 3.7-9.5) months, respectively. All 20 patients with Ex19del and L858R EGFR mutations who received amivantamab and lazertinib as their first line treatment achieved an objective response. Amivantamab is currently under evaluation in Phase III clinical trials for the first line treatment of NSCLCs with Exon20ins EGFR mutations in combination with chemotherapy (PAPILLON), for the first line therapy of Ex19del and L858R mutated NSCLCs in combination with lazertinib (MARIPOSA) and in combination with chemotherapy and lazertinib in NSCLCs who progressed on osimertinib (MARIPOSA-2).

Keywords: NSCLC; amivantamab; exon 20 insertion of EGFR.

Figure 1

Bispecific structure of amivantamab with binding of EGFR and MET on the surface of the cells.

Figure 2

Schematic representation of the design of clinical trials evaluating amivantamab (A) CHRYSALIS, (B) PAPILLON, (C) MARIPOSA and (D) MARIPOSA-2. TKI: Tyrosine kinase inhibitor; T790M+ and T790M-: in patients with tumors with and without the missense mutation of EGFR T790M; C797S+ and C797S-: in patients with tumors with and without the missense mutation of EGFR C797S; MET Exon 14 skipping: tumors harboring the mutation of MET in the splicing site for the exon 14; NSCLC EGFR+: Non small cell lung cancer with EGFR mutations; AUC: area under the curve; ECOG PS: Eastern Cooperative Oncology Group performance status; mts: metastasis; PFS: progression free survival; BIRC: Blinded Independent Central Review; Ex19del: the inframe deletion of nucleotides of exon 19 of EGFR, L858R: the missense mutation L858R of EGFR; QD every day. *Amivantamab will be administered as an IV infusion at a dose of 1400 mg (1750 mg if body weight is ≥80 kg) by once weekly up to Cycle 2 Day 1, then 1750 mg (2100 mg if body weight is ≥80 kg) on Day 1 of each 21-day cycle, starting with Cycle 3. **Participants will receive amivantamab 1050 milligrams (mg) intravenously (IV) for body weight less than (<) 80 kilograms (kg) and 1400 mg for body weight greater than or equal to (≥) 80 kg, in 28-day cycles: once weekly in Cycle 1 (with a split dose on Days 1–2), and then every 2 weeks in subsequent cycles. ***Participants will receive Pemetrexed, and Carboplatin as intravenous (IV) infusion for up to 4 cycles (each cycle consists of 21 days). After 4 cycles, participants will receive Pemetrexed and eventually Lazertinib and/or Amivantamab as maintenance until disease progression.