NEWS & PERSPECTIVE
FDA approves amivantamab + chemotherapy in NSCLC with EGFR exon 20 insertion mutations
Alterations in the epidermal growth factor receptor (EGFR) gene occur in up to 40% of non-small cell lung cancers (NSCLCs), among which exon 20 insertions are the third most common type of mutation and account for up to 12% of EGFR-mutated (EGFRm) cases.1,2 Exon 20 insertions alter the conformation of the kinase-active site, hindering the binding capabilities of currently approved EGFR tyrosine kinase inhibitors (TKIs), resulting in low response rates and poor overall survival.1,2 Amivantamab is a bispecific antibody against both EGFR and mesenchymal-epithelial transition factor (MET) that received accelerated United States (US) Food and Drug Administration (FDA) approval in 2021 for advanced NSCLC with EGFR exon 20 insertions.1,2 Recently, amivantamab in combination with chemotherapy received full FDA approval for the first-line treatment of locally advanced or metastatic NSCLC with EGFR exon 20 insertions based on its superior efficacy compared to chemotherapy alone as demonstrated in the phase 3 PAPILLON study.1,3
Amivantamab is a fully human bispecific antibody that binds to both EGFR and MET, inhibiting their respective ligands from activating downstream signaling pathways that drive tumor growth.4 Moreover, amivantamab increases its anti-tumoral effect via engaging macrophages, monocytes, and natural killer cells with its fragment crystallizable (Fc) domain, and facilitates the internalization and degradation of EGFR and MET.1,4 A previous phase 1 trial (CHRYSALIS) has demonstrated the safety and efficacy of amivantamab in NSCLC patients with EGFR exon 20 insertions, reaching an objective response of 40% and a median duration of response of 11.1 months.1,4 In this trial, almost all patients who had received amivantamab in combination with chemotherapy achieved a partial response, suggesting a potential synergy between amivantamab with chemotherapy.1
In the captioned phase 3 PAPILLON trial, the efficacy and safety of amivantamab plus chemotherapy was investigated as a first-line treatment in patients with advanced NSCLC with EGFR exon 20 insertions.1 A total of 308 patients with advanced NSCLC who had EGFR exon 20 insertions who had not received previous systemic therapy were randomized 1:1 to receive amivantamab plus chemotherapy (n=153) or chemotherapy alone (n=155).1
PFS was significantly longer in the amivantamab-chemotherapy group than in the chemotherapy group (median PFS: 11.4 months vs. 6.7 months; HR=0.40; 95% CI: 0.30-0.53; p<0.001).1 Separation of the PFS curves was early and clear, indicating rapid disease control which improved over 18 months of follow-up, reaching a PFS rate of 31% in the amivantamab-chemotherapy group and only 3% in the chemotherapy group.1 Furthermore, the PFS benefit was observed across all prespecified subgroups regardless of race, age, sex, history of smoking, Eastern Cooperative Oncology Group (ECOG) performance-status score, and history of brain metastases.1
A higher objective response (complete or partial) rate was also reported in the amivantamab-chemotherapy group (73% vs. 47%; rate ratio=1.50; 95% CI: 1.32-1.68; p<0.001), as well as a greater mean percent decrease in tumor size (53% vs. 34%) compared to the chemotherapy group.1 Although data maturity at the interim overall survival analysis was only at 33% maturity, it was suggestive of better survival outcomes with amivantamab-chemotherapy compared to chemotherapy alone (HR=0.67; 95% CI: 0.42-1.09; p=0.11).1
In the amivantamab-chemotherapy group, the majority of grade 3 or higher adverse events were dermatological toxicities associated with amivantamab and reversible hematologic effects associated with chemotherapy, and discontinuations of amivantamab from adverse events were rare (7%).1 While the incidence of infusion-related reactions was higher in the amivantamab-chemotherapy group over chemotherapy only (42% vs. 1%), it was lower than in those who received amivantamab monotherapy in previous studies (67%).1 To mitigate the infusion-related reactions, prophylaxis with pre-infusion glucocorticoids is being prospectively evaluated in phase 2 trials and subcutaneous formulations are also under development.1
In summary, the efficacy and safety results of the PAPILLON trial are consistent with initial and long-term data from the CHRYSALIS trial.1 The significantly longer PFS and consistent safety results with amivantamab plus chemotherapy over chemotherapy alone supported its role as the potential standard-of-care in the first-line treatment of patients with advanced NSCLC with EGFR exon 20 insertions.1
