On September 19, the U.S. Food and Drug Administration (FDA) approved amivantamab-vmjw (Rybrevant) with carboplatin and pemetrexed for adults with locally advanced or metastatic non–small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor.
The anticancer activity of amivantamab stems from three distinct mechanisms of action: ligand-blocking; receptor degradation; and immune cell–directing activity, such as antibody-dependent cellular cytotoxicity and trogocytosis.
Efficacy and Safety
Efficacy was evaluated in MARIPOSA-2 (ClinicalTrials.gov identifier NCT04988295), a randomized, open-label, multicenter trial in 657 patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations and disease progression on or after receiving osimertinib. Patients were randomly assigned (1:2:2) to receive amivantamab with carboplatin and pemetrexed (amivantamab/CP), carboplatin and pemetrexed (CP), or amivantamab as part of another combination regimen.
The major efficacy outcome measure was progression-free survival as assessed by blinded independent central review for the comparison between amivantamab/CP and CP. Overall response rate and overall survival were key secondary outcome measures. Median progression-free survival was 6.3 months (95% confidence interval [CI] = 5.6–8.4 months) with amivantamab/CP and 4.2 months (95% CI = 4.0–4.4 months) with CP (hazard ratio = 0.48; 95% CI = 0.36–0.64; P < .0001). The confirmed overall response rate was 53% (95% CI = 44%–62%) with amivantamab/CP and 29% (95% CI = 23%–35%) with CP (P < .0001).
At the prespecified second interim analysis of overall survival, with 85% of the deaths needed for the final analysis, there was no statistically significant difference in overall survival. The stratified overall survival hazard ratio was 0.73 (95% CI = 0.54–0.99).
The most common adverse reactions (≥ 20%) were rash, infusion-related reactions, fatigue, nail toxicity, nausea, constipation, edema, stomatitis, decreased appetite, musculoskeletal pain, vomiting, and COVID-19 infection.
Dosing and Regulatory Information
The recommended amivantamab-vmjw dose is based on baseline body weight. See the prescribing information for specific dosage information.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence, and the FDA collaborated with the Australian Therapeutic Goods Administration (TGA), the Brazilian Health Regulatory Agency (ANVISA), and Health Canada. The application reviews are ongoing at the other regulatory agencies. The review also used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
