This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may depend on confirmation and description of clinical benefit in the confirmatory trial. Rybrevant is the first fully human, bispecific antibody approved for the treatment of patients with non–small cell lung cancer (NSCLC) that targets EGFR exon 20 insertion mutations, which are the third most prevalent activating EGFR mutation.
The FDA also approved the Guardant360 CDx (Guardant Health) test as a companion diagnostic tool for amivantamab, a bispecific antibody directed against EGF and MET receptors. In an interview, Dr. Joshua Sabari, a medical oncologist at NYU Langone's Perlmutter Cancer Center in New York City, stated, "With deeper understanding of genetic alterations like EGFR exon 20 insertion mutations, we are able to target the disease in new ways and improve treatment outcomes for patients. Amivantamab brings an important new therapeutic approach to physicians caring for patients with this serious and rare type of lung cancer."
FDA approval was based on positive results from the ongoing multicenter, open-label, phase l CHRYSALIS trial evaluating 81 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Patients weighing less than 80 kg received 1,050 mg of amivantamab, and patients weighing 80 kg or more received 1,400 mg of amivantamab; doses were administered weekly for 4 weeks, then every 2 weeks, until disease progression or unacceptable toxicity.
The key efficacy outcome measures were ORR, according to Response Evaluation Criteria in Solid Tumors, version 1.1, by blinded independent central review, and DOR. Other outcome measures included clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). The ORR was 40% (95% CI, 29%-51%), with three patients (4%) attaining complete response and 29 patients (36%) achieving partial response (PR). The responses were durable, with an average DOR of 11.1 months (95% CI, 6.9-not reached), and 20 patients (63%) had a response of 6 months or longer. The average PFS was 8.3 months (95% CI, 6.5-10.9 months) and average OS was 22.8 months (95% CI, 14.6 months-not reached). The CBR (>PR or stable disease >11 weeks) was 74% (95% CI, 63%-83%).
This agent is administered via IV infusion after dilution, and dosing is based on body weight. The most common adverse events—occurring in at least 20% of patients—included rash, infusion-related reactions, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. The most common grade 3 or 4 laboratory abnormalities (occurring in >2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased alkaline phosphatase, increased glucose, increased gamma-glutamyl transferase, and decreased sodium.
The manufacturer states that Rybrevant should be withheld in patients who develop symptoms of interstitial lung disease, and that should be permanently discontinued if interstitial lung disease is confirmed. Patients taking Rybrevant should limit sun exposure during and for 2 months after treatment. Rybrevant may cause problems with vision and can also cause fetal harm when administered to a pregnant woman; therefore, the pregnancy status of females of reproductive potential should be established before treatment is started.
Rybrevant is being studied in a comprehensive clinical-development program for patients with untreated advanced EGFR-mutated NSCLC, including the phase lll MARIPOSA trial investigating Rybrevant in combination with lazertinib. Another phase lll trial, PAPILLON, is examining Rybrevant in combination with carboplatin-pemetrexed in patients with advanced or metastatic EGFR-mutated NSCLC with exon 20 insertion mutations.
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