On May 21, 2021, amivantamab-vmjw, a bispecific antibody directed against EGFR and MET receptors, was granted accelerated approval for treatment of adults with locally advanced or metastatic non–small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations, as detected by a U.S. Food and Drug Administration (FDA)-approved test, whose disease has progressed on or after platinum-based chemotherapy.1,2 The FDA also approved the Guardant360® CDx as a companion diagnostic for amivantamab.
Supporting Efficacy Data
Approval was based on findings in the multicenter, multicohort, phase I CHRYSALIS trial (ClinicalTrials.gov identifier NCT02609776).2 Efficacy was evaluated in 81 patients who had advanced NSCLC with EGFR exon 20 insertion mutations and disease progression on or after platinum-based chemotherapy. Patients received intravenous (IV) amivantamab at 1,050 mg (for patients weighing < 80 kg) or 1,400 mg (for those weighing ≥ 80 kg) once weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity.
Among all 81 patients, median age was 62 years (range = 42–84 years), 59% were female, and 49% were Asian, 37% were White, and 2.5% were Black. Eastern Cooperative Oncology Group performance status was 1 in 67%, 74% had a baseline body weight of < 80 kg, 95% had adenocarcinoma, and 46% had received prior immunotherapy. The median number of prior therapies was two (range = 1–7), and 53% never smoked. All patients had metastatic disease, and 22% had previously treated brain metastases.
The main efficacy outcome measures were overall response rate on Response Evaluation Criteria in Solid Tumors version 1.1, as evaluated by blinded independent central review and response duration. An objective response was achieved in 32 patients (40%, 95% confidence interval [CI] = 29%–51%), with a complete response in 3 (3.7%). Median response duration was 11.1 months (95% CI = 6.9 months to not evaluable), with 63% of responses lasting at least 6 months.
How It Works
Amivantamab is a bispecific antibody that binds to the extracellular domains of EGFR and MET. In in vitro and in vivo studies amivantamab disrupted EGFR and MET signaling functions through blocking ligand binding and, in exon 20 insertion mutation models, produced degradation of EGFR and MET. The presence of EGFR and MET on the surface of tumor cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity and trogocytosis mechanisms, respectively.
How It Is Used
The recommended dose of amivantamab is 1,050 mg for patients with a baseline body weight of < 80 kg and 1,400 mg for those with a body weight of ≥ 80 kg, administered via IV infusion weekly for 4 weeks, and then every 2 weeks thereafter until disease progression or unacceptable toxicity. The first dose should be given as a split infusion in week 1, on days 1 and 2. Product labeling provides instructions on infusion rates for both doses.
Patients should receive premedication with an antihistamine, antipyretic, and a glucocorticoid prior to the first infusion (week 1, days 1 and 2). Antihistamine and antipyretic treatment should be given before all doses of amivantamab; glucocorticoid administration is required only for the week 1, days 1 and 2 doses, and as necessary for subsequent infusions.
Product labeling provides instructions for two sequential dose reductions for adverse reactions; treatment should be discontinued if a third dose reduction is required. Product labeling provides instructions for dosage modifications, including dose reduction, infusion interruption, and withholding and discontinuing treatment, for adverse reactions including infusion-related reactions, interstitial lung disease/pneumonitis, dermatologic adverse reactions, and other grade 3 or 4 adverse reactions.
Infusion should be interrupted at the first sign of infusion-related reactions; treatment should be permanently discontinued for recurrent grade 3 or any grade 4 reactions. Treatment should also be permanently discontinued for any-grade confirmed interstitial lung disease/pneumonitis, grade 3 dermatologic reactions that fail to improve or any grade 4 reaction, any other grade 3 adverse reaction that fails to recover to grade ≤ 1 within 4 weeks, any grade 4 adverse reaction that fails to recover to grade ≤ 1 within 4 weeks, and any recurrent grade 4 reaction.
Safety data are from 129 patients in the CHRYSALIS trial who had locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations and disease progression on or after platinum-based chemotherapy who received the recommended dose of amivanta-mab. Among these patients, 44% were exposed to treatment for at least 6 months and 12%, for at least 1 year.
Among the 129 patients, the most common adverse events of any grade (≥ 20%) were rash (84%), infusion-related reactions (64%), paronychia (50%), musculoskeletal pain (47%), dyspnea (37%), nausea (36%), fatigue (33%), edema (27%), stomatitis (26%), cough (25%), constipation (23%), and vomiting (22%). The most common grade 3 to 4 adverse events included rash (3.9%) and infusion-related reactions, paronychia, and diarrhea (3.1% each). The most common grade 3 to 4 laboratory abnormalities were decreased albumin (8%), decreased phosphate (8%), decreased lymphocytes (8%), and decreased potassium (6%).
Serious adverse events occurred in 30% of patients, with those occurring in at least 2% including pulmonary embolism, intersititial lung disease/pneumonitis, dyspnea, musculoskeletal pain, pneumonia, and muscular weakness. Adverse events led to dose interruption in 78% of patients, with infusion-related reactions requiring infusion interruptions in 59% of patients; other adverse events requiring dose interruption in at least 5% of patients included dyspnea, nausea, rash, vomiting, fatigue, and diarrhea. Dose reductions due to adverse events occurred in 15% of patients, with the most common causes (≥ 2%) including rash and paronychia.
Adverse events led to permanent discontinuation of treatment in 11%, with the most common causes (≥ 1%) being pneumonia, infusion-related reactions, intersitital lung disease/pneumonitis, dyspnea, pleural effusion, and rash. Fatal adverse events occurred in two patients (1.5%), due to pneumonia in one patient and sudden death in one patient.
Amivantamab has warnings/precautions for infusion-related reactions, interstitial lung disease/pneumonitis, dermatologic adverse reactions (eg, rash, including acneiform dermatitis and toxic epidermal necrolysis), ocular toxicity, and embryofetal toxicity. Patients with worsening eye symptoms should receive a prompt referral to an ophthalmologist. Patients should be advised not to breastfeed while receiving amivantamab.
1. U.S. Food and Drug Administration: FDA grants accelerated approval to amivantamab-vmjw for metastatic non–small cell lung cancer. Available at www.fda.gov/drugs/drug-approvals-and-databases. Accessed June 14, 2021.
2. Rybrevant (amivantamab-vmjw) injection, for intravenous use, prescribing information, Janssen Pharmaceutical Companies, May 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761210s000lbl.pdf. Accessed June 14, 2021.