FDA Approves RYBREVANT (Amivantamab-vmjw) for the Treatment of Adult Patients with Locally Advanced or Metastatic NSCLC with EGFR Exon 20 Insertion Mutations

 

On May 21, 2021, the U.S. Food and Drug Administration (FDA) approved RYBREVANT (amivantamab-vmjw) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) Exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. This indication is approved under accelerated approval based on overall response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

The approved recommended dosage of RYBREVANT is based on baseline body weight as listed below:

  • Baseline body weight < 80 kg: 1050 mg intravenously (IV).
  • Baseline body weight ≥ 80 kg: 1400 mg IV.

RYBREVANT is administered as an IV infusion weekly for 4 weeks according to specified rates, and via a peripheral line in the full prescribing information linked below.

  • The initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 2 weeks thereafter.
  • Patients should be pre-medicated with antihistamine, antipyretic, and glucocorticoid prior to receiving RYBREVANT.

After Week 4, patients are dosed every 2 weeks.

Additional information regarding dosage and administration, including infusion rates and pre-medications, as well as warnings and precautions about infusion-related reactions (IRR), interstitial lung disease/pneumonitis, dermatologic adverse reactions, ocular toxicity, and embryo-fetal toxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA), and Pharmacokinetics (PK)

MOA: Amivantamab-vmjw is a bispecific antibody that binds to the extracellular domains of EGFR and MET receptors.

General PK: Amivantamab-vmjw exposures increase proportionally over a dosage range from 350 to 1750 mg (0.25 to 1.25 times the maximum approved recommended dosage). Steady state of amivantamab-vmjw concentrations is achieved by the 9th infusion. The accumulation ratio at steady state is 2.4.

Distribution: The amivantamab-vmjw mean (± SD) volume of distribution is 5.13 (± 1.78) L.

Elimination: The mean (± SD) clearance of amivantamab-vmjw is 360 (± 144) mL/day and the terminal half-life is 11.3 (± 4.53) days.

Immunogenicity: In CHRYSALIS trial, 3 of the 286 (1%) patients who were treated with RYBREVANT and evaluable for the presence of anti-drug antibodies (ADA), tested positive for treatment-emergent anti-amivantamab-vmjw antibodies with titers of 1:40 or less. There are insufficient data to evaluate the effect of ADA on the PK, safety, or efficacy of RYBREVANT.

Use in Specific Populations

No clinically meaningful differences in the PK of amivantamab-vmjw were observed based on age (32 to 87 years), sex, race, creatinine clearance (CLcr 29 to 276 mL/min), or mild hepatic impairment [(total bilirubin ≤ ULN and AST > ULN) or (ULN < total bilirubin ≤ 1.5 times ULN)]. The PK of amivantamab-vmjw have not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min) or patients with moderate (total bilirubin 1.5 to 3 times ULN) to severe (total bilirubin > 3 times ULN) hepatic impairment.

Body Weight: Amivantamad-vmjw is administered according to body weight. Increases in body weight increase the volume of distribution and clearance of amivantamab-vmjw. Amivantamab-vmjw exposures are 30-40% lower in patients who weighed ≥ 80 kg compared to patients with body weight < 80 kg at the same dose. Exposures of amivantamab-vmjw are comparable between patients who weighed < 80 kg and received 1050 mg dose and patients who weighed ≥ 80 kg and received 1400 mg dose.

Efficacy and Safety

Efficacy of RYBREVANT (amivantamab-vmjw) was evaluated in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in a multicenter, open-label, multi-cohort clinical trial CHRYSALIS. The major efficacy outcome measure was ORR according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by Blinded Independent Central Review (BICR). An additional efficacy outcome measure was DOR by BICR. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions (≥ 20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased alkaline phosphatase, increased glucose, increased gamma-glutamyl transferase, and decreased sodium.

Full prescribing information is available at https://go.usa.gov/xHSN2.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.