Amivantamab Plus Lazertinib in Patients With EGFR-Mutant NSCLC After Progression on Osimertinib and Platinum-Based Chemotherapy: Results From CHRYSALIS-2 Cohort A

J Thorac Oncol. 2025 May;20(5):651-664. doi: 10.1016/j.jtho.2024.12.029. Epub 2025 Jan 2.

Abstract

Introduction: Treatment options for patients with EGFR-mutated NSCLC with disease progression on or after osimertinib and platinum-based chemotherapy are limited.

Methods: CHRYSALIS-2 cohort A evaluated amivantamab plus lazertinib in patients with EGFR exon 19 deletion- or L858R-mutated NSCLC with disease progression on or after osimertinib and platinum-based chemotherapy. Primary end point was investigator-assessed objective response rate (ORR). The patients received 1050 mg of intravenous amivantamab (1400 mg if ≥ 80 kg) plus 240 mg of oral lazertinib.

Results: In cohort A (N = 162), the investigator-assessed ORR was 28% (95% confidence interval [CI]: 22-36). The blinded independent central review-assessed ORR was 35% (95% CI: 27-42), with a median duration of response of 8.3 months (95% CI: 6.7-10.9) and a clinical benefit rate of 58% (95% CI: 50-66). At a median follow-up of 12 months, 32 of 56 responders (57%) achieved a duration of response of more than or equal to 6 months. Median progression-free survival by blinded independent central review was 4.5 months (95% CI: 4.1-5.8); median overall survival was 14.8 months (95% CI: 12.2-18.0). Preliminary evidence of central nervous system antitumor activity was reported in seven patients with baseline brain lesions and no previous brain radiation or surgery. Exploratory biomarker analyses using next-generation sequencing of circulating tumor DNA revealed responses in patients with and without EGFR- or MET-dependent resistance. The most frequent adverse events were rash (grouped term; 81%), infusion-related reaction (68%), and paronychia (52%). The most common grade greater than or equal to 3 treatment-related adverse events were rash (grouped term; 10%), infusion-related reaction (9%), and hypoalbuminemia (6%).

Conclusions: For patients with limited treatment options, amivantamab plus lazertinib demonstrated an antitumor activity with a safety profile characterized by EGFR- or MET-related adverse events, which were generally manageable.

Trial registration: ClinicalTrials.gov NCT04077463.

Keywords: Amivantamab; Biomarker analyses; Lazertinib; NSCLC.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / administration & dosage
  • Acrylamides / pharmacology
  • Acrylamides / therapeutic use
  • Adult
  • Aged
  • Aged, 80 and over
  • Aniline Compounds / pharmacology
  • Aniline Compounds / therapeutic use
  • Antibodies, Bispecific
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Cohort Studies
  • Disease Progression
  • ErbB Receptors / genetics
  • Female
  • Humans
  • Indoles
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / pathology
  • Male
  • Middle Aged
  • Morpholines* / therapeutic use
  • Mutation
  • Pyrimidines
  • Survival Rate

Substances

  • Acrylamides
  • amivantamab
  • Aniline Compounds
  • EGFR protein, human
  • ErbB Receptors
  • Morpholines
  • osimertinib
  • Indoles
  • Pyrimidines
  • Antibodies, Bispecific

Associated data

  • ClinicalTrials.gov/NCT04077463