Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study

Ann Oncol. 2024 Jan;35(1):77-90. doi: 10.1016/j.annonc.2023.10.117. Epub 2023 Oct 23.

Abstract

Background: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial.

Patients and methods: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion.

Results: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy.

Conclusions: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.

Keywords: EGFR-mutated; NSCLC; amivantamab; lazertinib; post-osimertinib.

Publication types

  • Clinical Trial, Phase III

MeSH terms

  • Acrylamides*
  • Aniline Compounds*
  • Antibodies, Bispecific*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Carboplatin / adverse effects
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Disease Progression
  • ErbB Receptors / genetics
  • Humans
  • Indoles*
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Morpholines*
  • Mutation
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrazoles*
  • Pyrimidines*

Substances

  • Acrylamides
  • amivantamab-vmjw
  • Aniline Compounds
  • Antibodies, Bispecific
  • Carboplatin
  • EGFR protein, human
  • ErbB Receptors
  • Indoles
  • lazertinib
  • Morpholines
  • osimertinib
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines