Amivantamab Plus Lazertinib Demonstrates Robust Activity in Atypical EGFR-Mutated Advanced NSCLC

Updated results from the CHRYSALIS-2 study demonstrate that amivantamab, an EGFR–MET bispecific antibody, combined with lazertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), shows clinically meaningful antitumor activity among patients with advanced non-small cell lung cancer (NSCLC) harboring atypical EGFR mutations.

“Patients with atypical EGFR-mutated advanced NSCLC have significantly worse outcomes compared with those with common EGFR mutations when receiving EGFR-targeted therapies,” stated Pascale Tomasini, MD, Aix Marseille University, Marseille, France, and coauthors. “Amivantamab plus lazertinib has shown potent clinical activity across a wide range of EGFR alterations.”

In cohort C of this open-label study, investigators enrolled 105 patients with atypical EGFR mutations, including G719X (56%), S768I (23%), and L861Q (26%), who were either treatment-naive or had previously received first- or second-generation EGFR TKIs. Patients received 1050 mg (1400 mg for those ≥80 kg) of amivantamab once weekly for the first 4 weeks and once every 2 weeks thereafter, in combination with 240 mg of once daily lazertinib. Patients with coexisting exon 20 insertions, exon 19 deletions, or exon 21 L858R mutations were excluded.

The primary end point was investigator-assessed objective response rate (ORR). Key secondary end points included duration of response, progression-free survival (PFS), and overall survival (OS).

At analysis, the ORR was 52%, with a median duration of response of 14.1 months. Median PFS was 11.1 months, and median OS was not estimable in the intention-to-treat population. Among treatment-naive participants, the ORR was 57%, with a median duration of response of 20.7 months; median PFS was 19.5 months, and median OS was not estimable. By mutation subtype, the ORR was 45% in patients with P-loop and αC-helix compressing mutations (n = 38), 64% in those with classical-like mutations (n = 14), and 67% in those with T790M-like mutations (n = 3). Adverse events were consistent with prior findings and were primarily grade 1 or 2.

“In participants with atypical EGFR-mutated advanced NSCLC, amivantamab–lazertinib demonstrated clinically meaningful antitumor activity with no new safety signals,” concluded Dr Tomasini and colleagues.

“This combination is another treatment option for patients with NSCLC harboring these rare EGFR mutations,” added Journal of Clinical Oncology associate editor Thomas Stinchcombe, MD, Duke University Medical Center, Durham, North Carolina.

Source: 

Tomasini P, Wang Y, Li Y, et al. Amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer: Results from CHRYSALIS-2. J Clin Oncol. Published online: December 1, 2025. doi:10.1200/JCO-24-02835