Nearly 3.5 Years of Survival—What CHRYSALIS-2 Means for Atypical EGFR-Mutated NSCLC

Patients with atypical EGFR-mutated advanced non–small cell lung cancer (NSCLC) historically face worse long-term outcomes with EGFR-targeted therapies than patients harboring classical exon 19 deletion or L858R mutations. Afatinib, the standard-of-care option for this population, demonstrated a median overall survival (OS) of 19.4 months in a global cohort of 38 patients with atypical EGFR mutations.

Against this backdrop, updated data from the CHRYSALIS-2 trial (NCT04077463) suggest that amivantamab (ami, Rybrevant; Janssen Biotech, Inc) plus lazertinib (laz, Lazcluze; Janssen Biotech, Inc) may represent a meaningful step forward for this underserved population. The data were presented at the 2026 American Society of Clinical Oncology Annual Meeting in Chicago.

Amivantamab as an Approved Therapy for NSCLC

Amivantamab is a bispecific antibody targeting both EGFR and MET receptors and has emerged as a key treatment option for patients with EGFR-mutated metastatic NSCLC. Since its initial FDA approval in 2021, its indications have expanded considerably¹:

• 2021: Monotherapy for adults with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations following progression on platinum-based chemotherapy
• 2024 (3 new indications):
  • In combination with chemotherapy as first-line treatment for locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations
  • In combination with lazertinib (Lazcluze; Janssen Biotech, Inc) as first-line treatment for locally advanced or metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations
  • In combination with chemotherapy for locally advanced or metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations, following progression on an EGFR tyrosine kinase inhibitor

This rapid expansion across multiple lines of therapy and mutation subtypes reflects the growing body of evidence supporting amivantamab-based regimens in EGFR-mutated NSCLC.¹

Amivantamab and the CHRYSALIS-2 Trial

Amivantamab-based regimens have demonstrated broad activity across multiple lines of therapy in classical EGFR-mutated and exon 20 insertion-mutated advanced NSCLC. In the phase 3 MARIPOSA trial (NCT04487080), first-line ami-laz significantly prolonged OS compared with osimertinib in patients with classical EGFR-mutated disease (HR, 0.75; P = .005).²

An earlier report from CHRYSALIS-2 in 49 patients with atypical EGFR-mutated advanced NSCLC receiving first-line ami-laz showed an objective response rate (ORR) of 57%, median response duration of 20.7 months, and median progression-free survival of 19.5 months. OS data were still maturing at that time.²

Measuring Success in CHRYSALIS-2

Cohort C of the global phase 1/1b CHRYSALIS-2 study enrolled patients with atypical EGFR mutations, excluding exon 20 insertions and co-mutations with classical EGFR. Eligible patients were either treatment-naive or had received up to 2 prior lines of therapy, which could have included a first- or second-generation EGFR tyrosine kinase inhibitor. All patients received intravenous ami-laz.²

The primary end point of ORR has been previously reported; the analysis presented here focuses on OS—a key secondary end point—in the treatment-naive population (n = 49).²

Amivantamab Improved OS

As of the October 31, 2025, data cutoff, the median follow-up was 31.3 months (range, 0.1-53.2 months). The updated analysis findings revealed a median OS of 41.0 months (95% CI, 27.7-not estimable), with 55% of patients alive at 3 years and 46% alive at 4 years. These figures represent a substantial improvement over historical benchmarks for this mutation subgroup.²

Notably, 20% of patients (10/49) remained on first-line treatment at the time of data cutoff, with a treatment duration ranging from 2.5 to 4.4 years. Seven patients received ami-based therapy for more than 3 years. The long-term safety profile was consistent with that in prior reports, with no new safety signals identified.²

Among patients who discontinued first-line treatment due to disease progression, 71% went on to receive subsequent therapy, most commonly platinum-based chemotherapy (55%).²

Amivantamab Combinations Represent the Future of NSCLC Care

First-line ami-laz produced a clinically meaningful median OS of nearly 3.5 years in patients with atypical EGFR-mutated advanced NSCLC, a population with historically limited options. With durable responses, a manageable safety profile, and now a recently FDA-approved subcutaneous formulation of amivantamab, this regimen may offer both survival benefit and a more convenient treatment experience for patients in this setting.

REFERENCES

1. McMullen N, Perkey C, Maksour M. Amivantamab for EGFR-mutated metastatic non–small cell lung cancer. Pharmacy Practice in Focus: Oncology. October 15, 2025. Accessed May 27, 2026. https://www.pharmacytimes.com/view/amivantamab-for-egfr-mutated-metastatic-non-small-cell-lung-cancer

2. Neal JW, Cho BC, Wang Y. Overall survival of first-line amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer (NSCLC): updated results from the CHRYSALIS-2 study. Presented at: 2026 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2026; Chicago, IL. Abstract 8501.