Amivantamab Regimen Boosts Survival in EGFR+ NSCLC Subtype

Overall survival (OS) improved among patients with atypical EGFR-mutated advanced non–small cell lung cancer (NSCLC) who received first-line amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze), according to a presentation on findings from cohort C of the phase 1/1b CHRYSALIS-2 study (NCT04077463) at the 2026 American Society of Clinical Oncology Annual Meeting (ASCO).¹

At a median follow-up of 31.3 months, patients who received the combination (n = 49) achieved a median OS of 41.0 months (95% CI, 27.7-not evaluable [NE]). The 12-, 24-, and 36-month OS rates were 85%, 72%, and 55%, respectively.

To contextualize these findings, Neal and his coauthors also conducted a descriptive, retrospective, observational analysis of OS in a real-world atypical EGFR-mutated NSCLC cohort that received a physician-selected frontline EGFR TKI. At a median follow-up of 13.4 months, the median OS in the physician-selected group (n = 69) was 15.2 months (95% CI, 11.2-24.8).

“The single-arm study in 49 patients of amivantamab [plus] lazertinib in first-line atypical EGFR-mutant [NSCLC] demonstrates a clinically meaningful OS of almost 3.5 years,” Joel Neal, MD, PhD, a professor of medicine (Oncology) at Stanford Cancer Institute in Palo Alto, California, said during the presentation. “These responses were durable, regardless of demographics, baseline tumor mutations, and disease characteristics, and with longer follow-up, we observed no new safety signals.”

How was CHRYSALIS-2 designed?

CHRYSALIS-2 was an open-label study that evaluated lazertinib as monotherapy or in combination with amivantamab in patients with advanced NSCLC.² All patients were required to have evaluable disease, an ECOG performance statis of 0 or 1, and meet the study protocol defined laboratory criteria without having a history of red blood cell transfusion, platelet transfusion, or granulocyte-colony stimulating factor support within 7 days prior to the date of the test.

During the dose escalation phase, the recommended phase 2 combination doses were determined to be intravenous (IV) amivantamab at 1050 mg, or 1400 mg if a patient weighed 80 kg or more, and oral lazertinib at 240 mg.¹

The dose expansion phase comprised 6 cohorts: patients with EGFR exon 19 deletions (Ex19del) or L858R who were post-osimertinib (Tagrisso) and platinum-based chemotherapy (cohort A); those who were post-standard of care and platinum-based chemotherapy with EGFR exon 20 insertions (cohort B); those with atypical EGFR mutations who were treatment naive or post-EGFR TKIs/chemotherapy (cohort C); those with EGFR Ex19del or L858R who were post-osimertinib and underwent biomarker validation (cohort D); those with EGFR Ex19del or L858R who were post-osimertinib, were MET positive per immunohistochemistry (IHC) analysis who were treated with amivantamab plus lazertinib (cohort E); and those with EGFR Ex19del or L858R who were post-osimertinib, were MET positive per IHC analysis who received amivantamab monotherapy (cohort F).

The study’s primary end point was investigator-assessed overall response rate per RECIST 1.1 criteria. Key secondary end points encompassed duration of response (DOR), clinical benefit rate (CBR), progression-free survival (PFS), OS, and safety.

At baseline, the median age in cohort C was 60 years. Most patients were male (55%) and Asian (57%). The most frequent EGFR mutations included G719X (55%), S786X (27%), and L86X (24%). Compound mutations were reported in 35% of tumors.

What additional efficacy and safety data were reported?

At a median follow-up of 16.1 months, the ORR in cohort C was 57% and the CBR was 84%. The median DOR was 20.7 months and the median PFS was 19.5 months (95% CI, 11.2-NE). The median duration of treatment was 13.3 months (range, < 0.1-53.2), and 39% of patients who received first-line amivantamab plus lazertinib remained on treatment for over 2 years.

In terms of subsequent therapy, most patients who experienced disease progression and discontinued first-line treatment were able to receive subsequent therapy (71%; n = 20/ 28). Subsequent treatment regimens consisted of platinum-based chemotherapy–containing regimens (55%), TKI-based regimens (30%), and other treatments (15%).

Neal noted that the safety profile of the combination was manageable and consistent with prior reports of IV amivantamab plus lazertinib.; no new safety signals were identified. Most adverse effects (AEs) were grade 1 or 2; the most common any-grade treatment emergent AEs (TEAEs) related to EGFR inhibition included paronychia (78%), rash (65%), diarrhea (35%), stomatitis (35%); and pruritic (31%). TEAEs related to MET inhibition consisted of hypoalbuminemia (61%) and peripheral edema (41%). Other any-grade TEAEs included infusion-related reactions (61%), increased alanine aminotransferase levels (53%), and increased aspartate aminotransferase levels (49%). Grade 3 or higher TEAEs included rash (14%), paronychia (8%), hypoalbuminemia (6%), and infusion-related reactions (6%).

“Amivantamab is being tested in other indications, most notably in HPV-unrelated head and neck squamous cell carcinoma after disease progression on checkpoint inhibition and chemotherapy,” Neal concluded in his presentation.

Disclosures: Neal reported receiving honoraria from IDEOlogy Health, Medical Educator Consortium, Medscape, MJH Life Sciences, Navya Network Inc, PlatformQ/Medlive CME, Projects in Knowledge, and Research to Practice. He received research funding from Adaptimmune (Inst), Boehringer Ingelheim (Inst), Exelixis (Inst), Genentech/Roche (Inst), GlaxoSmithKline (Inst), Janssen (Inst), Merck (Inst), Nektar (Inst), Novartis (Inst), Nuvalent, Inc., Revolution Medicines, and Takeda (Inst). He also holds consulting or advisory roles with Abbvie, Amgen, Anheart Therapeutics, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Iovance Biotherapeutics, Janssen Oncology, Lilly, Natera, Novartis, Novocure, Nuvation Bio, Oxford BioTherapeutics, Regeneron, Summit Therapeutics, Taiho Pharmaceutical, and Takeda. He has stock and other ownership interests with SecondLook Health.

References

1. Neal JW, Yang JCH, Cho BC, et al. 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. J Clin Oncol. 2026;44(suppl 16):8501. doi:10.1200/JCO.2026.44.16_suppl.8501
2. A study of lazertinib as monotherapy or in combination with amivantamab in participants with advanced non-small cell lung cancer (Chrysalis-2). ClinicalTrials.gov. Updated May 8, 2026. Accessed May 29, 2026. https://clinicaltrials.gov/study/NCT04077463