Johnson & Johnson’s RYBREVANT® plus LAZCLUZE® delivers a median overall survival of 41 months in atypical EGFR-mutated NSCLC, with durable benefit and consistent safety in Phase 1/1b CHRYSALIS-2.
Written By: Fariha Sameen, PharmD
Reviewed By: Pharmacally Editorial Team
Johnson & Johnson presented updated long-term results from the Phase 1/1b CHRYSALIS-2 (NCT04077463) study at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, highlighting durable survival with RYBREVANT® (amivantamab) plus LAZCLUZE® (lazertinib) in patients with advanced non-small cell lung cancer (NSCLC) harboring atypical EGFR mutations.
The data, presented during an oral session showed a median overall survival (OS) of 41.0 months in treatment-naïve patients, approaching 3.5 years and demonstrating sustained long-term benefit in this difficult-to-treat subgroup.
Addressing an Unmet Need
Atypical EGFR mutations, including G719X, S768X, and L861X, account for approximately 10% to 20% of EGFR-mutated NSCLC cases but are associated with poorer outcomes than common EGFR mutations. Current first-line targeted therapies typically achieve median overall survival of less than two years in this population.
The CHRYSALIS-2 results suggest that simultaneous EGFR and MET targeting may extend survival beyond what has historically been achieved with single-agent EGFR inhibitors.
Cohort C Results
Cohort C enrolled 49 patients with atypical EGFR-mutated advanced NSCLC, excluding EGFR exon 20 insertion mutations. More than one-third of participants harbored multiple atypical EGFR alterations. At a median follow-up of 31.3 months, the combination achieved a median OS of 41.0 months, with overall survival rates reaching 55% at three years and 46% at four years.
Clinical activity remained consistent across mutation subgroups and key baseline characteristics, including patients with central nervous system metastases and TP53 co-mutations. Notably, 41% of patients remained on treatment for at least two years, reinforcing the durability of benefit. The study previously reported a confirmed objective response rate of 57%.
Mechanistic Rationale
RYBREVANT is a bispecific antibody that targets both EGFR and MET while engaging immune-mediated tumor cell killing. LAZCLUZE, a third-generation EGFR tyrosine kinase inhibitor with central nervous system penetration, complements this approach by suppressing signaling pathways involved in tumor growth and treatment resistance. Together, the agents provide broader pathway coverage than single-agent EGFR inhibition.
Safety Profile
Extended follow-up identified no new safety signals. Most treatment-emergent adverse events were Grade 1 or 2 in severity. The most frequently reported adverse events included paronychia (78%), rash (65%), hypoalbuminemia (61%), and infusion-related reactions (61%). Overall, the safety profile remained consistent with previous analyses of the combination.
Implications for Patient Care
Lead investigator Joel Neal, MD, PhD, of Stanford Medicine, noted that treatment decisions for atypical EGFR-mutated NSCLC often involve uncertainty because currently available EGFR inhibitors show variable activity across mutation subtypes. The durability of responses and survival outcomes observed in CHRYSALIS-2 may help redefine treatment expectations for this patient population.
The findings add to growing evidence supporting RYBREVANT-based combinations across EGFR-mutated NSCLC and may help guide future first-line treatment strategies for patients with atypical EGFR mutations, a population that remains underrepresented in prospective clinical studies.
While RYBREVANT-based regimens are already approved in several EGFR-driven NSCLC settings, these results further strengthen the rationale for targeting multiple disease drivers early in treatment to improve long-term outcomes.
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About the Writer
Fariha Sameen, PharmD (LinkedIn), is a clinical pharmacy professional with hands-on experience in patient counselling, medication review, therapeutic monitoring, and clinical documentation across multiple departments. She has experience identifying and assessing drug-related problems and supporting medication safety practices. Her interests include pharmacovigilance, ADR reporting, clinical research, and medical writing focused on clear, evidence-based communication.