RYBREVANT Plus LAZCLUZE Achieves Nearly 3.5-Year Median Overall Survival in Atypical EGFR-Mutated NSCLC
Key Insights
Johnson & Johnson's RYBREVANT plus LAZCLUZE combination demonstrated a median overall survival of 41.0 months in patients with atypical EGFR (search)-mutated advanced non-small cell lung cancer in the CHRYSALIS-2 study.
The treatment showed consistent clinical activity across atypical EGFR (search) mutation subgroups, with 41% of patients remaining on RYBREVANT for two years or longer.
The safety profile remained consistent with previous reports, with most adverse events being Grade 1 or 2, and no new safety signals observed with extended follow-up.
Johnson & Johnson announced updated results from the Phase 1/1b CHRYSALIS-2 study evaluating RYBREVANT (amivantamab-vmjw) in combination with LAZCLUZE (lazertinib) for patients with advanced non-small cell lung cancer (NSCLC) harboring atypical epidermal growth factor receptor (EGFR (search)) mutations. The data, presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, demonstrated encouraging long-term survival outcomes in this historically difficult-to-treat patient population.
Significant Survival Benefit in Challenging Patient Population
In Cohort C of the CHRYSALIS-2 study, the combination achieved a median overall survival of 41.0 months (95% confidence interval, 27.7-not estimable) at a median follow-up of 31.3 months. Overall survival rates were 55% at three years and 46% at four years. The study enrolled 49 patients with atypical EGFR (search)-mutated advanced NSCLC, excluding EGFR exon 20 insertion mutations.
The most common atypical EGFR (search) mutations included G719X (55%), S768X (27%), and L861X (24%), with 35% of patients harboring multiple atypical mutations. The study previously reported an objective response rate of 57% as its primary endpoint.
"For patients with non-small cell lung cancer harboring atypical EGFR (search)-mutations, first-line treatment decisions are often clouded by uncertainty regarding the efficacy of currently available EGFR tyrosine kinase inhibitors," said Joel Neal, M.D., Ph.D., principal investigator of the study and Professor of Medicine in the Division of Oncology at Stanford Medicine. "The responses we've seen in this trial suggest the potential for more durable disease control, and the overall survival data reinforce that picture."
Addressing Critical Unmet Medical Need
Patients with atypical EGFR (search)-mutated NSCLC represent approximately 10-20% of all EGFR-mutated cases and typically experience poorer outcomes than those with common EGFR mutations. Median overall survival with current standard of care single-agent therapies remains under two years, highlighting a significant treatment gap.
"Disease progression and molecular resistance remain critical barriers in EGFR (search)-mutated non-small cell lung cancer," said Yusri Elsayed, M.D., M.H.Sc., Ph.D., Global Therapeutic Area Head, Oncology, Johnson & Johnson. "RYBREVANT-based combinations demonstrate the power of changing the biology by addressing multiple disease drivers from the start rather than relying on single-pathway strategies."
Consistent Activity Across Mutation Subgroups
The analysis revealed consistent clinical activity across atypical EGFR (search) mutation subgroups, as well as across patient and disease characteristics including central nervous system metastases and TP53 status. Notably, 41% of patients remained on RYBREVANT treatment for two years or longer, supporting the durable survival observed with this combination.
Manageable Safety Profile
The safety profile of RYBREVANT plus LAZCLUZE remained consistent with previous reports, with no new safety signals observed during extended follow-up. Most adverse events were Grade 1 or 2. The most common treatment-emergent adverse events occurring in more than 30% of patients included paronychia (78%), rash (65%), hypoalbuminemia (61%), and infusion-related reactions (61%).
Dual-Targeting Mechanism of Action
RYBREVANT is a first-in-class, fully human bispecific antibody targeting both EGFR (search) and mesenchymal-epithelial transition (MET) receptors while engaging the immune system. This dual-targeting approach is designed to address multiple disease drivers simultaneously, potentially overcoming resistance mechanisms that limit single-pathway therapies.
LAZCLUZE is an oral, third-generation, brain-penetrant EGFR (search) tyrosine kinase inhibitor that targets both the T790M mutation and activating EGFR mutations while sparing wild-type EGFR.
Broader Clinical Development Program
RYBREVANT-based regimens are currently approved for patients with EGFR (search)-mutated advanced NSCLC across common mutations (exon 19 deletions and exon 21 L858R substitution mutations) and exon 20 insertion mutations, including in the first-line setting. The National Comprehensive Cancer Network Clinical Practice Guidelines include amivantamab-vmjw as a Category 1 preferred option in combination with lazertinib for first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations.
Study Design and Patient Population
CHRYSALIS-2 is an open-label Phase 1/1b study evaluating the safety and pharmacokinetics of LAZCLUZE as monotherapy or in combination with RYBREVANT in participants with advanced NSCLC. The study enrolled 460 patients with advanced NSCLC. Cohort C specifically evaluated patients with atypical EGFR (search)-mutated advanced NSCLC who were treatment-naïve or had received up to two prior lines of therapy.