Amivantamab Plus Lazertinib Expands Options for Atypical EGFR NSCLC
Key Clinical Summary
- In the phase 1/1b CHRYSALIS-2 Cohort C study, amivantamab plus lazertinib achieved an objective response rate of 52% in advanced non–small cell lung cancer (NSCLC) with atypical epidermal growth factor receptor (EGFR) mutations.
- Among treatment-naïve patients, median progression-free survival reached 19.5 months, with median duration of response of 20.7 months.
- Safety was consistent with prior experience, with mostly grade 1-2 adverse events, although venous thromboembolism remained an important management consideration.
Patients with NSCLC harboring atypical EGFR mutations have historically faced limited treatment options and poorer outcomes than those with common EGFR alterations. New data from CHRYSALIS-2 Cohort C suggest that the combination of amivantamab and lazertinib may offer a clinically meaningful option for this difficult-to-treat population.
Study Findings
CHRYSALIS-2 Cohort C evaluated amivantamab plus lazertinib in 105 patients with advanced or metastatic NSCLC harboring atypical EGFR mutations such as G719X, L861X, and S768I. Patients could be treatment-naïve or have received up to 2 prior lines of therapy, including first- or second-generation EGFR tyrosine kinase inhibitors. Patients with exon 20 insertions, exon 19 deletions, or L858R mutations were excluded.
At a median follow-up of 16.1 months, the investigator-assessed objective response rate in the overall population was 52%. All responses were partial responses. Median duration of response was 14.1 months, median progression-free survival was 11.1 months, and median overall survival was not estimable.
Outcomes were stronger in the first-line setting. Among 49 treatment-naïve patients, objective response rate was 57%, median duration of response was 20.7 months, and median progression-free survival was 19.5 months. Median overall survival was not estimable, and 77% of patients were alive at 24 months. In previously treated patients, response rate was 48%, median duration of response was 11.0 months, and median progression-free survival was 7.8 months.
The study also found activity across multiple atypical mutation subtypes. Response rates were 45% in patients with P-loop and αC-helix compressing mutations, 64% in those with classical-like mutations, and 67% in those with T790M-like mutations. Solitary vs compound atypical EGFR mutations did not appear to have a major effect on response.
Clinical Implications
For clinicians and managed care stakeholders, the findings are notable because atypical EGFR-mutated NSCLC remains an area of unmet need. Current treatment options are limited, and outcomes with available EGFR tyrosine kinase inhibitors have been variable across mutation subtypes.
The combination of amivantamab, an EGFR-MET bispecific antibody, and lazertinib, a third-generation EGFR tyrosine kinase inhibitor, may provide broader pathway inhibition than tyrosine kinase inhibitor monotherapy alone. The reported progression-free survival of 19.5 months in treatment-naïve patients compares favorably with historical outcomes described in the article for afatinib and osimertinib in similar populations.
Safety will remain central to implementation. The most common treatment-emergent adverse events were rash, paronychia, hypoalbuminemia, and infusion-related reactions, which were mostly low grade. However, venous thromboembolism occurred in 30% of patients, and grade 3 events occurred in 10%, supporting the importance of prophylactic anticoagulation strategies now recommended in ongoing studies and prescribing guidance.
The study authors concluded that amivantamab-lazertinib demonstrated “clinically meaningful and durable antitumor activity” in patients with atypical EGFR-mutated advanced NSCLC and did so with “no new safety signals.” They also noted that this is, to their knowledge, the largest prospective single-cohort study in this rare molecular subgroup.
Conclusion
Amivantamab plus lazertinib showed durable activity and a manageable safety profile in advanced NSCLC with atypical EGFR mutations, particularly in treatment-naïve patients. For a population with few effective options, the regimen may represent an important emerging treatment strategy.
Reference
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. 2026;44(1):54-65. doi:10.1200/JCO-24-02835
