This study demonstrates that Amivantamab combined with Lazertinib shows significant antitumor activity and controllable safety in patients with advanced non-small cell lung cancer carrying atypical EGFR mutations, providing a novel therapeutic option for this difficult-to-treat population.
Literature Overview
This article, "Amivantamab Plus Lazertinib in Atypical EGFR-Mutated Advanced Non–Small Cell Lung Cancer: Results From CHRYSALIS-2," published in the Journal of Clinical Oncology, reviews and summarizes the efficacy and safety of Amivantamab (an EGFR-MET bispecific antibody) combined with Lazertinib (a third-generation EGFR-TKI) in patients with advanced non-small cell lung cancer (NSCLC) harboring atypical EGFR mutations (e.g., G719X, S768I, L861X). The study shows that this combination therapy achieves an overall response rate (ORR) of 52% in the total population, with a median duration of response (DoR) of 14.1 months, and demonstrates good tolerability. These results provide new clinical evidence for this group of patients who currently have limited treatment options.Background Knowledge
EGFR mutations are important molecular markers in non-small cell lung cancer, with atypical mutations (e.g., G719X, S768I, L861Q) accounting for approximately 5%-10% of all EGFR mutations. Compared with common EGFR mutations (e.g., Ex19del, L858R), atypical mutations generally show lower response rates to first- or second-generation EGFR-TKIs (e.g., erlotinib, afatinib) and are associated with poorer prognosis. Although afatinib has received FDA approval for certain atypical mutation patients, its efficacy remains limited, especially in those with compound mutations. The third-generation EGFR-TKI osimertinib also shows variable efficacy in this population, with some patients responding poorly. Therefore, more effective treatment strategies are still needed for patients with advanced NSCLC harboring atypical EGFR mutations. Amivantamab is a bispecific antibody targeting both EGFR and MET, and exerts antitumor activity through multiple mechanisms (e.g., receptor degradation, immune cell activation). Lazertinib is a highly selective, third-generation EGFR-TKI with good central nervous system (CNS) penetration. The combination of these two agents offers complementary mechanisms and can effectively inhibit both EGFR signaling and MET-mediated resistance pathways. This study, based on CHRYSALIS-2 Cohort C, evaluates the efficacy and safety of the combination in patients with atypical EGFR-mutated NSCLC, offering new evidence for clinical treatment.
Research Methods and Experiments
CHRYSALIS-2 Cohort C enrolled 105 patients with advanced NSCLC harboring atypical EGFR mutations (e.g., G719X, S768I, L861X), including 49 treatment-naive patients and 56 who had received one or two prior lines of treatment (mainly EGFR-TKIs). All patients received Amivantamab (weekly intravenous infusion for the first 4 weeks, then every 2 weeks) in combination with Lazertinib (daily oral dose of 240 mg). The primary endpoint was the investigator-assessed objective response rate (ORR). Secondary endpoints included duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Safety assessments focused on the incidence and severity of treatment-emergent adverse events (TEAEs).Key Conclusions and Perspectives
Research Significance and Prospects
This study is the first to evaluate the efficacy of Amivantamab plus Lazertinib in patients with atypical EGFR-mutated NSCLC in a larger cohort, showing durable antitumor activity and manageable safety. Compared with current therapies (e.g., afatinib, osimertinib), this combination shows improved outcomes in terms of ORR, PFS, and OS, particularly in treatment-naive patients. The findings provide a new clinical treatment pathway for this patient group and highlight the need for further real-world evaluation of long-term efficacy and safety. Additionally, optimizing strategies for VTE prevention, such as prophylactic anticoagulation, represents an important direction for future research.
Conclusion
This study confirms that Amivantamab combined with Lazertinib provides strong antitumor activity in patients with advanced NSCLC harboring atypical EGFR mutations, with an ORR of 52% and durable responses. In treatment-naive patients, the ORR increased to 57%, and the median PFS reached 19.5 months, significantly outperforming traditional EGFR-TKIs. Regarding safety, the main adverse events were grade 1–2, including rash, paronychia, and hypoalbuminemia, with a VTE incidence of 30% and no high-grade events. These results offer a new treatment option for patients with atypical EGFR mutations, and future studies should further assess the real-world efficacy and safety of this regimen, as well as explore optimized anticoagulation strategies to reduce the risk of VTE.
