Editor's Note: The CHRYSALIS-2 study (NCT04077463) Cohort C investigated the combination of amivantamab and lazertinib for the treatment of patients with atypical EGFR-mutant non-small cell lung cancer (NSCLC). The study enrolled patients with various EGFR mutations who were either treatment-naive or had received limited prior treatment. The results demonstrated that the amivantamab+lazertinib combination showed promising antitumor activity, particularly in treatment-naive patients. The overall response rate was 51% (95% CI: 41%-61%), with a response rate of 55% (95% CI: 40%-69%) in treatment-naive patients. In this subgroup, the median progression-free survival (PFS) for the amivantamab+lazertinib combination was 19.5 months (95% CI: 11.0-not estimable). Overall, these findings suggest that amivantamab+lazertinib has potential as a new treatment option for patients with advanced NSCLC carrying atypical EGFR mutations. Principal investigator Dr. Byoung Chul Cho from Yonsei Cancer Center in Korea discussed the results of this study in an international media interview.1. Could you discuss the unmet needs in treating patients with atypical EGFR-mutant NSCLC?
Dr. Cho: It is well known that patients with atypical EGFR-mutant NSCLC exhibit resistance to all available EGFR tyrosine kinase inhibitors (TKIs). The efficacy of first-generation EGFR-TKIs in this population has been reported as quite modest, with inconsistent data, response rates of 10%-20%, and a median PFS of less than five months. Afatinib, a second-generation EGFR-TKI, is the only drug approved by the FDA for treating patients with atypical EGFR-mutant NSCLC. The objective response rate with afatinib is 50%, but the median PFS is only 9-10 months. Patients with atypical EGFR-mutant lung cancer have a poorer prognosis compared to those with common EGFR mutations.
2. Can you discuss the goals and main outcomes of the CHRYSALIS-2 study analysis?
Dr. Cho: We evaluated the efficacy and tolerability of amivantamab+lazertinib in patients with advanced atypical EGFR-mutant NSCLC. Cohort C specifically enrolled patients with atypical EGFR-mutant lung cancer, defined as those with S768I, L861Q, G719X mutations, excluding EGFR exon 20 insertion mutations. In first-line treatment, the objective response rate for amivantamab+lazertinib was approximately 51%, with a median PFS of around 20 months, which is longer than the PFS reported for commonly used EGFR-TKIs. The adverse events (AEs) were consistent with previous reports. Most of the grade 1 or 2 AEs associated with EGFR and MET inhibition were skin-related, with rash and paronychia being the most common. In refractory patients, the combination of amivantamab and lazertinib also demonstrated treatment activity, with an objective response rate of 45% and a median PFS of 5.7 months. These data are significant even for treating refractory patients.
3. In Cohort C of CHRYSALIS-2, 30% of patients experienced venous thromboembolism (VTE) during treatment. How do you manage this issue?
Dr. Cho: VTE is a known adverse reaction of the amivantamab+lazertinib combination, with most VTEs occurring within the first four months of combination therapy. Prophylactic use of anticoagulants can effectively prevent VTE in these patients.
4. Do you believe this combination has the potential to become a new standard treatment for this patient population?
Dr. Cho: While we cannot definitively answer this question, the data from Cohort C of the CHRYSALIS-2 study demonstrates that amivantamab+lazertinib has significant activity in patients with atypical EGFR-mutant lung cancer, with the longest median PFS nearly double that of commonly used EGFR-TKIs. Beyond PFS, the overall survival (OS) data, with a median follow-up of 17 months, shows promise. The median OS for first-line treatment was not reached (NR), but given that the median OS for existing EGFR-TKI treatments is around 20-25 months, these results are encouraging. Finally, we demonstrated that amivantamab+lazertinib’s efficacy in first-line treatment surpasses the efficacy data from various first-line treatments in the real world. All of this suggests that amivantamab+lazertinib has potential as a first-line treatment.
5. Could you outline the next steps in researching the amivantamab+lazertinib combination in the atypical EGFR-mutant NSCLC population?
Dr. Cho: Based on the CHRYSALIS-2 data, amivantamab+lazertinib has shown activity across all types of EGFR-mutant lung cancer, including both common and uncommon EGFR mutations. The current study has been completed. Several ongoing studies are exploring the potential of subcutaneous administration of amivantamab+lazertinib compared to intravenous (IV) administration.
Byoung Chul Cho
medical oncologist and Professor in the Division of Medical Oncology at Yonsei Cancer Center, Kore
