Amivantamab/Lazertinib Shows Potential in Atypical EGFR-Mutant Lung Cancer

3D rendering of lungs with tumors: © Crystal Light - stock.adobe.com

Currently, afatinib (Gilotrif) is the only approved treatment for advanced non–small cell lung cancer (NSCLC) with atypical EGFR mutations, including S768I, L861Q, and G719X. However, its effectiveness is limited.

Cohort C of the CHRYSALIS-2 study (NCT04077463) investigated the combination of amivantamab (Rybrevant) and lazertinib (Leclaza), which has proven efficacy in more common EGFR mutations, in patients with these atypical mutations. The study enrolled patients with various EGFR mutations who were treatment-naive or had limited prior treatments.

Results showed promising antitumor activity with this combination, especially in patients who were treatment naive. The overall response rate was 51% (95% CI, 41%-61%) and 55% (95% CI, 40%-69%) in patients who were treatment-naive. The median progression-free survival (PFS) was 19.5 months (95% CI, 11.0-not estimable) in this patient subset.

Overall, this demonstrated potential as a new treatment option for patients with advanced NSCLC harboring atypical EGFR mutations. Further research is ongoing to evaluate its long-term benefits and optimal use.

In an interview with Targeted Oncology^TM, Byoung Chul Cho, MD, PhD, medical oncologist at Yonsei Cancer Center in South Korea, discussed the findings from this study.

Byoung Chul Cho, MD, PhD

Targeted Oncology: What are the unmet needs in this patient population?

Cho: This patient population is known to be resistant to all available EGFR [tyrosine kinase inhibitors (TKIs)]. Efficacy with first-generation EGFR TKIs was reported to be fairly modest, with response rates of 10% to 20% [and] a median PFS of less than 5 months. Those data usually are inconsistent. The second-generation EGFR TKI afatinib is the only FDA-approved drug for those patients with atypical EGFR-mutant NSCLC. With the afatinib, the objective response rate is 50% and median PFS is only 9 to 10 months. Those patients with atypical EGFR-mutant lung cancer have a poorer prognosis than those with a common EGFR mutation.

What were the goals of this analysis?

We evaluated amivantamab plus lazertinib for efficacy and tolerability in advanced, atypical EGFR-mutant NSCLC.

Can you summarize the findings of your analysis?

Cohort C enrolled only atypical EGFR-mutant lung cancer, defined as patients with S768I, L861Q, G719X, etc., and excluding EGFR exon 20 insertion mutations. In the first-line setting, amivantamab plus lazertinib showed an objective response rate of about 51% and median PFS of about 20 months, which is longer than those reported with classic EGFR TKIs. Adverse events were consistent with prior reports. A majority of grade 1 or 2 adverse events associated with EGFR and MET inhibition were rash, with rash and paronychia being the most common.

In the refractory setting, we also demonstrated activity of amivantamab plus lazertinib, with an objective response rate of 45%, [and] a median PFS of 5.7 months. These combination data are meaningful in a refractory setting as well.

In this cohort, 30% of patients experienced venous thrombosis (VTE) from treatment. How was this approached?

VTE is a known [adverse] effect of amivantamab plus lazertinib, and the majority of VTE occurs within 4 months of initiation of the combination treatment. Prophylactic use of anticoagulation effectively prevents occurrence of VTE in our patients.

Do you see this combination having the potential to become a new standard-of-care in this patient population?

Although we cannot provide a clear answer to this question, with our study, we demonstrated that amivantamab plus lazertinib has important activity in patients with atypical EGFR-mutant lung cancer. We demonstrated the longest median PFS with this combination, and it is almost double that we see of classical EGFR TKIs. In addition to PFS, we also demonstrated promising overall survival with a median follow-up of 17 months. Median survival in first-line setting was not estimable, which is promising given the fact that median overall survival with available EGFR TKI treatment is known to be around 20 to 25 months.

Lastly, we demonstrated superior efficacy of amivantamab plus lazertinib in the first-line setting compared [with] a variable treatment in the first-line setting from real-world data. I assume all these data suggest the potential of amivantamab plus lazertinib in the first-line setting.

What are the next steps for researching this combination in this population?

Based on CHYRSALIS-2 data, amivantamab plus lazertinib demonstrated activity in all types of EGFR-mutant lung cancer, including common and uncommon mutations. Currently, the study is stopping. There are several ongoing studies exploring the potential of subcutaneous amivantamab instead of [intravenous (IV)] in combination with lazertinib.

REFERENCE:

Cho BC, Wang Y, Felip E, et al. Amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer (NSCLC): Results from CHRYSALIS-2. J Clin Oncol. 2024;42(suppl 16):8516. doi:10.1200/JCO.2024.42.16_suppl.8516