In a cohort E of the phase I CHRYSALIS study, the amivantamab and lazertinib regimen showed durable clinical activity in the setting of patients with osimertinib-relapsed EGFR-mutated advanced non-small cell lung cancer (NSCLC), consistent with preclinical studies, suggesting improved anti-EGFR activity in osimertinib-resistant models.
The activity of the combination after disease progression on or after osimertinib suggests that dual blockade of EGFR and MET by amivantamab can potentiate the initial anti-EGFR activity of lazertinib and may delay development of resistance through EGFR secondary resistance mutations and MET bypass pathways, although direct comparison with single-agent lazertinib was not performed in this study. The findings are published by Prof. Byoung Chul Cho of the Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine in Seoul, Republic of Korea, and colleagues on 14 September 2023 in the Nature Medicine.
EGFR mutations are among the most common activating mutations in NSCLC, with ex19del and L858R mutations accounting for approximately 85–90% of all cases. Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), is the current standard of care for the treatment of EGFR ex19del and L858R NSCLC. Despite good initial disease control, patients nearly always develop resistance to osimertinib. Recent studies have evaluated chemotherapy plus immunotherapy and anti-angiogenic therapy in this patient population, but no subsequent targeted therapeutic approaches without chemotherapy are approved in the osimertinib-relapsed setting.
The most prevalent EGFR-dependent mechanism of resistance to osimertinib is C797S mutation of the EGFR gene. Other EGFR-dependent resistance mechanisms that have been identified include L792X, G796X, L718Q and EGFR amplification. Among EGFR-independent resistance mechanisms, MET amplification has been most frequently reported, with activation of MAPK or PI3K pathways, gene fusions and histologic transformations also reported. However, in up to 50% of patients who experience progression on osimertinib, no clear mechanism of resistance has been identified.
Overcoming osimertinib resistance is further complicated by heterogeneous patterns of resistance and presence of co-occurring resistance mechanisms, which can occur even within a single patient. Additionally, the mechanism of osimertinib resistance can be influenced by whether progression occurred in the first-line or second-line setting. Given the complexity of osimertinib patterns of resistance, the inherent resistance of this population to immune checkpoint inhibitor monotherapy and the lack of approved targeted therapies, current treatment guidelines recommend platinum-based chemotherapy regimens after progression on osimertinib.
Given the tolerable safety profiles of both amivantamab, an EGFR-MET bispecific antibody and lazertinib, a third-generation EGFR TKI, and the potential for improved antitumuor activity, the amivantamab and lazertinib regimen was evaluated in the ongoing CHRYSALIS study, with preliminary efficacy assessed in patients with EGFR ex19del or L858R metastatic NSCLC whose disease progressed on osimertinib or another third-generation EGFR TKI but who had not received cytotoxic chemotherapy in the metastatic setting (cohort E).
It is an open-label, dose-escalation and dose-expansion phase I study. In the dose-escalation phase, the recommended phase II combination dose was established; in the dose-expansion phase, the primary endpoints were safety and overall response rate (ORR), and key secondary endpoints included progression-free survival (PFS) and overall survival.
The safety profile of amivantamab and lazertinib was generally consistent with previous experience of each agent alone, with 4% experiencing grade ≥3 events; no new safety signals were identified.
In an exploratory cohort of 45 patients who were enrolled without biomarker selection, the primary endpoint of investigator-assessed ORR was 36% (95% confidence interval 22–51). The median duration of response was 9.6 months, and the median PFS was 4.9 months.
Next-generation sequencing and immunohistochemistry analyses identified high EGFR and/or MET expression as potential predictive biomarkers of response, which will need to be validated with prospective assessment.
Additional studies to corroborate the results are currently underway. The CHRYSALIS-2 study is evaluating the amivantamab and lazertinib regimen in the post-platinum-based chemotherapy/post-osimertinib setting, with results demonstrating a consistent level of antitumour activity (ORR 33% by blinded independent central review and DoR of 9.6 months), suggesting similar efficacy as observed in this current analysis. Similarly to this analysis, cohort D of the CHRYSALIS-2 study is investigating potential biomarker strategies and evaluating the amivantamab and lazertinib regimen in the post-osimertinib and chemotherapy-naïve setting.
The study was funded by Janssen R&D.
Reference
Chul Cho B, Kim D-W, Spira AI, et al. Amivantamab plus lazertinib in osimertinib-relapsed EGFR-mutant advanced non-small cell lung cancer: a phase 1 trial. Nature Medicine; Published online 14 September 2023. DOI: https://doi.org/10.1038/s41591-023-02554-7
