Amivantamab plus lazertinib shows durable clinical activity in osimertinib-relapsed, epidermal growth factor receptor-mutated advanced non-small cell lung cancer in a phase I study.
Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), is the current standard-of-care treatment for EGFR-mutated non-small cell lung cancer (NSCLC). However, resistance is common, and there are no approved targeted therapies in the osimertinib-relapsed setting.
The CHRYSALIS study, an ongoing phase I trial, evaluated amivantamab plus lazertinib for treating EGFR-mutated metastatic NSCLC after disease progression on osimertinib. The study’s results are published in the journal Nature Medicine.
Study Population
A total of 91 patients were enrolled, with 45 patients in the osimertinib-relapsed cohort. The median age was 65 years, with 56% females in the osimertinib-relapsed cohort. More patients exhibited ex19del (69%) than L858R intrinsic mutations.
The Amivantamab and Lazertinib Regimen Is Tolerable
The median follow-up was 11.1 and 13.3 months for the osimertinib-relapsed and all-treated populations, respectively. Both cohorts exhibited similar safety profiles for the amivantamab and lazertinib regimen, which was also similar to the previously described safety for amivantamab at its recommended phase-2 dose.
In the osimertinib-relapsed cohort, the most commonly reported adverse events (AEs) were rash (80%) and infusion-related reactions (78%). Other common AEs were consistent with anti-EGFR and anti-MET activity. Grade ≥3 AEs were reported in 56% of patients, of which 16% were deemed treatment-related. Serious AEs occurred in 38% of patients, of which 4% were deemed treatment-related. Treatment-related AEs leading to dose reduction and treatment discontinuation occurred in 18% and 4% of patients, respectively.
Amivantamab Plus Lazertinib Shows Efficacious and Durable Clinical Activity
In the osimertinib-relapsed cohort enrolled without biomarker selection, the investigator-assessed overall response rate (ORR) was 36% (95% confidence interval: 22–51) at a median follow-up of 11.1 months, with one complete response (CR) and 15 partial responses (PRs). ORRs were similar between patients who had received osimertinib as first-line or second-line therapy. The ORR was 33% for patients with EGFR ex19del versus 43% for patients with EGFR L858R. Most responses were observed within 6 weeks.
The median duration of response was 9.6 months, with 69% of patients achieving responses lasting more than or equal to 6 months. The clinical benefit rate (CBR) (defined as CR, PR, or stable disease for ≥11 weeks) was 64%. The median progression-free survival (PFS) was 4.9 months.
High EGFR and MET Expression Emerge as Potential Predictive Biomarkers
High EGFR and MET expression were identified as potential predictive biomarkers of response through next-generation sequencing and immunohistochemistry (IHC) analyses. In osimertinib-relapsed patients, 38% had EGFR-based and/or MET-based osimertinib resistance mutations. Among them, 47% achieved an ORR-based response to amivantamab plus lazertinib, with 10.4 months median response duration, 82% CBR, and 6.7 months median PFS.
Among the remaining patients without an identified EGFR/MET-based resistance mechanism, 29% reached ORR, with 8.3 months median response duration, 54% CBR, and 4.1 months median PFS. With unknown resistance mechanisms, the ORR was 44%, and among those with EGFR/MET-independent mechanisms, none achieved a response. IHC-positive patients (EGFR/MET expression) showed a 90% response rate, with 9.7 months median response duration, 100% CBR, and 12.5 months median PFS. IHC-negative patients demonstrated 10% ORR, 2.7 months response duration, 50% CBR, and 4.0 months median PFS.
Source:
Cho, B. C., Kim, D., Spira, A. I., Gomez, J., Haura, E. B., Kim, S., Sanborn, R. E., Cho, E. K., Lee, K. H., Minchom, A., Lee, J. S., Han, J., Nagasaka, M., Sabari, J. K., Ou, S. I., Lorenzini, P., Bauml, J., Curtin, J. C., Roshak, A., . . . Park, K. (2023). Amivantamab plus lazertinib in osimertinib-relapsed EGFR-mutant advanced non-small cell lung cancer: a phase 1 trial. Nature Medicine, 29(10), 2577–2585. https://doi.org/10.1038/s41591-023-02554-7
