Amivantamab plus lazertinib in osimertinib-relapsed EGFR-mutant advanced non-small cell lung cancer: a phase 1 trial

Abstract

Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) often develop resistance to current standard third-generation EGFR tyrosine kinase inhibitors (TKIs); no targeted treatments are approved in the osimertinib-relapsed setting. In this open-label, dose-escalation and dose-expansion phase 1 trial, the potential for improved anti-tumor activity by combining amivantamab, an EGFR-MET bispecific antibody, with lazertinib, a third-generation EGFR TKI, was evaluated in patients with EGFR-mutant NSCLC whose disease progressed on third-generation TKI monotherapy but were chemotherapy naive (CHRYSALIS cohort E). In the dose-escalation phase, the recommended phase 2 combination dose was established; in the dose-expansion phase, the primary endpoints were safety and overall response rate, and key secondary endpoints included progression-free survival 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 overall response rate was 36% (95% confidence interval, 22-51). The median duration of response was 9.6 months, and the median progression-free survival 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. ClinicalTrials.gov identifier: NCT02609776 .

Fig. 1. Patient flow diagram and regimen dosing schema.

a, Patient flow for the three cohorts from the dose-escalation and dose-expansion phases of CHRYSALIS. b, Dosing schema for amivantamab and lazertinib. Blue symbols indicate intravenous administration of an amivantamab dose.

Fig. 2. Anti-tumor activity of amivantamab + lazertinib combination in part 2 expansion cohort E: osimertinib-relapsed NSCLC with common EGFR mutations (panels a and b) and among patients with and without identified EGFR-based and/or MET-based resistance (panels c and d).

a, Waterfall plot displaying best percent change from baseline in sum of lesion diameters among patients enrolled in the osimertinib-relapsed cohort by receipt of osimertinib/lazertinib as first-line (yellow) or second-line (blue/green) therapy. Teal bars denote patients who received the third-generation EGFR TKI lazertinib instead of osimertinib. Four patients did not have any post-baseline disease assessments and are not included in the plot. b, Spider plot displaying percent change from baseline in sum of diameters of target lesions over time in patients enrolled in the osimertinib-relapsed cohort. Best response of CR (green), PR (blue), SD (orange) and PD (red) are indicated. Gray lines represent patients who were not evaluable (NE). Four patients did not have any post-baseline disease assessments and are not included in the plot. c, Waterfall plot displaying best percent change from baseline in sum of diameters of target lesions among 17 patients with identified EGFR-based and MET-based osimertinib resistance mechanisms. d, Waterfall plot displaying best percent change from baseline in sum of diameters of target lesions among 28 patients with unknown or EGFR-independent and MET-independent osimertinib resistance mechanisms identified by NGS. Additional alterations identified in each patient are indicated by the symbols. Asterisks denote patients who did not have tumor NGS. SoD, sum of diameters; UNK, unknown.

Fig. 3. Anti-tumor activity in patients by IHC expression analysis and NGS-identified osimertinib resistance mechanisms.

Waterfall plot displaying best percent change from baseline in sum of diameters of target lesions among 20 patients who had tumor samples available for exploratory analysis using IHC staining for EGFR and MET expression. IHC-positive patients had combined EGFR and MET H-scores ≥400, and IHC-negative patients had combined EGFR and MET H-scores <400. The table below the waterfall plot indicates the type of resistance mechanism identified using NGS. Patients with both EGFR-based and EGFR/MET-independent resistance are categorized as having EGFR-based resistance (Fig. 2a).

Extended Data Fig. 1. (A) PFS and (B) OS K-M Curve.

In both K-M curves, the dotted lines represent the 95% confidence intervals. K-M, Kaplan-Meier; OS, overall survival; PFS, progression free survival.

Extended Data Fig. 2. Distribution of EGFR and MET H-Scores by (A) IHC status or (B) EGFR mutation type.

In each set of data points, the middle bar represents the mean. EGFR, epidermal growth factor receptor; Ex19del, Exon 19 deletion; IHC, immunohistochemistry.