PERSPECTIVE: Tepotinib + cetuximab for RAS/BRAF wild-type left-sided metastatic colorectal cancer (mCRC) and acquired resistance to anti-EGFR antibody therapy due to MET amplification (METamp)


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Stephen Falk1, David Cunningham2, Janet Graham3, Justin Mencel2, Paul Ross4, Barbara Ellers-Lenz1, Gordon Otto1, Audrey Seronde1, Josep Tabernero5
1Other, 2Royal Marsden NHS Foundation Trust, 3Beatson West of Scotland Cancer Centre, 4Guy’s and St Thomas’ NHS Foundation Trust, 5Vall d’Hebron Institute of Oncology

Abstract

Background

METamp is a secondary genetic change or co-driver in patients (pts) with mCRC and acquired resistance to anti-EGFR therapy, which can contribute to disease progression.

Tepotinib (a highly selective, potent MET inhibitor) + gefitinib has shown improved progression-free survival (PFS; 16.6 vs 4.2 months; hazard ratio [HR]=0.13) and overall survival (OS; 37.3 vs 13.1 months; HR=0.08) in 19 pts with EGFR-mutant METamp NSCLC and acquired EGFR tyrosine kinase inhibitor resistance versus chemotherapy (INSIGHT: NCT01982955).

Method

This Phase II, multicenter, single-arm, open-label study will assess safety and tolerability, preliminary antitumor activity, and pharmacokinetic (PK) profiles of tepotinib + cetuximab in pts with RAS/BRAF wild-type left-sided mCRC and acquired resistance to anti-EGFR antibody-targeted therapy due to METamp (NCT04515394). A safety run-in (≥6 pts) will evaluate the recommended Phase II dose (RP2D) of tepotinib. Adult pts will be enrolled based on a confirmed advanced left-sided CRC diagnosis (RAS/BRAF wild-type), acquired resistance to anti-EGFR antibody, METamp confirmed by liquid and/or tissue biopsy and ECOG performance status 0/1.

The study will screen ~340 pts to account for METamp heterogeneity, and is being conducted in Belgium, Czech Republic, France, Italy, Russia, Spain, the UK, and the US. At present, there are 31 active centers in Spain (8 centers), France (6), the UK (2), Russia (8), Belgium (1), and the US (6). Approximately 42 pts are planned to receive study treatment at the RP2D: ~22 in Cohort A (second-line; outside the US) and 20 in Cohort B (≥third-line; US only).

The primary endpoint is investigator-assessed objective response per RECIST 1.1. Secondary endpoints are investigator-assessed duration of response (DOR), PFS, OS, tolerability and safety, and cetuximab immunogenicity. Additional endpoints include PK profiles and expression of resistance biomarkers. Retrospective assessment of overall response, DOR, and PFS by an independent review committee may be conducted. No formal statistical hypothesis will be tested in this exploratory study.

Results

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Conclusion

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Impact statement

The dual approach of MET inhibition (tepotinib) plus an anti-EGFR (cetuximab) targeting MET pathway activation and maintaining EGFR pathway inhibition may provide a new treatment option for patients with mCRC and acquired resistance to anti-EGFR antibody therapy due to METamp.