5O - Deciphering resistance mechanisms in cancer: Insights from the final report of MATCH-R study with focus on molecular drivers

Background

Understanding the resistence mechanisms of tumor is crucial for advancing cancer therapies. The prospective MATCH-R study (NCT02517892), led by Gustave Roussy, aims to characterize these mechanisms to innovative cancer treatments. This report presents the final results of the MATCH-R study conducted from 2015 to 2022.

Methods

Patients in different oncological settings who accepted a biopsy were included. After evaluation of tumor content (TC) in frozen tissue biopsies, targeted NGS (1030%) were performed before and/or after the targeted therapy. PDX were established by implanting tumor fragments into NOD scid gamma (NSG) mice and amplified up to five passages to generate a viable bank.

Results

Out of 1194 of patients (pts) enrolled, 19.3% (n=230/1194) experienced screen failure before biopsy and 8.8% (n=105/1194) had non-contributive biopsies (TC<10%). A total of 1287 biopsies were collected from 859 pts, with the highest incidences being lung (38.8%), gastrointestinal (16.3%) and prostate (14.1%) cancer. Overall, 38.2% (n=328) of the 859 pts harbored a molecular targetable driver. The most common oncogenic drivers were EGFR (42.1%), FGFR (14.3%), ALK (11.9%), BRAF (8.2%), and KRAS (5.2%). Of these, 66.2% (n=217/328) had a biopsy at progression on target therapy. Among resistant cases, 41.0% (n=89/217) had no identified molecular mechanism, 34.1% (n=74/217) showed on-target resistance and 24.9% (54/217) exhibited a by-pass resistance mechanism. Molecular profiling of the 54 patients with by-pass resistance identified 60 variants, with PIK3CA (18.3%), KRAS (11.7%), PTEN (11.7%), AKT1 (6.7%), and NRAS (5.0%) being the most altered genes. A total of 282 biopsies from 240 patients were implanted in mice, successfully establishing 123 PDX models achieving a 43.6% success rate. PDX models are available for EGFR (n=30), FGFR (n=26), ALK (n=17), KRAS (n=17), BRAF (n=5) and NTRK (n=2) driven cancers.

Conclusions

The MATCH-R Study shows clinical feasibility of repeated biopsies and PDX establishment, providing insights into resistance mechanisms in cancer, which holds promise for personalized therapies and improved patient outcomes.

Editorial acknowledgement

Clinical trial identification

NCT02517892.

Legal entity responsible for the study

Gustave Roussy.

Funding

Gustave Roussy.

Disclosure

All authors have declared no conflicts of interest.