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Purpose: MET amplification (amp) is a driver of acquired resistance to epidermal growth factor receptor (EGFR) antibodies in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC). Savolitinib is an oral small molecule tyrosine kinase inhibitor that has demonstrated anti-tumor activity in MET-driven advanced solid tumors. We report the results of a phase 2 study of savolitinib in patients with mCRC with MET amp detected by circulating cell free (cf)DNA., Methods: Patients with chemotherapy refractory mCRC and MET amp detected by cfDNA were treated with savolitinib until unacceptable toxicity or disease progression. The primary endpoint was objective response rate. Secondary endpoints were clinical activity and safety., Results: Five patients were enrolled and treated. Best overall response was stable disease (SD) in two patients, progressive disease (PD) in two patients, and one patient unevaluable for response. The majority of treatment-emergent adverse events (TEAEs) were grade 1 or 2. The most common TEAEs included fatigue (n = 3) and nausea (n = 3). There were no grade 4 or 5 TEAEs., Conclusion: Savolitinib was well tolerated; however, in this small group of biomarker-selected patients, we observed no evidence of anti-tumor activity., Trial Registration: Clinicaltrials.gov Identifier: NCT03592641. Registered on July 17, 2018., Competing Interests: Declarations. Ethics Approval: Approval was obtained from the NCI Adult Central Institutional Review Board – Early Phase Emphasis. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. Consent to Participate: Informed consent was obtained from all individual participants included in the study. Competing Interests: JJ: Consultant or advisory role: AstraZeneca, Cardinal Health Research funding or contracted research: Roche/ Genentech, AztraZeneca JS: Consultant or advisory role: Abbvie, Amgen, Astellas, AstraZeneca, Bayer, Beigene, BMS, Daiichi-Sankyo, Eli Lilly, GE Healthcare, GSK, Incyte, Ipsen, Johnson and Johnson, Jazz Pharmaceuticals, Leap, Merck, Natera, Pfizer, Roche/Genentech, Regeneron, Sanofi, Taiho, Takeda, Xilio Therapeutics Stock options- Triumvira Immunologics Research funding or contracted research: Abbvie, Amgen, Apollo Therapeutics, AStar D3, Bayer, Beigene, Curegenix, Daiichi-Sankyo, Eli Lilly, Erasca, GSK, Leap Therapeutics, Novartis, Pfizer, Quanta Therapeutics, Revolution Medicines, Roche/ Genentech HJL: Stock options – Fulgent, 3 T Bioscience, Breakbio; Advisory Board-BMS, Adagene, 3 T Bioscience, Merck, Merck KG, Abbvie, Bayer; Research funding or contracted research: UM1CA186717, P30CA014089. MC: Honoraria-Amgen, AstraZeneca, Astellas, Bayer, Basilea, Bristol-Myers Squibb, Eisai, Exelixis, I-Mab, Ipsen, Incyte, Genetech/Roche, Natera, Pfizer, Seattle Genetics, Taiho, Tempus, QED; Employment – Replimune., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Acquired resistance to epidermal growth factor receptor (EGFR) targeted antibodies represents a clinical challenge in the treatment of gastrointestinal tumors such as metastatic colorectal cancer, but its molecular mechanisms are incompletely understood. We scanned KRAS exon 2/3/4, NRAS exon 2/3/4 and the overlapping epitopes of the EGFR antibodies cetuximab and panitumumab for mutations in pre- and post-treatment tumor tissue of 21 patients with gastrointestinal cancer treated with chemotherapy +/- EGFR antibodies by next-generation sequencing ("tumor tissue" cohort). We describe a novel EGFR exon 12 mutation acquired in tumors of 1 out of 3 patients treated with panitumumab. The EGFR G465R mutation introduces a positive charge within the overlap of the panitumumab and cetuximab epitopes. It abrogates antibody binding and mediates cross-resistance to both antibodies in EGFR G465R-transfected Ba/F3 cells. In circulating tumor DNA from an independent "liquid biopsy" cohort of 27 patients, we found this novel mutation in 1 out of 6 panitumumab-treated cases while about one third of patients show acquired RAS mutations. We show that acquired resistance by epitope-changing mutations also emerges during panitumumab treatment, which can be easily detected by a liquid biopsy approach even before clinical resistance occurs and this may help in tailoring EGFR-targeted therapies.