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Background Colorectal cancer (CRC) has been shown to acquire RAS and EGFR ectodomain mutations as mechanisms of resistance to epidermal growth factor receptor (EGFR) inhibition (anti-EGFR). After anti-EGFR withdrawal, RAS and EGFR mutant clones lack a growth advantage relative to other clones and decay; however, the kinetics of decay remain unclear. We sought to determine the kinetics of acquired RAS/EGFR mutations after discontinuation of anti-EGFR therapy. Patients and methods We present the post-progression circulating tumor DNA (ctDNA) profiles of 135 patients with RAS / BRAF wild-type metastatic CRC treated with anti-EGFR who acquired RAS and/or EGFR mutations during therapy. Our validation cohort consisted of an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling. A separate retrospective cohort of 80 patients was used to evaluate overall response rate and progression free survival during re-challenge therapies. Results Our analysis showed that RAS and EGFR relative mutant allele frequency decays exponentially (r 2=0.93 for RAS ; r 2=0.94 for EGFR) with a cumulative half-life of 4.4 months. We validated our findings using an external dataset of 73 patients with a ctDNA profile suggestive of prior anti-EGFR exposure and serial sampling, confirming exponential decay with an estimated half-life of 4.3 months. A separate retrospective cohort of 80 patients showed that patients had a higher overall response rate during re-challenge therapies after increasing time intervals, as predicted by our model. Conclusion These results provide scientific support for anti-EGFR re-challenge and guide the optimal timing of re-challenge initiation. [ABSTRACT FROM AUTHOR]

MET amplification (amp) is rare in untreated metastatic colorectal cancer (mCRC), but cell-free DNA (cfDNA) analysis identifies it in ∼20% with anti-EGFR monoclonal antibody (mAb)-refractory disease. CfDNA analysis reveals both focal gene amp and gene copy number gain due to chromosomal aneuploidy (non-focal MET amp). We analyzed cfDNA from Japanese (JPN) and United States (US) patients (pts) with anti-EGFR mAb-refractory mCRC to investigate the prevalence of focal and non-focal MET amp. We studied MET amp in pts with mCRC in the Nationwide Cancer Genome Screening Project in JPN (GOZILA; UMIN000029315; JPN cohort) and in a phase I/II trial of cabozantinib (C) +/- panitumumab (P) in pts with RAS wild-type mCRC (NCT02008383; US cohort). MET amp was detected with the Guardant360 assay. Focal MET amp was defined as either the only amp on chromosome (chr) 7q or MET copy number ³4. Non-focal MET amp was defined as co-amp with ³1 other genes (CDK6 or BRAF) located on chr 7q and MET copy number <4. 244 JPN cohort pts were analyzed from 2/2018-12/2018, and 81 pts in the US cohort, from 8/2014-2/2018. In pts with prior anti-EGFR mAb (JPN: n = 184; US: n = 70), focal and non-focal MET amp were detected in 8 (4.3%) and 30 (16.3%) pts in the JPN cohort, and in 9 (12.9%) and 4 (5.7%) US pts. Without prior anti-EGFR mAb (JPN: n = 60; US: n = 11), focal and non-focal MET amp were detected in 1 (1.7%) and 4 (6.7%) pts in the JPN cohort, and 0 (0%) and 1 (9.1%) US pts. The focal MET amp rate combined was 6.7% (17/254) with prior anti-EGFR mAb. In the US cohort, 4/6 pts with focal MET amp treated with C or C+P had a reduction in RECIST lesions as best response, with one PR, while 2 pts with non-focal MET amp had tumor growth as best response. The prevalence of focal MET amp detected by cfDNA analysis in mCRC pts was similar in the JPN and US cohorts. Given preliminary efficacy results from the US trial, focal MET amp may be a [A1] predictor of benefit from a MET inhibitor. A clinical trial evaluating a MET inhibitor in mCRC pts with focal MET amp is underway. The authors. Has not received any funding. A. Kawazoe: Honoraria (self), Research grant / Funding (institution): Ono Oharmaceutical; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Takeda Pharmaceutical; Research grant / Funding (institution): Astellas Pharmaceutical; Research grant / Funding (institution): MSD. Y. Nakamura: Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Taiho Pharmaceutical. J.I. Odegaard: Full / Part-time employment: Guardant Health. M.I. Lefterova: Full / Part-time employment: Guardant Health. R. Lanman: Full / Part-time employment: Guardant Health. T. Yoshino: Research grant / Funding (institution): Novartis Pharma K.K.; Research grant / Funding (institution): MSD.K.K.; Research grant / Funding (institution): Sumitomo Dainippon Pharma Co., Ltd.; Research grant / Funding (institution): CHUGAI PHARMACEUTICAL CO., LTD.; Research grant / Funding (institution): Sanofi K.K.; Research grant / Funding (institution): DAIICHI SANKYO COMPANY, LIMITED; Research grant / Funding (institution): PAREXEL International Inc.; Research grant / Funding (institution): ONO PHARMACEUTICAL CO., LTD.. J.H. Strickler: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self): Chugai; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Leadership role, Research grant / Funding (institution): OncoMed; Advisory / Consultancy: Celgene; Advisory / Consultancy: Proteus Digital Health; Advisory / Consultancy: Chengdu Kanghong Biotechnology Co., Ltd; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Leap Therapeutics; Research grant / Funding (institution): MedImmune. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]