2223 - Microsatellite Instability Status in Metastatic Colorectal Cancer and Effect of Immune Checkpoint Inhibitors on Survival in MSI-High Metastatic Colorectal Cancer

Background

Tumour mismatch repair (MMR) predicts benefit of immune checkpoint inhibitors (ICIs) in metastatic colorectal cancer (mCRC). We conducted a large-scale prospective observational trial on microsatellite instability (MSI) status in mCRC: SCRUM-Japan GI-SCREEN CRC-MSI.

Methods

mCRC patients (pts) appropriate for systemic chemotherapy were eligible. Paired tumor and normal DNA extracted from FFPE samples were analyzed by the MSI Analysis System, which includes 5 mononucleotide markers. Tumours exhibiting ≥2 unstable markers were defined as MSI-H, while those with ≤1 were labelled MSI-L/MSS.

Results

From 2/2016 to 3/2018, 1,711 pts were enrolled, and 1,696 samples were submitted. MSI status was determined in 1,676 pts (98.8%); 51 pts (3.0%) were MSI-H. For MSI-H vs. MSI-L/MSS pts: Median age (years) 64/64; male gender (%) 49.0 vs. 56.2, p = 0.31; right-sided primary (%) 70.6 vs. 25.0, p < 0.001; and poorly differentiated histology (%) 33.3 vs. 8.9, p < 0.001. Of the 864 pts who received parallel NGS testing, median tumor mutation burdens (TMB) in MSI-H and MSI-L/MSS were 32.8 and 12.6 mt/Mb, p < 0.001. High TMB, defined as > 20 mt/Mb, was observed in 27/29 (93.1%) MSI-H pts. The frequency of representative gene mutations (%) for MSI-H vs. MSI-L/MSS pts were: TP53 17.2 vs. 66.1, p < 0.001; PIK3CA 48.3 vs. 13.2, p < 0.001; BRAF 34.5 vs. 7.5, p < 0.001; MSH2 17.2 vs. 0, p < 0.001; CTNNB1 17.2 vs. 0.6, p < 0.001; and ERBB2 10.3 vs. 1.4, p < 0.001. ERBB2 amplification was detected only in MSI-L/MSS pts (2.3%). Two-year survival rates from first-line systemic therapy in 695 pts with MSI-L/MSS, 9 pts with MSI-H treated with ICI in any-line, and 13 pts with MSI-H not treated with ICI, were 72.3, 74.1, and 47.0%, respectively.

Conclusions

MSI-H mCRC tumors were more frequent in right-sided colon primaries and with poorly differentiated histology. Median TMB was significantly greater in MSI-H pts, and a very high burden was frequently seen. Survival in MSI-H mCRC was poor before ICIs; these agents may improve outcomes for MSI-H pts.

Clinical trial identification

UMIN000020437.

Editorial acknowledgement

Legal entity responsible for the study

GI-SCREEN-Japan.

Funding

MSD.

Disclosure

W. Okamoto: Research grant / Funding (institution): MSD. Y. Nakamura: Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Taiho Pharmaceutical. Y. Komatsu: Speaker Bureau / Expert testimony, Research grant / Funding (self): Taiho Pharmaceutical; Speaker Bureau / Expert testimony, Research grant / Funding (self): Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (self): Chugai Pharma; Speaker Bureau / Expert testimony: Merck Serono; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Honoraria (self), Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Bayer; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono Pharmaceutical; Speaker Bureau / Expert testimony: Yakult Honsha; Speaker Bureau / Expert testimony, Research grant / Funding (self): Takeda; Speaker Bureau / Expert testimony, Research grant / Funding (self): Sanofi; Speaker Bureau / Expert testimony: Bristol-Myers Squibb Japan; Speaker Bureau / Expert testimony: Daiichi Sankyo; Speaker Bureau / Expert testimony: TOWA; Speaker Bureau / Expert testimony: Nipro Corporation; Research grant / Funding (self): MSD; Research grant / Funding (self): Astellas Pharma; Research grant / Funding (self): Sumitomo Dainippon Pharma; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Sysmex; Research grant / Funding (self): Yakult Pharmaceutical. T. Denda: Speaker Bureau / Expert testimony: Taiho Pharmaceutical; Speaker Bureau / Expert testimony: Yakult Honsha; Speaker Bureau / Expert testimony: Chugai Pharma; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): MSD. H. Hara: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self): Yakult Honsha; Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self), Research grant / Funding (institution): Takeda; Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Sumitomo Dainippon Pharma; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Bristol-Myers Squibb-Ono Pharmaceutical; Research grant / Funding (institution): BeiGene. Y. Narita: Speaker Bureau / Expert testimony: Chugai Pharma; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono Pharmaceutical; Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Taiho Pharmaceutical; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony, Research grant / Funding (self): Bristol-Myers Squibb. H. Kawakami: Honoraria (self), Advisory / Consultancy: Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb Japan; Honoraria (self), Advisory / Consultancy: Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy: Lilly Japan; Honoraria (self): Chugai/Roche; Honoraria (self): Yakult Pharmaceutical; Honoraria (self): Takeda; Honoraria (self): MSD K.K; Honoraria (self): Merck Serono; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo; Honoraria (self): Bayer; Honoraria (self): AstraZeneca; Research grant / Funding (institution): Chugai Pharma; Research grant / Funding (institution): Eisai. T. Esaki: Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb Japan; Honoraria (self): Eisai; Honoraria (self), Research grant / Funding (institution): Daiichi Sankyo; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self): Chugai Pharma; Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self): Takeda; Honoraria (self), Research grant / Funding (institution): Bayer; Honoraria (self): Sanofi; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Sumitomo Dainippon Pharma; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Nihonkayaku; Research grant / Funding (institution): Pfizer. T. Nishina: Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self): Lilly; Honoraria (self), Research grant / Funding (institution): Merck Serono; Honoraria (self): Takeda; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Nihonkayaku; Research grant / Funding (institution): Sumitomo Dainippon Pharma; Research grant / Funding (institution): Lilly Japan; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Ono Pharmaceutical. N. Izawa: Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: Sanofi; Advisory / Consultancy: MSD; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Bayer; Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck Serono. T. Moriwaki: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Taiho Pharmaceutical; Speaker Bureau / Expert testimony: Chugai Pharma; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Yakult Honsha; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Takeda; Speaker Bureau / Expert testimony: Novelpharm; Speaker Bureau / Expert testimony: Merck Serono; Speaker Bureau / Expert testimony: Sanofi; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Eisai. T. Kato: Honoraria (self), Research grant / Funding (self): Chugai Pharma; Honoraria (self): Takeda; Honoraria (self): Bayer; Honoraria (self): Lilly; Honoraria (self): Yakult Honsha; Honoraria (self): Sanofi. F. Nagashima: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Taiho Pharmaceutical; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Ono Pharmaceutical; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck Serono; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Takeda; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Chugai Pharma; Speaker Bureau / Expert testimony: Yakult Honsha; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sumitomo Dainippon Pharma; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Kyowa Hakko Kirin; Speaker Bureau / Expert testimony: Mitsubishi Tanabe Pharma; Speaker Bureau / Expert testimony: Nestle health science; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Janssen; Research grant / Funding (institution): OncoTherapy Science; Research grant / Funding (institution): Zeria Pharmaceutical; Research grant / Funding (institution): Lilly Japan; Research grant / Funding (institution): Yakult Pharmaceutical; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Shionogi; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): J-Pharma; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Mochida Pharmaceutical Co. Ltd.; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): NanoCarrier; Research grant / Funding (institution): Baxalta/Shire. T. Satoh: Honoraria (self), Advisory / Consultancy: Bayer Yakuhin; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Advisory / Consultancy: Takara Bio; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Honoraria (self), Advisory / Consultancy: Nihonkayaku; Advisory / Consultancy: Merck Serono; Honoraria (self), Research grant / Funding (institution): Chugai Pharma; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Takeda; Honoraria (self), Research grant / Funding (institution): Yakult Honsha; Honoraria (self), Research grant / Funding (institution): Merck; Honoraria (self): Astellas Pharma; Honoraria (self): Taiho Pharmaceutical; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): Sumitomo Dainippon Pharma. S. Nomura: Full / Part-time employment, An Immediate Family Member: Asahi Kasei; Honoraria (self): Taiho Pharmaceutical. T. Yoshino: Research grant / Funding (institution): Novartis Pharma; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Sumitomo Dainippon Pharma; Research grant / Funding (institution): Chugai Pharmaceutical; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Parexel International; Research grant / Funding (institution): Ono Pharmaceutical. K. Akagi: Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: MSD K.K; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: AstraZeneca Japan. All other authors have declared no conflicts of interest.