553O - Prognostic value of KRAS and BRAF mutations in microsatellite stable (MSS) and unstable (MSI) stage III colon cancer: An ACCENT/IDEA pooled analysis of 7 trials

Background

Whether KRAS and BRAFV600E mutations are prognostic in stage III CC remains controversial and has never been clearly analyzed in the subgroup of MSI-H patients (pts) due to sample size limitations. The prognostic value of individual KRAS mutations has also not been widely studied.

Methods

We studied the prognostic impact of individual KRAS exon 2 and BRAFV600E mutations in pts with surgically resected stage III CC who participated in 7 clinical trials from the ACCENT/IDEA databases. Associations between mutations and time to recurrence (TTR), overall survival (OS) and survival after recurrence (SAR) were assessed by Cox model, stratified by study and adjusted for sex, age, performance status, T and N stage, disease grade, and primary tumor location. The prognostic value of individual KRAS exon 2 submutations (G12A, G12C, G12D, G12R, G12S, G12V, G13D and others) was also analyzed.

Results

8286 pts were included, 11.6% were MSI-H (N=967) with 5 yr recurrence rates of 24.1% for MSI-H and 30.3% for MSS subgroups. BRAFV600E, KRAS exon 2 mutants or double wild type represented 40.6%, 18.1% and 41.3% of the MSI-H group and 7.8%, 38.6% and 53.7% of the MSS group, respectively. In the MSS group, 5y TTR rates of 61.7%, 66.4% and 73.2% emerged in pts with BRAFV600E , KRAS exon 2 mutants and in double wild-type pts, respectively, (adjHR: 1.34 and 1.32, both p<0.001), while in the MSI group shorter TTR in mutated subgroups was not seen with 5y TTR rates of 76.1%, 75.8% and 75.6%, respectively (adjHR: 1.01 and 0.98, both p>0.05). Similar results were found for OS. However, SAR was significantly shorter for pts with tumors harboring a KRAS exon 2 or BRAFV600E mutation in both MSS (adjHR: 1.16 and 2.05; both p<0.0001) and MSI (adjHR: 1.76 and 2.00; both p<0.05) pts. No major differences were noted in the prognostic value of KRAS exon 2 submutations.

Conclusions

In the largest analysis of the association of KRAS exon 2 and BRAFV600E mutations and disease outcome in resected stage III CC, either mutation was associated with significantly shorter DFS, OS and SAR in MSS tumors, but only with shorter SAR in MSI-H tumors. In addition, all KRAS codon 12 and 13 mutations had similar prognostic value.

Clinical trial identification

IDEA France: NCT00958737 PMID: 29620995 C07: NCT00004931 PMID: 17470851 C89803: PMID: 17687149 PETACC3: PMID: 19451425 C08: PMID: 20940184 PETACC8: EudraCT 2005-003463-23 PMID: 24928083 N0147: NCT00079274 PMID: 22474202

Editorial acknowledgement

Legal entity responsible for the study

ACCENT group.

Funding

Has not received any funding.

Disclosure

J. Taieb: Financial Interests, Personal, Advisory Board: MSD, Merck, Servier, Pierre Fabre, Amgen, Bristol Myers Squibb, Novartis, Pfizer; Financial Interests, Personal, Expert Testimony: Astellas; Financial Interests, Personal, Invited Speaker: Amgen, Bristol Myers Squibb, Merck, MSD, Novartis; Non-Financial Interests, , Leadership Role, President of the scientific committee of the ARCAD foundation until end 2022: ARCAD Foundation; Non-Financial Interests, Leadership Role, Chair of the ARCAD pancreas research group: ARCAD Foundation; Non-Financial Interests, Leadership Role, Member of the administrative council, the scientific committee, the executive board and responsible for the international relationships /partnership for FFCD in the prodige intergroup: Federation Francophone de Cancerologie Digestive (FFCD). F.A. Sinicrope: Financial Interests, Personal, Advisory Board: Roche, Eisai, Guardant Health; Financial Interests, Institutional, Royalties: Roche/Ventana Medical Systems. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi Sankyo, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Pierre Fabre, GSK, Roche, Astellas; Financial Interests, Institutional, Invited Speaker: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb. T. George: Financial Interests, Personal, Advisory Board: Pfizer Oncology, Tempus Labs; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb, AZ, Lilly, Bayer, Incyte, Ipsen, Seagen, Genentech, Astellas, GSK, BioMed Valley Discoveries, Amgen, OncoC4, Jounce. R. Goldberg: Financial Interests, Personal, Other, DMC: AstraZeneca, Bayer, Inspirna, Sorrento; Financial Interests, Personal, Advisory Board, New drug development advice: Compass Therapeutics; Financial Interests, Personal, Other, New drug development advice: AbbVie; Financial Interests, Personal, Expert Testimony, expert witness in patent law trial: Taiho; Financial Interests, Personal, Advisory Board, Device development advice: Focal Medical; Financial Interests, Personal, Other, DMS: IQVIA; Financial Interests, Personal, Other, Drug development advice: Eisai, Innovative Cellular Therapeutics, Merck, Modulation Therapeutics, Takeda; Financial Interests, Personal, Advisory Board, drug development advice: GSK; Financial Interests, Personal, Advisory Board, genetic testing advice: Haystack Oncology; Financial Interests, Personal, Other, DMC and drug development advice: G1 Therapeutics; Financial Interests, Personal, Stocks/Shares, stock options: Compass Therapeutics, Focus Medical, Haystack Oncology; Non-Financial Interests, Other, Board member of an advocacy group: Fight Colorectal Cancer; Non-Financial Interests, , Leadership Role, Associate Group Chair, NCI funded cooperative oncology group: Alliance for Clinical Trials in Oncology. T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bayer Yakuhin, Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K., Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Other, Consultancy: Sumitomo Corp.; Financial Interests, Institutional, Invited Speaker: Ono Pharmaceutical Co., Ltd, Sanofi K.K., Daiichi Sankyo Co., Ltd., MSD K.K., Pfizer Japan Inc., Eisai Co., Ltd.; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical Co., Ltd., Molecular Health GmbH, Ono Pharmaceutical Co., Ltd., Amgen K.K., Genomedia Inc., Sysmex Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Roche Diagnostics K.K.; Financial Interests, Personal, Research Grant: FALCO Biosystems Ltd.. E. Van Cutsem: Financial Interests, Personal, Advisory Board: AbbVie, ALX, Amgen, Array, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, Zymeworks; Financial Interests, Institutional, Research Grant: Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. T. André: Financial Interests, Personal, Advisory Board, Advosiry Board on February 12, 2021: Astellas pharma; Financial Interests, Personal, Advisory Board, Advisory Board on February 2021: Kaleido Biosciences; Financial Interests, Personal, Invited Speaker, and advisory board 2021: Amgen; Financial Interests, Personal, Invited Speaker, Invited speaker in a symposuim december 2020: AstraZeneca; Financial Interests, Personal, Advisory Board, and consultant fees and consultant contract 2021 and 2022: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Advisory board in Janaury 2020 : Clovis; Financial Interests, Personal, Advisory Board, Advisory board in January 2020: Gritstone Oncology; Financial Interests, Personal, Advisory Board, Advisory board 2020: Haliodx; Financial Interests, Personal, Advisory Board, and consultant fees/consultant contract and invited speaker: MSD Oncology; Financial Interests, Personal, Invited Speaker, and other: Pierre Fabre; Financial Interests, Personal, Invited Speaker, in an symposuim in 2020: Roche; Financial Interests, Personal, Invited Speaker, in a meeting in 2019: Ventana; Financial Interests, Personal, Invited Speaker, In a educational meeting in 2019: Sanofi; Financial Interests, Personal, Advisory Board, in a symposuim in 2020: Servier; Financial Interests, Personal, Expert Testimony, Consultant with personnal fees and invited speaker: Servier; Financial Interests, Personal, Advisory Board, in 2019: GSK; Financial Interests, Personal, Invited Speaker, in 2020 and 2021: GSK; Financial Interests, Personal, Invited Speaker, Virtual symposuimLecture: 1 MSI-H CRC: Implementation of Immunotherapy in clinical practice (30 minutes) – (this will be pre-recorded)Q&A – Live Q&A – (10 minutes) (on July 2, 2021): MSD Oncology; Financial Interests, Personal, Invited Speaker, June 2022 : Sanofi; Financial Interests, Personal, Advisory Board, Contract 2021, 2022, 2023 : Merck & Co., Inc; Financial Interests, Personal, Advisory Board, Contrat 2019, 2020, 2021, 2022 : Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Contract 2021 : Gritstone Oncologie; Financial Interests, Personal, Invited Speaker, June 2022 and June 2023 during ESMO GI meeting: Seagen; Financial Interests, Personal, Invited Speaker, Contract of consulting 2021 and 2022 and 2023: MSD Oncology; Financial Interests, Personal, Advisory Board, September 2022: GSK, Seagen; Financial Interests, Personal, Invited Speaker, Contract of consulting 2022 and 2023: GSK; Financial Interests, Personal, Invited Speaker, Contract of consulting 2022: Nordic Pharma; Financial Interests, Personal, Invited Speaker, October 2022: Merck Serono; Financial Interests, Personal, Other, Educational in 2022: Roche; Financial Interests, Personal, Other, Contract of consulting 2020, 2021, 2022,2023: Servier; Financial Interests, Personal, Advisory Board, 2023 : Aptide Health, Glilead; Financial Interests, Institutional, Other, Investigator and scientific committee president: Gercor Academic group; Financial Interests, Institutional, Invited Speaker, PI Garnet study: GSK; Financial Interests, Institutional, Invited Speaker, Keynote 164 and 171 and 811 and C08: MSD; Financial Interests, Institutional, Invited Speaker, Bristol Myers Squibb CA209-8HW, Bristol Myers Squibb CA209-142, Bristol Myers Squibb CA209-577: Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker, SPOTLIGHT study: Astellas; Financial Interests, Personal, Invited Speaker, and international PI (trial chair Solstice study): Servier; Financial Interests, Personal, Invited Speaker, MOUNTAINEER and MOUNTAINEER-03 study (PI for France) 2022, 2023: Seagen; Non-Financial Interests, Invited Speaker, Investigator: Gercor group; Non-Financial Interests, Invited Speaker, President since October 2022: ARCAD Foundation . P. Laurent-Puig: Financial Interests, Personal, Invited Speaker: Amgen, Roche, Sanofi; Financial Interests, Personal, Advisory Board: Biocartis, Pierre Fabre; Financial Interests, Personal, Ownership Interest: Methys DX; Financial Interests, Institutional, Research Grant: Federation Francophone de Cancerologie Digestive; Non-Financial Interests, Leadership Role: President of Canceropole Ile de France. Q. Shi: Financial Interests, Personal, Advisory Board: Regeneron Pharmaceuticals, Inc., Kronos Bio; Financial Interests, Personal, Advisory Board, DSMB: Hoosier Cancer Research Network, Yiviva Inc., Mirati Therapeutics Inc; Financial Interests, Institutional, Research Grant: Genentech, Bristol Myers Squibb, Novartis, Johnson & Johnson. All other authors have declared no conflicts of interest.