614P - Effect of KRASG12 mutations on overall survival in patients with refractory metastatic colorectal cancer: A post-hoc analysis of the phase III SUNLIGHT trial

Background

SUNLIGHT, a randomized phase 3 study comparing trifluridine/tipiracil (FTD/TPI) + bevacizumab (FTD/TPI + bev) vs FTD/TPI monotherapy in patients (pts) with metastatic colorectal cancer (mCRC), demonstrated a 3.3-month increase in overall survival (OS) from 7.5 months with FTD/TPI monotherapy to 10.8 months with FTD/TPI + bev (HR, 0.61; 95% CI, 0.49 – 0.77; P<0.001). Here reported are data on the effects of KRAS^G12 mutational status on OS.

Methods

A post-hoc analysis of the SUNLIGHT trial was conducted in pts with a KRAS^G12 mutation to assess the effect of the mutation on OS in the overall population treated with FTD/TPI monotherapy and FTD/TPI + bev. In addition, a subgroup analysis according to the KRAS^G12 mutational status was conducted to assess the treatment benefit associated with FTD/TPI + bev vs FTD/TPI monotherapy on OS.

Results

In the overall population, a similar OS trend was observed regardless of KRAS^G12 mutational status. In pts with a KRAS^G12 mutation, mOS was 8.34 months (95% CI: 7.49 – 9.59); whereas, in pts with no KRAS^G12 mutation, mOS was 9.17 months (95% CI: 8.15 – 10.94). A non-detrimental effect on OS was observed in pts with a KRAS^G12 mutation vs in pts with no KRAS^G12 mutation (HR, 1.09; 95% CI: 0.87 – 1.36) in the overall population treated with both FTD/TPI monotherapy and FTD/TPI + bev. Similar results were observed when the analysis was restricted to the RAS mutant subgroup. In the subgroup analysis, pts treated with FTD/TPI + bev were more likely to benefit with a higher OS than those treated with FTD/TPI monotherapy in each subgroup (KRAS^G12 mutated or not). In the KRAS^G12 mutant subgroup, mOS was 9.36 months (95% CI: 8.15 – 10.94) with FTD/TPI + bev vs 7.23 months (95% CI: 6.31 – 9.13) with FTD/TPI monotherapy (HR, 0.67; 95% CI: 0.48 – 0.93). In the subgroup with no KRAS^G12 mutation, mOS was 11.27 months (95% CI: 9.56 – 14.19) with FTD/TPI + bev vs 7.13 months (95% CI: 5.88 – 8.87) with FTD/TPI monotherapy (HR, 0.59; 95% CI: 0.43 – 0.81).

Conclusions

The presence of a KRAS^G12 mutation had no detrimental effect on OS, with a similar OS trend regardless of whether the pts had a KRAS^G12 mutation or not. The benefit of FTD/TPI + bev vs FTD/TPI on OS was confirmed independently of the KRAS^G12 mutational status.

Clinical trial identification

NCT04737187.

Editorial acknowledgement

Legal entity responsible for the study

Servier and Taiho Oncology, Inc.

Funding

Servier and Taiho Oncology, Inc.

Disclosure

J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics, TheraMyc, Hutchinson MediPharma International, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc, Scorpion Therapeutics, Tolremo Therapeutics; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex / HMP; Financial Interests, Personal, Invited Speaker, educacional collaboration: MJH Life Sciences; Financial Interests, Personal, Advisory Board: Cardiff Oncology; Financial Interests, Personal, Stocks/Shares: Oniria Therapeuics; Financial Interests, Institutional, Research Grant, ACRCelerate: Colorectal Cancer Stratified: Fundación Científica de la Asociación Española Contra el Cáncer; Financial Interests, Institutional, Research Grant, OPTIMISTICC: Opportunity to Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer: Cancer Research UK; Financial Interests, Institutional, Funding, Clinical Trials & Research: Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, Janssen-Cilag International NV, Merck Health KGAA, Merck, Sharp & Dohme de España, SA, Novartis Farmacéutica SA, PharmaMar SA, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA, Inc, BeiGene, Boehringer Ingelheim, HalioDX SAS, Hutchinson Medipharma, MedImmune, Menarini, Merus N V, Pfizer, Mirati; Non-Financial Interests, Member of Board of Directors, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer -AECC; Non-Financial Interests, , Member of Board of Directors, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, , Leadership Role, External Scientific Committee: Institute for Health Research INCLIVA – Clinical Hospital of Valencia, IdiSNA –Universidad de Navarra; Non-Financial Interests, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, Principal Investigator, Clinical Trials & Research: AstraZeneca Pharmaceutics LP, Array Biopharma Inc., BeiGene, Boehringer Ingelheim, Debiopharm International SA, Bristol Myers Squibb International Corporation, Celgene International SARL, F. Hoffmann-La Roche Ltd, Genentech Inc.; Non-Financial Interests, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer -EORTC; Non-Financial Interests, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Other, Coordinating PI & Steering Committee Member. Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutical LP, Boehringer Ingelheim; Non-Financial Interests, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc.; Non-Financial Interests: HalioDX SAS. G. Prager: Financial Interests, Personal, Advisory Board: Merck, Amgen, Servier, Bayer, Pierre Fabre, CECOG, Daiichi Sankyo Austria, AstraZeneca; Financial Interests, Personal, Invited Speaker: Roche, Sanofi, Lilly, Bristol Myers Squibb, MSD; Financial Interests, Institutional, Local PI: Incyte, Servier, Bristol Myers Squibb, Novartis. M. Fakih: Financial Interests, Personal, Advisory Role: Amgen, Taiho Pharmaceutical, Bayer, Pfizer, Seagen, GSK, Incyte, Nouscom, Roche/Genentech, Mirati Therapeutics, Bristol Myers Squibb, Eisai, Merck; Financial Interests, Personal, Speaker’s Bureau: Guardant Health; Financial Interests, Personal, Financially compensated role: Amgen; Financial Interests, Institutional, Funding: Amgen, Verastem. F. Ciardiello: Financial Interests, Personal, Advisory Board: Roche, Merck Serono, Servier, Pierre Fabre, Pfizer; Financial Interests, Institutional, Research Grant: Merck Serono, Roche, Amgen; Financial Interests, Institutional, Local PI: Pfizer, Pierre Fabre, Servier. 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. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board: Hoffman La - Roche, Servier, Amgen, Merck Serono, Sanofi, Bayer, Pierre Fabre, MSD; Financial Interests, Personal, Invited Speaker: Organon, Novartis; Financial Interests, Personal, Other, Educational training: Seagen International GmbH; Financial Interests, Institutional, Funding: Hoffmann-La Roche Ltd, Sanofi Aventis Recherche & Développement, Amgen Inc., Boehringer Ingelheim, Novartis Farmacéutica SA, Bristol Myers Squibb International Corporation, BeiGene, HalioDX SAS, Janssen-Cilag SA, Merck Health KGAA, Merck Sharp & Dohme de España SA, PharmaMar SA, Servier, Taiho Pharma USA Inc, Hutchison MediPharma International, Menarini, Merus NV, Pfizer, Mirati, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, Celgene International SARL, Debiopharm International SA, Genentech Inc, MedImmune; Non-Financial Interests, , Other, Coordinator of the SEOM +MIR Section of Residents and Young Assistants: Sociedad Española de Oncología Médica (SEOM); Non-Financial Interests, , Other, Speaker of the ESMO Academy: European Society for Medical Oncology (ESMO); Non-Financial Interests, Other, Volunteer member of the ASCO Annual Meeting Scientific Program Committee: Developmental Therapeutics – Immunotherapy: American Society of Clinical Oncology (ASCO); Other, Travel, accommodations, expenses.: Roche, Merck Serono, Sanofi, Amgen, Array BioPharma, Servier, Bristol Myers Squibb. F.J.S.M. Cruz: Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Janssen Oncology, Novartis. L.S. Wyrwicz: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Servier; Financial Interests, Personal and Institutional, Local PI: Bristol Myers Squibb, MSD, Servier, BeiGene, Roche, AstraZeneca; Financial Interests, Personal, Steering Committee Member: AstraZeneca. E. Martinelli: Financial Interests, Personal, Invited Speaker: Merck-Serono, Bayer, Merck S.p.a, ESMO; Financial Interests, Personal, Writing Engagement, Advisory board and invited speaker and travel grant: Pierre Fabre; Financial Interests, Personal, Writing Engagement, Advisory board and Invited speakers: Incyte; Financial Interests, Personal, Writing Engagement, Advisory board and invited speaker: Servier, Roche; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Writing Engagement, Travel grant: AstraZeneca; Financial Interests, Personal, Writing Engagement, Advisory board: MSD. L. Salvatore: Financial Interests, Personal, Speaker, Consultant, Advisor: Servier, MSD, AstraZeneca, Bayer, Merck, Amgen, Pierre Fabre, Takeda. P.G. Poureau: Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Servier, Ipsen; Financial Interests, Personal, Financially compensated role: Merck, Pierre Fabre, Ipsen; Financial Interests, Personal, Funding: Servier. G. Liposits: Financial Interests, Personal, Other, Received funding for working in an expert panel: Nutricia AS; Financial Interests, Personal, Invited Speaker, Workshop: Servier; Non-Financial Interests, Member: International Society of Geriatric Oncology (SIOG). C. Cremolini: Financial Interests, Personal, Advisory Board: Roche, MSD, Amgen, Pierre Fabre, Nordic Pharma; Financial Interests, Personal, Invited Speaker: Bayer, Servier, Merck Serono; Financial Interests, Institutional, Coordinating PI: Roche, Bayer, Servier, Merck. D.P. Modest: Financial Interests, Personal, Invited Speaker: Amgen, Servier, Merck, Onkowissen, MSD, Bristol Myers Squibb, AstraZeneca, PierreFabre, Lilly, Cureteq, GSK, Seagen, Medison, COR2ED, JE, 21up; Financial Interests, Personal, Advisory Board: Amgen, Servier, Merck, MSD, Bristol Myers Squibb, Incyte, Takeda, G1, Onkowissen, PierreFabre, AstraZeneca; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Coordinating PI: Servier. N. Causse-Amellal, L. Roby, D. Skanji: Financial Interests, Personal, Full or part-time Employment: Servier. J. Taieb: Financial Interests, Personal, Advisory Board: MSD, Astellas, Merck, Servier, Pierre Fabre, Amgen, Bristol Myers Squibb, Novartis, Pfizer; 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). All other authors have declared no conflicts of interest.