Background

Based on the Ph 3 BEACON study (NCT02928224), BRAF inhibitor (i) encorafenib (E) + EGFRi cetuximab (C) was approved for treatment (tx) of previously treated patients (pts) with BRAF ^V600E mCRC, with mPFS of 4.3 months (mo) and ORR of 19.5%. In the Ph 2 ANCHOR study (NCT03693170), mPFS was 5.8 mo and ORR was 48% with 1L EC + binimetinib in BRAF ^V600E mCRC. To further assess 1L approaches, the ongoing Ph 3 BREAKWATER study (NCT04607421) is evaluating EC ± chemo vs standard-of-care chemo in BRAF ^V600E mCRC. We present updated safety and PK data, and new antitumor activity data from BREAKWATER SLI.

Methods

Inclusion criteria for the SLI were BRAF ^V600E mCRC (blood or tumor tissue), ≤1 prior systemic tx for mCRC, and ECOG PS 0/1. Pts previously treated with BRAFi/EGFRi or both oxaliplatin and irinotecan were excluded. Pts received E 300 mg daily + C 500 mg/m² every 2 weeks (Q2W) + either mFOLFOX6 Q2W (n=27) or FOLFIRI Q2W (n=30) in 28-day cycles until disease progression or unacceptable toxicity. Primary endpoint was frequency of dose-limiting toxicities (DLTs). Secondary endpoints included safety, PK, and antitumor activity.

Results

In this updated analysis (May 16, 2022 cutoff), SAEs occurred in 48.1% and 33.3%, and tx-related SAEs (any drug) in 25.9% and 13.3% of pts, in EC + mFOLFOX6 and EC + FOLFIRI, respectively. One DLT (grade ≥3 neutropenia) was seen in EC + FOLFIRI. In EC + FOLFIRI, in the presence of steady-state E, AUC_last of irinotecan and its active metabolite, SN-38, decreased by 24.9% and 26.8%, respectively, consistent with a predicted CYP3A-mediated drug interaction. In EC + mFOLFOX6, in the presence of steady state E, AUC_last of platinum in plasma and plasma ultrafiltrate, increased by 15% and 6%, respectively. Antitumor activity data are in the table.

Conclusions

EC + chemo was generally tolerable. Preliminary promising antitumor activity was seen in 1L and 2L BRAF ^V600E mCRC, supporting the ongoing study. Table: LBA26

Clinical trial identification

NCT04607421.

Editorial acknowledgement

Medical writing support was provided by Asu Erden, PhD, of Health Interactions, Nucleus Global, and was funded by Pfizer.

Legal entity responsible for the study

The BREAKWATER trial is sponsored by Pfizer in collaboration with Merck KGaA, Ono Pharmaceutical, and Eli Lilly and Company.

Funding

Pfizer.

Disclosure

J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daichii 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, Avvinity, Scandion Oncology, Ona Therapeutics, Sotio Biotech, Inspirna Inc; Financial Interests, Personal, Invited Speaker, educational collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex; Financial Interests, Personal, Invited Speaker, educacional collaboration: MJH Life Sciences; 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, Invited Speaker, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer -AECC; Non-Financial Interests, Invited Speaker, 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, 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, Principal Investigator, Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutics LP, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS; Non-Financial Interests, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., Hutchinson Medipharma, HalioDX SAS; Non-Financial Interests: Hutchinson Medipharma. T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai, Merck Biopharma, Bayer, Ono, MSD; Financial Interests, Institutional, Invited Speaker: Ono, Sanofi, Daiichi Sankyo, Chugai, Pfizer; Financial Interests, Institutional, Research Grant: Taiho, MSD, Ono, Amgen, Genomedia, Sysmex, Daiichi Sankyo, Chugai, Boehringer Ingelheim. T.W. Kim: Financial Interests, Institutional, Research Grant: AstraZeneca, SanofiAventis. R. Yaeger: Financial Interests, Personal, Advisory Board, Consulting or Advisory Role: Array BioPharma, Mirati Therapeutics, Natera; Financial Interests, Institutional, Funding, Research Funding: Array BioPharma, Boehringer Ingelheim, Mirati Therapeutics, Pfizer. J. Desai: Financial Interests, Institutional, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Bayer, BeiGene, Daiichi Sankyo, Eisai, GlaxoSmithKline, Merck KGaA, Pierre Fabre; Financial Interests, Institutional, Funding, Research Funding: AstraZeneca/MedImmune, BeiGene, Bionomics, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Novartis, Roche. H.S. Wasan: Financial Interests, Personal, Advisory Board, Advisory Boards and Invited Speaker: Incyte, Pierre Fabre, Servier, Bayer, Roche/Genentech/ FM AG, SIRTEX medical ERYTECH, Celgene, Array BioPharma, Merck KGaA: BMS; Financial Interests, Personal, Invited Speaker, Trial steering committee and advisory: Zymeworks; Financial Interests, Personal and Institutional, Invited Speaker, Trial PI steering committee and advisory: Sirtex Medical; Financial Interests, Personal, Other, Consultancy for Submission for UK approval (BSI): ONCOSL; Non-Financial Interests, Advisory Role, Trial steering committee: Pfizer; Non-Financial Interests, Advisory Role, UK NICE submission: Bayer, Pierre Fabre. E. Van Cutsem: Financial Interests, Personal, Advisory Board, Advisory board and/or Speaking: AbbVie, Array, Astellas, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi, Halozyme, GSK, Helsinn, Incyte, Ipsen, Janssen Research, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Pierre Fabr; Financial Interests, Institutional, Funding, research grant paid to institution: Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. 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, Invited Speaker: Pfizer, Pierre Fabre, Servier. T. Maughan: Financial Interests, Personal, Advisory Role: Pierre Fabre, Vertex, AstraZeneca; Financial Interests, Institutional, Funding, Research Funding: Almac Diagnostics, AstraZeneca, Merck KgAA, PsiOxus Therapeutics . C. Eng: Financial Interests, Personal, Other, Consulting: Bayer, Boston Scientific, GSK, Halio Dx, Merck, Mirati, Hookipa, J&J, Merck, Natera, Roche, Seagen, Taiho, Veloxis; Financial Interests, Personal, Funding, Research Funding: VUMC, Elevar, Hutchinson, Merck, Pfizer. J. Tie: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Pierre Fabre, Inivata; Financial Interests, Personal, Invited Speaker: Servier, Merck Serono; Financial Interests, Personal, Other, Consultancy: Haystack Oncology. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board: Hoffman La - Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array Biopharma, Sanofi, Bayer; Financial Interests, Institutional, Research Grant: Hoffman La-Roche, Sanofi Aventis, Amgen, Merck Serono, MSD, Boehringer Ingelheim, AbbVie, Pierre-Fabre, Novartis, Bristol-Myers Squibb, GlaxoSmithKline, Medimmune, Array Pharmaceuticals, AstraZeneca. 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, GlaxoSmithKline; Financial Interests, Institutional, Invited Speaker: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol Myers Squibb. X. Zhang: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Personal, Royalties: Johns Hopkins University. R. Chavira: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. T. Usari: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer, Viatris. E. Hahn: Financial Interests, Personal, Full or part-time Employment: Pfizer. S. Kopetz: Financial Interests, Personal, Advisory Board: Roche, EMD Serono, Merck, Novartis, Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca, Bayer, Pierre Fabre, Redx Pharma, Ipsen, Daiichi, Natera, HalioDx, Jacobio, Pfizer, Repare Therapeutics, GlaxoSmithKline, Jazz, Xilis, AbbVie, Gilead, Mirati, Flame, Servier, Carina, Bicara, Endeavor BioMedicines, Numab Pharma, Janssen; Financial Interests, Personal, Other, Research: Inivata; Financial Interests, Personal, Stocks/Shares: Lutris, Iylon, Navire, Xilis.

Background

HER2 amplification/overexpression (HER2+) occurs in ∼3-5% of patients (pts) with metastatic colorectal cancer (mCRC). The primary analysis of MOUNTAINEER (NCT03043313) in cohorts A+B treated with tucatinib (TUC) + trastuzumab (Tras) was previously reported and showed tolerability and a confirmed objective response rate (cORR) per blinded independent central review (BICR) of 38.1%. Here, additional results of TUC monotherapy (cohort C) are reported.

Methods

have been reported in a prior presentation (Strickler et al. ESMO-WCGI 2022 abstract no. LBA-2). Eligible pts had HER2+ (per local IHC, ISH, or NGS testing) RAS WT mCRC refractory to standard of care. Pts who initially received TUC monotherapy could cross over and receive TUC + Tras for radiographic progression or stable disease by 12 weeks. Prespecified analyses for cohort C include ORR by 12 weeks and disease control rate (DCR) by BICR; cORR by BICR for crossover pts, and safety for monotherapy and crossover pts.

Results

As of 28 Mar 2022, 86 pts received ≥1 dose of study treatment in cohorts A+B and 30 pts in cohort C. The ORR by week 12 in cohort C was 3.3% (95% CI, 0.1, 17.2) with DCR of 80.0%. Twenty-eight of 30 pts (93.0%) crossed over to received TUC + Tras, with cORR of 17.9% (95% CI, 6.1, 36.9). The most common AEs with TUC monotherapy were diarrhoea (33.3%), abdominal pain (20.0%), and fatigue (20.0%), which were grade (gr) 1 or 2; the most common gr ≥3 events were ALT/AST increase (6.7% for both). The most common AE for post-crossover pts was diarrhoea (35.7%) which was gr 1 or 2; the most common gr ≥3 events were ALT/AST increase (7.1% and 10.7%, respectively). There were no fatal AEs with TUC monotherapy or TUC + Tras.

Conclusions

TUC monotherapy and TUC + Tras after crossover were well tolerated, consistent with the primary analysis. Disease stabilization was observed in most pts on TUC monotherapy; radiographic responses increased slightly after Tras addition. Monotherapy, crossover, and response data from the primary analysis show that concurrent initiation of dual HER2 blockade with TUC + Tras achieves optimal clinical benefit.

Clinical trial identification

NCT03043313.

Editorial acknowledgement

Under guidance of the authors, assistance in medical writing was provided by Irene Park, PhD, of Seagen Inc. and was funded by Seagen Inc. in accordance with Good Publication Practice (GPP3) guidelines.

Legal entity responsible for the study

Seagen Inc.

Funding

This study was sponsored by Seagen Inc., Bothell WA, USA. in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.

Disclosure

J.H. Strickler: Financial Interests, Personal, Advisory Board: SeaGen, AstraZenca, Amgen, Pfizer, Bayer, AbbVie, Natera, Viatris, Inivata, Silverback Therapeutics; Financial Interests, Personal, Other, Consulting: Mereo, GSK, Pionyr Immunotherapeutics; Financial Interests, Institutional, Invited Speaker: SeaGen, Roche Genentech, AbbVie, AstraZeneca, Amgen, AStar D3, Sanofi, Curegenix, Nektar, Leap Therapeutics, Daiichi Sankyo, Erasca, Gossamer Bio, Silverback Therapeutics. A. Cercek: Financial Interests, Personal, Other, Consulting: Array Biopharma, Bayer, Proteus; Financial Interests, Institutional, Research Grant: AbbVie, Rgenix, Seagen Inc., Tesaro. S. Siena: Financial Interests, Personal, Other, Consulting: Amgen, Bayer, Bristol-Myers Squibb, CheckmAb, Clovis Oncology, Daiichi Sankyo, Incyte, Merck, Novartis, Seagen Inc., Roche/Genentech; Financial Interests, Personal, Ownership Interest, Equity ownership: Guardant, Myriad; Financial Interests, Personal, Royalties: Amgen; Financial Interests, Institutional, Research Grant: MSD Oncology; Financial Interests, Personal, Other, Travel expenses: Amgen, Bayer, Roche. 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: Amgen; Financial Interests, Personal, Invited Speaker, Ivited speaker in a symposuim december 2020: AstraZeneca; Financial Interests, Personal, Advisory Board, and consultant fees and consultant contract: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board, Advisory board in January 2020: Clovis; Financial Interests, Personal, Advisory Board, Advisory board in january 2020: Gritstone Oncology; Financial Interests, Personal, Advisory Board: 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, Expert Testimony, consultant contract: Seagen; 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, Expert Testimony, Contract: Merck & Co., Inc, Gritstone Oncologie; Financial Interests, Personal, Advisory Board, Contrat: BMS; Financial Interests, Institutional, Other, Investigator and scientific comitee president: Gercor Academic group; Financial Interests, Institutional, Invited Speaker, PI Garnet study: GSK; Financial Interests, Institutional, Invited Speaker, Keynote 164 and 171 and 811: MSD; Financial Interests, Institutional, Invited Speaker, BMS CA209-8HW, BMS CA209-142, BMS CA209-577: BMS; Financial Interests, Institutional, Invited Speaker, SPOTLIGHT study: Astellas; Financial Interests, Personal, Invited Speaker, and internationnal PI: Servier; Non-Financial Interests, Invited Speaker, Vice President: Gercor group; Non-Financial Interests, Invited Speaker, Member of scientific commitee: ARCADFoundation. K. Ng: Financial Interests, Personal, Other, Consulting: Bayer, Genentech/Roche, Lilly, Seagen Inc., Tarrex Biopharma, X-Biotix Therapeutics; Financial Interests, Institutional, Research Grant: Celgene, Genentech/Roche, Gilead, Pharmavite, Revolution Medicines, Trovagene. E. Van Cutsem: Financial Interests, Personal, Advisory Board: AbbVie, Astellas, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Halozyme, GSK, Helsinn, Incyte, Ipsen, Janssen Research, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Pierre Fabre, Roche, Seagen Inc., Servier, Sirtex, Terumo, Taiho, TRIGR, Zymeworks; Financial Interests, Institutional, Research Grant: Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Seagen Inc., Servier. C. Wu: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Array Biopharma, Pfizer; Financial Interests, Personal, Invited Speaker: PrecisCA; Financial Interests, Institutional, Invited Speaker, PI for investigator initiated clinical trial: Vaccinex; Financial Interests, Institutional, Invited Speaker, local PI for phase 3 clinical trial: Boston Biomedical Inc; Financial Interests, Institutional, Invited Speaker: Lycera, Seagen, Symphogen, Rapt Therapeutics, INBRX; Non-Financial Interests, Advisory Role, Safety monitoring committee: Seagen. A.S. Paulson: Financial Interests, Personal, Invited Speaker, Medical education, non-branded, industry sponsored: Ideo Oncology; Financial Interests, Personal, Advisory Board: Amgen, BMS, Eisai, Ipsen, Incyte, Exelixis, AAA, Pfizer, QED, Lilly, Mirati, Hutchinson, Astellas; Financial Interests, Personal, Stocks/Shares: alexion, Actinium, Aptose; Financial Interests, Invited Speaker: Ipsen, Hutchinson, BMS, Exelixis, hutchinson med, Taiho, Lilly, AstraZeneca, Incyte, Seattle Genetics, Deciphera, Tempus, Zentalis, G1 therapeutics, Merck, Camurus, Novartis, Surface, Relay Therapeutics; Financial Interests, Institutional, Invited Speaker: Mirati, Bayer. J. Hubbard: Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Institutional, Advisory Board: Incyte, Bayer, BeiGene; Financial Interests, Institutional, Invited Speaker: Boston Biomedical, Senhwa Biosciences, Bayer, Merck, Taiho Pharmaceutical, TreoBio, Hutchison MediPharma, Seattle Genetics, Tovogene, TriOncology, Incyte, Pionyr, G1 Therapeutics, eFFECTOR Therapeutics, Roche. A. Coveler: Financial Interests, Institutional, Invited Speaker: Seagen, AbGenomics, Novocure, Amgen, Actuate Therapeutics, Surface Oncology, Nucana, Nextrast. C. Fountzilas: Financial Interests, Institutional, Research Grant: Pfizer Inc, Taiho Oncology, Merck Sharp & Dohme Corp., National Comprehensive Cancer Network; Financial Interests, Institutional, Invited Speaker: Seattle Genetics, Inc., TransThera Biosciences, AstraZeneca, Aravive, Inc., Merck Sharp & Dohme Corp., Puma Biotechnology, Kadmon, Astellas Pharma, Pfizer Inc, Dragonfly Therapeutics, MedImmune, LLC., Hoosier Cancer Research Network, Incyte Corporation, Rafael Pharmaceuticals, Kinex Phamaceuticals, Syndax Pharmaceuticals, SWOG, National Cancer Institute, Erythech Pharma, Lilly, Corcept Therapeutics, Ipsen. A. Kardosh: Financial Interests, Personal, Advisory Board: Exelixus; Financial Interests, Personal, Full or part-time Employment: OHSU. P.M. Kasi: Financial Interests, Personal, Advisory Board, Consultancy/Advisory Board: Foundation Medicine, Natera Oncology, AstraZeneca, Merck MSD, Tempus, Bayer, Lilly, Delicath Systems, QED Therapeutics, Servier, Taiho Oncology, Exact Sciences, Eisai; Financial Interests, Institutional, Advisory Board, Consultancy/Advisory Board: Taiho, Ipsen; Financial Interests, Institutional, Funding, Investigator initiated trial cooperative group PI trial support and funding: Tersera; Financial Interests, Institutional, Funding, Investigator initiated trial trial support and funding: Boston Scientific. H.J. Lenz: Financial Interests, Personal, Advisory Board, Advisory Role and Lectures: Bayer; Financial Interests, Personal, Advisory Board, Advisory ROle and Lectures: Merck; Financial Interests, Personal, Advisory Board, Advisory Role and lecture: ROche; Financial Interests, Personal, Advisory Board: Jazz Pharmaceuticals, oncocyte, Orion, Astellas, BMS; Financial Interests, Personal, Advisory Board, Scientific Advisory Board: 3T Biosscience; Financial Interests, Personal, Advisory Board, Advisory Board: Fulgent. K.K. Ciombor: Financial Interests, Personal, Advisory Board: Pfizer, Merck, Lilly/Loxo, Replimune, Personalis; Financial Interests, Personal, Invited Speaker: Seagen; Financial Interests, Institutional, Invited Speaker: Genentech, Merck, Incyte, Seagen, BMS, Nucana, Daiichi Sankyo, Calithera, Array. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board: Hoffman La - Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array Biopharma, Sanofi, Bayer; Financial Interests, Institutional, Research Grant: Hoffman La-Roche, Sanofi Aventis, Amgen, Merck Serono, MSD, Boehringer Ingelheim, AbbVie, Pierre-Fabre, Novartis, Bristol-Myers Squibb, GlaxoSmithKline, Medimmune, Array Pharmaceuticals, AstraZeneca. D.L. Bajor: Financial Interests, Personal, Other, Consulting: Avoro Capital, BridgeBio Pharma, Cardinal Health, Tempus; Financial Interests, Institutional, Research Grant: Apixigen, Bristol-Myers Squibb/Celgene, Calithera Biosciences, GlaxoSmithKline, Rafael Pharma, Seagen Inc., Tesaro. M. Stecher: Financial Interests, Personal, Full or part-time Employment: Seagen Inc.; Financial Interests, Personal, Stocks/Shares: Seagen Inc. W. Feng: Financial Interests, Personal, Full or part-time Employment: Seagen Inc.; Financial Interests, Personal, Stocks/Shares: Seagen Inc. T. Bekaii-Saab: Financial Interests, Institutional, Research Grant: Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Lilly, Ipsen, Clovis, Seagen Inc., Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, BMS; Financial Interests, Personal, Royalties: Uptodate; Financial Interests, Personal, Other, WO/2018/183488: Human PD1 peptide vaccines and uses thereof – Licensed to Imugene: Imugene; Financial Interests, Personal, Other, WO/2019/055687: Methods and compositions for the treatment of cancer cachexia – Licensed to Recursion: Recursion; Financial Interests, Institutional, Other, Consulting: Ipsen, Arcus, Pfizer, Seagen Inc., Bayer, Genentech, Incyte, Eisai, Merck; Financial Interests, Personal, Other, Consulting: Stemline, AbbVie, Boehringer Ingelheim, Janssen, Daiichi Sankyo, Natera, TreosBio, Celularity, Exact Science, Sobi, Beigene, Kanaph, AstraZeneca, Deciphera, MJH Life Sciences, Aptitude Health, Illumina, Foundation Medicine; Non-Financial Interests, Personal, Advisory Role, IDMC/DSMB: Fibrogen, Suzhou Kintor, AstraZeneca, Exelixis, Merck, Eisai, PanCan; Financial Interests, Personal, Advisory Board: 1Globe, Imugene, Immuneering, Xilis, Replimune Artiva, Sun Biopharma.

Background

Some studies suggest that older patients have reduced or no benefit from the addition of oxaliplatin to fluoropyrimidines as adjuvant chemotherapy for stage III colon cancer (CC).

Methods

We studied the prognostic impact of age and treatment adherence/toxicity patterns according to age in patients with stage III CC who participated in 12 clinical trials from the ACCENT and IDEA databases and received 3 or 6 months (mo) of FOLFOX/CAPOX. Associations between age and time to recurrence (TTR), disease-free survival (DFS), overall survival (OS), survival after recurrence (SAR) and cancer-specific survival (CSS) were assessed by Cox model or a competing risk model, stratified by studies and adjusted for gender, performance status, T and N stage, and year of enrollment.

Results

17,608 patients were included. The age of 24% of patients was > 70 (N=4,278). Patients >70 were more often included in newer trials (29% in the period 2010-2015 vs 17% for 1998-2003, p<0.0001) and had higher rates of early treatment discontinuation (ETD). The rates of grade ≥3 adverse events were similar between the 2 groups, except for diarrhea for 6-mo CAPOX (18% vs 14%, p=0.03) and neutropenia for 3-mo FOLFOX (24% vs 18%, p=0.08) for patients < and >70 respectively). Comparing patients <70 and >70, TTR, DFS, OS, SAR and CSS were significantly shorter (except for TTR in patients treated with 6-mo regimens) although absolute differences were small (Table1).

Conclusions

In patients >70 with stage III CC enrolled in clinical trials, oxaliplatin-based adjuvant chemotherapy was well tolerated. Outcomes were inferior to those of patients under 70, but still provided clinically relevant benefit. Increased deaths from other causes and less intensive management at relapse may account for some of the differences in OS. Table: 317MO

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

C. Gallois: Financial Interests, Institutional, Invited Speaker: Sanofi Genzyme; Financial Interests, Institutional, Advisory Board: Servier. Q. Shi: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim Pharmaceuticals, Inc, Regeneron Pharmaceuticals, Inc.; Financial Interests, Institutional, Research Grant: Genetech, BMS, Novartis, Johnson & Johnson. T. André: Financial Interests, Personal, Advisory Board, Advisory 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: Amgen; Financial Interests, Personal, Invited Speaker, Invited speaker in a symposium December 2020: AstraZeneca; Financial Interests, Personal, Advisory Board, and consultant fees and consultant contract: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board, Advisory board in January 2020: Clovis; Financial Interests, Personal, Advisory Board, Advisory board in January 2020: Gritstone Oncology; Financial Interests, Personal, Advisory Board: 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 symposium in 2020: Roche; Financial Interests, Personal, Invited Speaker, in an meeting in 2019: Ventana; Financial Interests, Personal, Invited Speaker, In an educational meeting in 2019: Sanofi; Financial Interests, Personal, Advisory Board, in a symposium in 2020: Servier; Financial Interests, Personal, Expert Testimony, Consultant with personal 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, Expert Testimony, consultant contract: Seagen; Financial Interests, Personal, Invited Speaker, Virtual symposium Lecture: 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, Expert Testimony, Contract: Merck & Co., Inc, Gritstone Oncologie; Financial Interests, Personal, Advisory Board, Contrat: BMS; 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: MSD; Financial Interests, Institutional, Invited Speaker, BMS CA209-8HW, BMS CA209-142, BMS CA209-577: BMS; Financial Interests, Institutional, Invited Speaker, SPOTLIGHT study: Astellas; Financial Interests, Personal, Invited Speaker, and international PI: Servier; Non-Financial Interests, Invited Speaker, Vice President: Gercor group; Non-Financial Interests, Invited Speaker, Member of Scientific Sommittee: ARCADFoundation. A.F. Sobrero: Financial Interests, Personal, Advisory Board: Servier, BMS, MSD, Incyte; Financial Interests, Personal, Invited Speaker: Bayer, Pierre Fabre, Merck, Amgen, Sanofi; Financial Interests, Personal, Stocks/Shares: Bayer. S. Lonardi: Financial Interests, Personal, Advisory Board: Amgen, Merck Merono, Lilly, Servier, AstraZeneca, MSD, Incyte, Daiichi Sankyo, Bristol-Myers Squibb; Financial Interests, Personal, Invited Speaker: Pierre-Fabre, GlaxoSmithKline; Financial Interests, Institutional, Invited Speaker: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol-Myers Squibb. G. Yothers: Financial Interests, Personal, Other, Data monitoring Committee member for the agent Elflornithine: Orbus Theraputics, Inc.; Financial Interests, Institutional, Other, Deputy Group Statistician: NRG Oncology Foundation; Financial Interests, Personal, Other, Group Statistician: NSABP Foundation; Non-Financial Interests, Other, Executive Committee Member: Olympia Trial; Non-Financial Interests, Other, GI Cancer Steering Committee Member: NCI Cancer Therapy Evaluation Program (CTEP); Non-Financial Interests, Member: ASCO. T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai, Merck Biopharma, Bayer, Ono, MSD; Financial Interests, Institutional, Invited Speaker: Ono, Sanofi, Daiichi Sankyo, Chugai, Pfizer; Financial Interests, Institutional, Research Grant: Taiho, MSD, Ono, Amgen, Genomedia, Sysmex, Daiichi Sankyo, Chugai, Boehringer Ingelheim. J. Taieb: Financial Interests, Personal, Advisory Board: MSD, Roche, Merck, Servier, Pierre Fabre, Amgen, BMS, Novartis; Financial Interests, Personal, Invited Speaker: Amgen, BMS, Merck, MSD, Novartis, Pierre Fabre, Roche, Servier; 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). D. Papamichael: Financial Interests, Institutional, Advisory Board, Ad Board participation: Merck Serono; Financial Interests, Institutional, Advisory Board: Ipsen; Financial Interests, Institutional, Invited Speaker: Ipsen, Amgen; Financial Interests, Institutional, Research Grant: MSD; Non-Financial Interests, Advisory Role, IDMC member in one of their clinical trials: Servier; Non-Financial Interests, Advisory Role, Member of the Editorial Board: European Journal Of Surgery; Non-Financial Interests, Invited Speaker: Cyprus Cancer Research Institute; Non-Financial Interests, Advisory Role, Member of the Scientific Committee: European School of Oncology; Non-Financial Interests, Member, National Representatives Committee: SIOG - International Society of Geriatric Oncology. All other authors have declared no conflicts of interest.

Background

In the primary analysis of DYNAMIC, a randomised phase II study in patients (pts) with stage II CC, a ctDNA-guided approach versus standard management reduced ACT use without compromising recurrence-free survival (RFS). Notably, after ACT with oxaliplatin doublet or fluoropyrimidine alone, the 3-year RFS for ctDNA-positive pts in the ctDNA-guided group was 86.4%. Here we explore the relationship between post-op ctDNA and sites of recurrence, post-ACT ctDNA status and relapse, and the performance of post-op and post-ACT CEA from the same blood samples.

Methods

For ctDNA-positive pts at 4 and/or 7 weeks after surgery (post-op), post-ACT ctDNA results (collected 4 weeks after completing ACT) were correlated with recurrence status, as were post-op and post-ACT CEA results for all pts. Post-op ctDNA status and sites of recurrence were explored. A tumour-informed personalised assay was used to assess ctDNA.

Results

Of 291 ctDNA-guided pts, recurrence was seen in 23 (7.9%). Post-op ctDNA was negative in all 8 pts with locoregional relapse only, whereas 8 of 15 with distant relapse had a positive post-op ctDNA (P = 0.02). Of the 45 pts (15%) with a positive post-op ctDNA, post-ACT ctDNA was available in 38. 2 of 31 (6.5%) who converted to ctDNA negative after ACT recurred, compared to 5 of 7 (71%) who remained ctDNA positive (HR 17.3, 95% CI 3.3 - 90.2; P < 0.001). Median time to recurrence was 5 months (1 - 39 months) for post-ACT ctDNA-positive pts. Post-op CEA was elevated in 11 of 240 (4.6%) that were ctDNA-negative post-op, one (9%) of whom recurred, whereas 14 of 229 (6.1%) with a normal CEA recurred (P = 0.947). Post-ACT CEA was elevated in 3 of 28 (11%) pts with available CEA who converted from ctDNA positive post-op to ctDNA negative post-ACT, none of whom recurred, whereas 1 of 25 (4%) with a normal CEA recurred (P = 0.729).

Conclusions

For stage II CC pts, ctDNA analysis is more sensitive for predicting distant than locoregional recurrences. ctDNA clearance can be achieved with ACT in a high proportion of those with an initial positive post-op ctDNA and predicts for excellent outcome. In ctDNA-negative pts, CEA lacks sensitivity and specificity as a marker of recurrence risk.

Clinical trial identification

ACTRN12615000381583.

Legal entity responsible for the study

The Walter and Eliza Hall Institute of Medical Research.

Funding

Australian National Health and Medical Research Council, The Virginia and D.K. Ludwig Fund for Cancer Research, The Conrad R. Hilton Foundation, The Sol Goldman Charitable Trust, John Templeton Foundation, NIH, the Marcus Foundation.

Disclosure

J. Tie: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Pierre Fabre, Inivata; Financial Interests, Personal, Invited Speaker: Servier, Merck Serono; Financial Interests, Personal, Other, Consultancy: Haystack Oncology. J. Cohen: Financial Interests, Personal, Officer: Haystack Oncology. R. Wong: Financial Interests, Personal, Advisory Board, Advisory Board - OG cancer 21/03/2022: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board, Advisory Board - CRC 22/03/2022: Merck Serono; Non-Financial Interests, Principal Investigator, Payments to Monash University ECRU: AstraZeneca, Merck Sharpe Dohme, AstraZeneca; Non-Financial Interests, Principal Investigator, Payment to Monash University ECRU (final payment June 2020): Merck Serono. L.G. Horvath: Financial Interests, Personal, Advisory Board, Honorarium donated back to Chris O'Brien Lifehouse (My hospital): Imagion Biosystems; Financial Interests, Personal, Invited Speaker, No payment: ANZUP (Australia and New Zealand Urogenital and Prostate) Clinical Trials Group; Financial Interests, Personal, Stocks/Shares, Stock options: Imagion Biosystems; Financial Interests, Personal, Stocks/Shares: My Emergency Doctor; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Invited Speaker, MK7684-001MK3475-991: MSD; Financial Interests, Institutional, Invited Speaker, AMG160 Phase I AMG509 Phase I: Amgen; Financial Interests, Institutional, Invited Speaker, 9785-CL-0335 (ARCHES): Astellas; Financial Interests, Institutional, Invited Speaker, SHR3680-002: Jiangsu Hengrui Medicines; Financial Interests, Institutional, Invited Speaker, C344102: Pfizer; Financial Interests, Institutional, Invited Speaker, JPCM: Eli-Lilly; Financial Interests, Institutional, Invited Speaker, DASL-HiCAP: ANZUP; Financial Interests, Institutional, Invited Speaker, GALAHADACIS Prevalence: Janssen-Cilag; Financial Interests, Institutional, Invited Speaker, GSK204697: GlaxoSmithKline; Financial Interests, Institutional, Invited Speaker, XL184-021: Exelexis; Financial Interests, Institutional, Invited Speaker, BGB-A317BGB-283BGB-A317-290: Beigene; Financial Interests, Institutional, Invited Speaker, FPT155-001: Five Prime; Financial Interests, Institutional, Invited Speaker, AB928CSP0003: ARCUS; Financial Interests, Institutional, Invited Speaker, ENZAMETENZARAD: ANZUP; Financial Interests, Institutional, Invited Speaker, ATG-017: Antagene. C.S. Karapetis: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, BMS, Ipsen, Eli Lilly, Eisai, Roche, Takeda, Beigene; Financial Interests, Institutional, Invited Speaker: Takeda, Roche, Mirati, Daiichi Sankyo; Non-Financial Interests, Member: Medical Oncology Group of Australia, American Society of Clinical Oncology. N. Papadopoulos: Financial Interests, Personal, Advisory Role: Thrive Earlier Detection, Haystack Oncology, Neophore, Personal Genome Diagnostics, CAGE Pharma; Financial Interests, Personal, Stocks/Shares: Exact Science, Haystack Oncology, Neophore, Personal Genome Diagnostics, CAGE Pharma. C. Tomasetti: Financial Interests, Personal and Institutional, Royalties: exact sciences; Financial Interests, Personal, Advisory Board: prognomiQ; Financial Interests, Personal, Advisory Role: Bayer AG. K. Kinzler: Financial Interests, Personal, Advisory Role: Thrive Earlier Detection, Haystack Oncology, Neophore, Personal Genome Diagnostics, CAGE Pharma; Financial Interests, Personal, Stocks/Shares: Exact Science, Haystack Oncology, Neophore, Personal Genome Diagnostics, CAGE Pharma. B. Vogelstein: Financial Interests, Personal, Advisory Role: Thrive Earlier Detection, catalio capital management, Neophore, CAGE Pharma; Financial Interests, Personal, Stocks/Shares: Exact Science, catalio capital management, Neophore, Personal Genome Diagnostics, CAGE Pharma; Financial Interests, Personal, Advisory Role, Peter MacCallum Cancer Centre: Personal Genome Diagnostics. P. Gibbs: Financial Interests, Personal, Advisory Role: Haystack; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Advisory Board: Pierre faber, MSD; Financial Interests, Research Grant: BMS. All other authors have declared no conflicts of interest.

Background

Despite earlier screening and advancements in diagnostic and treatment modalities, nearly 25-40% of patients with resected stage I-III colorectal cancer (CRC) recur. A novel approach to post-surgical risk stratification for molecular residual disease (MRD) detection and treatment monitoring is needed to improve patient outcomes.

Methods

In this retrospective analysis of a U.S-based multi-institutional study, data from commercial circulating tumor DNA (ctDNA) testing of approximately 12,000 stage I-III CRC patients were analyzed. Complete clinical data was available for 400 patients with 2,140 plasma samples collected between 06/2019-04/2022. A personalized, tumor-informed multiplex PCR-based next-generation sequencing assay (Signatera™) was used to quantify ctDNA prior to surgery, postoperatively (MRD-window; within 8 weeks of surgery, prior to therapy) and during surveillance.

Results

Of 12,000 patients, ctDNA during the MRD-window was tested in 5,684 patients with an overall ctDNA positivity rate of 22.1% (1,259/5,684) and higher positivity rates among stage III (29.5%, 805/2732) patients. In patients with available clinical data (N=400), ctDNA during the MRD-window was tested in 124 patients with a positivity rate of 21.8% (27/124). During the follow-up period (median 626 days; range: 0-3517 days), 63.0% (17/27) of MRD-positive patients relapsed compared to 9.3% (9/97) of MRD-negative patients. Notably, of these 9 relapsed MRD-negative patients, 7 became ctDNA-positive on serial testing beyond 8 weeks. ctDNA positivity during the MRD-window, anytime post-surgery and during surveillance was significantly associated with shorter recurrence-free survival (HR=12.2, 95%CI: 5.3−27.8, p<0.0001), (HR=16.7, 95%CI: 7.4−37.4, p<0.0001), and (HR=25.4, 95%CI: 12.6−51.3, p<0.0001), respectively.

Conclusions

In this study utilizing real-world data from patients with early-stage CRC, postsurgical ctDNA detection at any time point was prognostic of relapse. Postsurgical ctDNA testing in early-stage CRC patients may enable personalized surveillance, intervention, and/or trial options, ultimately improving patient outcomes.

Legal entity responsible for the study

Natera, Inc.

Funding

Has not received any funding.

Disclosure

S.A. Cohen: Financial Interests, Personal, Advisory Board: Boston Biomedical, Polaris; Financial Interests, Personal, Speaker’s Bureau: Natera, Inc. P.M. Kasi: Financial Interests, Personal, Advisory Board, Consultancy/Advisory Board: Foundation Medicine, Natera Oncology, AstraZeneca, Merck MSD, Tempus, Bayer, Lilly, Delicath Systems, QED Therapeutics, Servier, Taiho Oncology, Exact Sciences, Eisai; Financial Interests, Institutional, Advisory Board, Consultancy/Advisory Board: Taiho, Ipsen; Financial Interests, Institutional, Funding, Investigator initiated trial cooperative group PI trial support and funding.: Tersera; Financial Interests, Institutional, Funding, Investigator initiated trial trial support and funding.: Boston Scientific. V.N. Aushev: Financial Interests, Personal and Institutional, Stocks/Shares: Natera, Inc. D.L. Hanna: Financial Interests, Personal, Advisory Board: Natera, Inc. G.P. Botta: Financial Interests, Personal, Advisory Board: Natera, Inc.; Financial Interests, Personal, Invited Speaker: Natera; Financial Interests, Personal, Funding: Carsgen. G. Laliotis: Financial Interests, Personal and Institutional, Stocks/Shares: Natera, Inc. S. Sharma: Financial Interests, Personal and Institutional, Stocks/Shares: Natera, Inc. S.R. Chandana: Financial Interests, Personal, Invited Speaker: Natera, Inc. S. Chakrabarti: Financial Interests, Personal, Invited Speaker, Speaker bureau: Natera Inc; Financial Interests, Personal, Other, Advisory role: QED THerapeutics. A. Kasi: Financial Interests, Personal, Other, Honoraria: OncLive; Financial Interests, Institutional, Funding: Tesaro, Halozyme, Astellas Pharma, Rafael Pharmaceuticals, Geistlich Pharma, Cardiff Oncology, FibroGen, Bavarian Nordic, Novocure; Financial Interests, Personal, Other, travel, accomodations: Halozyme, Rafael Pharmaceuticals. F. Dayyani: Financial Interests, Personal, Advisory Board: AstraZeneca, Natera, Inc., Exelixis, Genetech; Financial Interests, Personal, Other: Deciphera, Eisai, Exelixis, Ipsen, Natera, Inc., Sirtex; Financial Interests, Personal, Other, Natera, Inc.: Servier; Financial Interests, Personal, Research Grant: AstraZeneca, BMS, Taiho, Exelixis, Merck, Natera, Inc., Ipsen; Financial Interests, Personal, Research Grant, Natera, Inc.: Trishula. M. Malla: Financial Interests, Personal and Institutional, Research Grant, (Grant # 5U54GM104942-05): National Institute of General Medical Sciences-NIH; Financial Interests, Personal, Advisory Role, Natera, Inc.: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Natera, Inc.. A. Jurdi: Financial Interests, Personal and Institutional, Stocks/Shares: Natera, Inc.. A. Aleshin: Financial Interests, Personal and Institutional, Stocks/Shares: Natera, Inc.. S. Kopetz: Financial Interests, Personal, Advisory Board: Roche, EMD Serono, Merck, Novartis, Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca, Bayer, Pierre Fabre, Redx Pharma, Ipsen, Daiichi, Natera, HalioDx, Jacobio, Pfizer, Repare Therapeutics, GlaxoSmithKline, Jazz, Xilis, Abbvie, Gilead, Mirati, Flame, Servier, Carina, Bicara, Endeavor BioMedicines, Numab Pharma, Janssen; Financial Interests, Personal, Other, Research: Inivata; Financial Interests, Personal, Stocks/Shares: Lutris, Iylon, Navire, Xilis. All other authors have declared no conflicts of interest.

Background

We have previously reported modest activity for the combination of regorafenib and nivolumab (REGONIVO) in chemotherapy resistant MSS mCRC. Given the importance of CTLA-4 inhibition in T-cell priming, we explored the addition of ipilimumab to REGONIVO in a similar patient (pt) population.

Methods

Pts with chemotherapy resistant MSS mCRC were enrolled. The first-dose level (DL) consisted of regorafenib (R) at 80 mg QD x 21 days in 4-week cycles while ipilimumab (I) was administered at 1mg/kg Q6 weeks and nivolumab (N) at 240 mg Q 2 weeks. Dose-de-escalation was allowed (decreased in R) if the 1^st dose was not tolerated. A 20-pt expansion was enrolled at the recommended dose to establish safety and to explore efficacy.

Results

9 pts were enrolled on the safety cohort and established DL1 as the recommended dose level (RDL). 29 pts were enrolled at the RDL. 7 pts had liver metastases. Overall response rate (ORR), disease control rate (DCR) and progression free survival (PFS) are summarized in Table and are stratified by liver involvement, RAS, and BRAF status. With a median follow-up of 16 months (mo), the median overall survival (OS) was 7 mo in pts with liver mCRC, 14 mo in the overall population, and has exceeded 15 mo (not reached) in pts without liver disease. 5 pts remain on study without PD (12 – 19 mo since treatment start). 18/29 pts had paired ctDNA (baseline and 6 weeks), 8 pts had ctDNA clearance and experienced either PR or PFS > 8 mo. Immune-related toxicities included hepatitis (G3-4, 13.8%, n=4), skin rash (G3, 34.5%, n=10), colitis (G3, 6.9%, n=2), meningitis (G3, 3.4%, n=1), pneumonitis (G2, 3.4%, n=1), hypophysitis (G2, 3.4%, n=1), arthritis (G2, 13.8%, n=4), hypothyroidism (G2, 13.8%, n=4), and hyperthyroidism (G2, 3.4%, n=1). Table: 320MO

Conclusions

RIN has substantial activity in MSS mCRC patients without liver involvement with an iRECIST ORR of 36%, iDCR of 82%, and an iRECIST mPFS of 6 mo. Clinical benefits were seen irrespective of BRAF and RAS status.

Clinical trial identification

NCT04362839.

Editorial acknowledgement

no

Legal entity responsible for the study

The authors.

Funding

Institutional funding with drugs provided by BMS.

Disclosure

M.G. Fakih: Other, Research Grant: Amgen, AstraZeneca, Novartis; Other, Speaker’s Bureau: Amgen; Other, Advisory Role: Array, Bayer, GSK, Taiho, Incyte, Pfizer.

All other authors have declared no conflicts of interest.

Background

Intensive follow-up of patients (pts) after curative surgery for CRC is recommended by various scientific societies. However, the few clinical trials performed are controversial and no survival benefit has been demonstrated to date.

Methods

PRODIGE 13 is a cooperative prospective multicentre controlled phase III trial evaluating by double randomisation the impact of i) intensive radiological monitoring (CT-scan/6m) vs. a standard one (abdominal ultrasound/3m and thoracic radiography/6m) and ii) CEA assessment vs. no, in the follow-up of stage II or III CRC resected for cure. The primary endpoint was 5-year overall survival (OS). The result of the 2^d intermediate analysis: after curative surgery for primary CRC, the addition of CEA and/or CT does not provide any benefit in 5-year OS for the global population of the study. We report here the final results of the RFS.

Results

At all, 75.9% of the pts were < 75 years old (16% rectal, 44% left colon cancers (CC)). Among CC 52% were Stage II (25% adjuvant chemotherapy). With a median follow-up of 7,8 years, cancer recurrence was detected in 22,3% of the pts (39%/61% stage II/III). The recurrence was metastatic in 89.5% and local in 10.5% of the pts. Overall, 5.9% of the pts (95% CI,4.6%-7.2%) were treated for recurrence with curative intent (A: intensive imaging + CEA 37.6%; C: Standard imaging + CEA 50.5%; B: intensive imaging alone 35.1%; D: Standard imaging alone 30.2%; p= 0.0120). The 5-years RFS rates were respectively 71.8%, 74.6%, 69.0% and 67.5% in arm A, B, C and D. Compared with minimum follow-up (D), pts of the arm D had significantly longer RFS, 0,80 ([0.65;0.98]; p= 0.031). The 5-years RFS were respectively 73.2% [70.3;75.8] and 68.2% [65.2;71.0] in CTscan surveillance group vs. not (HR 0.86 [0.75;1]; p=0.052) and 70.4% [67.42; 73.1] and 71.0% [68.1; 73.75] in CEA surveillance vs. not respectively (HR 0.99 [0.86;1.15]; ns).

Conclusions

Among pts who had undergone curative surgery for primary CRC, intensive imaging, but not CEA screening, provided an increased rate of surgical treatment of recurrence with curative intent. There is no survival advantage to any strategy but a trend toward a better 5-years RFS in the CT scan surveillance group versus not.

Clinical trial identification

NCT00995202.

Legal entity responsible for the study

FFCD: Federation Francophone de Cancérologie Digestive.

Funding

FFCD: Federation Francophone de Cancérologie Digestive.

Disclosure

C. Lepage: Financial Interests, Personal, Invited Speaker: Ipsen, Amgen, Pierre Fabre; Financial Interests, Personal, Advisory Board: Novartis. All other authors have declared no conflicts of interest.