LBA28 - The PEGASUS trial: Post-surgical liquid biopsy-guided treatment of stage III and high-risk stage II colon cancer patients

Background

Retrospective studies demonstrated an impressive prognostic impact of circulating tumor DNA (ctDNA, LB) positivity on colon cancer (CC) relapse after radical resection as proxy of minimal residual disease (MRD). Initial evidence is accumulating that in some patients (pts) adjuvant treatment does not clear ctDNA and this associates with relapse. With these premises we designed the PEGASUS trial to prove the feasibility of using LB to guide the post-surgical and post-adjuvant clinical management of Stage-IIT4N0/III CC pts.

Methods

LB was performed using Guardant Reveal assay (v L1.2). In the post-surgical phase, LB+ pts received 3 months (mos) of CAPOX and LB- pts 6 mos of CAPE. To mitigate the risk of false negatives a LB was repeated after one cycle of CAPE and treatment escalated to CAPOX if LB+. At the end of adjuvant treatments, LB was repeated: CAPOX-treated pts were switched to FOLFIRI if LB+ or de-escalated to CAPE if LB-; CAPE-treated pts received CAPOX if LB+ or started the standard follow-up phase if LB-. Primary endpoint was the number of post-surgery false negative cases, defined as pts with two consecutive LB- experiencing disease relapse (accepted <14 relapses).

Results

From July 2020 to July 2022, 135 pts were included in 11 cancer centers in Italy and Spain. At data cut-off, median follow-up was 20,8 months, with data completeness of 91% in LB- and 92% in LB+. Post-surgery ctDNA was detected in 35/135 pts (26%), of which 12 (34%) experienced relapses, while 9 out of 100 LB- pts (9%) relapsed, being defined as false negatives. ctDNA+ was associated with a clear increase in the risk of relapse (HR 4.37, log rank P=0.0003). After 3 months of CAPOX, 11/35 LB+ pts were converted to LB- (31%), but 8/11 relapsed or LB re-positivized. Of the 23 LB+ pts receiving FOLFIRI after CAPOX, 12 remained LB+ (52%) among which 6 relapsed, while 11 were converted to LB- remaining relapse-free at the time of analysis (48%), thus suggesting an effect of FOLFIRI in the MRD setting.

Conclusions

LB may be used to guide the post-surgical clinical management of CC pts by reducing unnecessary toxicity and by improving the response to standard chemotherapy. Ongoing and newly designed randomized trials trials will define the clinical utility of LB for MRD in colon cancer.

Clinical trial identification

IFOM-CPT005/2019/PO004 EudraCT 2019-002074-32 NCT04259944.

Editorial acknowledgement

Legal entity responsible for the study

IFOM - the AIRC Institute of Molecular Oncology.

Funding

Guardant Health.

Disclosure

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, Coordinating PI: Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, Bristol -Myers Squibb. F. Pietrantonio: Financial Interests, Personal, Advisory Board: Amgen, Merck-Serono, MSD, Bayer, Organon, Astellas; Financial Interests, Personal, Invited Speaker: Amgen, Merck-Serono, BMS, Lilly, Servier, Bayer, Pierre-Fabre, AstraZeneca, Astellas; Financial Interests, Institutional, Research Grant: BMS, AstraZeneca, Incyte, Agenus. N. Tarazona Llavero: Financial Interests, Personal, Advisory Board: Merck, Guardant Health; Financial Interests, Personal, Invited Speaker: Merck, Pfizer, Servier, Amgen; Financial Interests, Institutional, Funding: Natera Inc; Non-Financial Interests, Member: SEOM Committee. C. Montagut Viladot: Financial Interests, Personal, Advisory Board: Merck Serono, Roche; Financial Interests, Personal, Invited Speaker: Merck Serono, Pierre Fabre, Guardant Health, Amgen; Financial Interests, Institutional, Royalties: Biocartis; Financial Interests, Institutional, Coordinating PI: Merck-Serono; Non-Financial Interests, Member: TTD (Grupo Tratamiento Tumores Digestivos). A. Sartore Bianchi: Financial Interests, Personal, Advisory Board: Amgen, Servier, Novartis; Financial Interests, Personal, Invited Speaker: Bayer, Guardant Health, Pierre Fabre. M.E. Elez Fernandez: Financial Interests, Personal, Advisory Board: Hoffman La - Roche, Servier, Amgen, Merck Serono, Sanofi, Bayer, Pierre Fabre, MSD, Takeda; Financial Interests, Personal, Invited Speaker: Organon, Novartis, Pfizer; 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. C. Santos Vivas: Financial Interests, Personal, Advisory Board: Sanofi, Amgen, Pierre-Fabre; Financial Interests, Personal, Other, Travel and accommodation: Merck KGaA, Merck. M. Mandalà: Financial Interests, Personal, Advisory Board: MSD, Novartis, Sanofi, BMS, Pierre Fabre; Financial Interests, Personal, Invited Speaker: Sun Pharma. S. Tamberi: Financial Interests, Personal, Advisory Board: Gilead, AstraZeneca. M.S. Sciallero: Financial Interests, Personal, Invited Speaker: MSD; Other, Travel/accomodation expenses: Amgen, PFIZER, SELGENE, TRIPLE-A. A. Cervantes: Financial Interests, Institutional, Advisory Board: MerckSerono, Amgen, Roche, Transgene, AnHeart Therapeutics, AbbVie, GSK; Financial Interests, Institutional, Invited Speaker: Amgen, Roche, Merck Serono, Foundation Medicine; Financial Interests, Personal, Other, Associate Editor: Annals of Oncology, ESMO Open; Financial Interests, Personal, Other, Editor in Chief: Cancer Treatment Reviews; Financial Interests, Institutional, Research Grant, Principal Investigator: Actuate Therapeutic, Amgen, Astellas Pharma, BeiGene, Bayer, AstraZeneca, BMS, Amcure, FibroGen, Lilly, Genentech, MedImmune, Merck Serono, Novartis, Natera, MSD, Servier, Sierra Oncology, Adaptimmune, Takeda, Affimed, Roche, Seamless, Gilead, Janssen, F. STAR Therapeutics, Ribon Therapeutics; Non-Financial Interests, Other, Scientific Director: INCLIVA Biomedical Research Institute. A. Bardelli: Financial Interests, Personal, Other, Receipt of honoraria or consultation fees: Guardant Health, Inivata; Financial Interests, Personal, Advisory Board, Scientific Advisory Board: Inivata, Neophore; Financial Interests, Personal, Advisory Board, Roche/Genentech Global CRC Advisory Board: Roche; Financial Interests, Personal, Stocks/Shares, Stock shareholder: Neophore, Kither; Financial Interests, Institutional, Research Grant, Receipt of grants/research supports: Neophore, AstraZeneca, Boehringer Ingelheim. 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, Debiopharm International SA, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb International Corporation, Celgene International SARL, F. Hoffmann-La Roche Ltd, Merck, Sharp & Dohme de España, SA, Genentech Inc, Janssen-Cilag International NV, Merck Health KGAA, 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, Leadership Role, External Scientific Committee: IdiSNA –Universidad de Navarra, Institute for Health Research INCLIVA – Clinical Hospital of Valencia; 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, 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, F. Hoffmann-La Roche Ltd, Debiopharm International SA, Bristol-Myers Squibb International Corporation, Celgene International SARL, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Menarini, Janssen-Cilag International NV, MedImmune, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA 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, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Pfizer, Servier; Non-Financial Interests, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, Merus NV, Taiho Pharma USA Inc; Non-Financial Interests, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System; Other, President: Oncology Master Plan – Catalonia Department of Health. S. Siena: Financial Interests, Personal, Advisory Board, Advisory Board Member: Agenus, AstraZeneca, BMS, Checkmab, Daiichi Sankyo, GSK, Novartis, Seagen, T-One-Therapeutics. All other authors have declared no conflicts of interest.