Circulating tumor DNA-guided de-escalation or escalation of adjuvant therapy in high-risk stage II and stage III colon cancer: the phase 2 PEGASUS trial

Oxaliplatin-fluoropyrimidine combinations are standard adjuvant therapy after radical resection of high-risk stage II and stage III colon cancer but expose many patients to toxicity while failing to prevent relapse in others. PEGASUS was a multicenter, single-arm, phase 2 trial evaluating the feasibility of an adaptive circulating tumor DNA (ctDNA)-guided treatment strategy in patients with resected microsatellite-stable, T4N0 or stage III colon cancer. Postsurgery ctDNA-positive patients received 3 months of CAPOX, escalating to 6 months of FOLFIRI if persistently positive, whereas confirmed ctDNA-negative patients received 6 months of capecitabine. The primary endpoint was the 2-year relapse-free rate among ctDNA-negative patients at 2 subsequent postsurgery liquid biopsies. Among the 135 enrolled patients, 26% (n = 35) were ctDNA positive at the postsurgery landmark, with a 3-year disease-free survival rate of 58% for ctDNA positive versus 83% for ctDNA negative (hazard ratio = 2.71; 95% CI = 1.35-5.45; P = 0.0036). With 100 rather than 134 ctDNA-negative cases, the observed 2-year relapse-free rate (88%, 90% CI = 81-93%) was below the predefined threshold (≥92%); the primary endpoint was not met. Versus a matched TOSCA ( NCT00646607 ) control cohort, ctDNA-guided strategy showed similar disease-free survival and substantially less neurotoxicity. Transcriptomic profiling linked the relapse to consensus molecular subtype 4, stroma-rich biology. These findings suggest that dynamic ctDNA-guided management can be leveraged operationally in clinical practice, highlighting the needs for randomized trials and more effective strategies for ctDNA-positive disease. ClinicalTrials.gov identifier: NCT04259944 .

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Journal
Nature Cancer
Published
2026-09-14
DOI
https://doi.org/10.1038/s43018-026-01237-9
Primary Topic
Cancer Genomics and Diagnostics
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article
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article

Circulating tumor DNA-guided de-escalation or escalation of adjuvant therapy in high-risk stage II and stage III colon cancer: the phase 2 PEGASUS trial

Mario Mandalà, Valentina Vettore, Josep M. Tabernero, Giorgio Patelli et al.
Nature Cancer
Cancer Genomics and Diagnostics
article

Circulating tumor DNA-guided de-escalation or escalation of adjuvant therapy in high-risk stage II and stage III colon cancer: the phase 2 PEGASUS trial

Mario Mandalà, Valentina Vettore, Josep M. Tabernero, Giorgio Patelli, Giovanni Crisafulli, Marta Guix, Ida Taglialatela, Andrea Sartore‐Bianchi, Élena Elez, Salvatore Siena, Paolo Luraghi, Sara Lonardi, Eliana Rulli, Enzo Médico, Federica Tosi, Noelia Tarazona, Cristina Santos, Alberto Bardelli, Filippo Pietrantonio, Silvia Marsoni, Claudio Isella, Joana Vidal, Giulia Maddalena, Luca Lazzari, Andrés Cervantes, Víctor Seguí, Michele Palazzo, Katia Bencardino, Valter Torri, Michele Prisciandaro, Maria Giulia Zampino, Francesca Bergamo, Clara Montagut, Davide Ciardiello, Stefano Tamberi, Federica Morano
article en

Abstract

Oxaliplatin-fluoropyrimidine combinations are standard adjuvant therapy after radical resection of high-risk stage II and stage III colon cancer but expose many patients to toxicity while failing to prevent relapse in others. PEGASUS was a multicenter, single-arm, phase 2 trial evaluating the feasibility of an adaptive circulating tumor DNA (ctDNA)-guided treatment strategy in patients with resected microsatellite-stable, T4N0 or stage III colon cancer. Postsurgery ctDNA-positive patients received 3 months of CAPOX, escalating to 6 months of FOLFIRI if persistently positive, whereas confirmed ctDNA-negative patients received 6 months of capecitabine. The primary endpoint was the 2-year relapse-free rate among ctDNA-negative patients at 2 subsequent postsurgery liquid biopsies. Among the 135 enrolled patients, 26% (n = 35) were ctDNA positive at the postsurgery landmark, with a 3-year disease-free survival rate of 58% for ctDNA positive versus 83% for ctDNA negative (hazard ratio = 2.71; 95% CI = 1.35-5.45; P = 0.0036). With 100 rather than 134 ctDNA-negative cases, the observed 2-year relapse-free rate (88%, 90% CI = 81-93%) was below the predefined threshold (≥92%); the primary endpoint was not met. Versus a matched TOSCA ( NCT00646607 ) control cohort, ctDNA-guided strategy showed similar disease-free survival and substantially less neurotoxicity. Transcriptomic profiling linked the relapse to consensus molecular subtype 4, stroma-rich biology. These findings suggest that dynamic ctDNA-guided management can be leveraged operationally in clinical practice, highlighting the needs for randomized trials and more effective strategies for ctDNA-positive disease. ClinicalTrials.gov identifier: NCT04259944 .

Nature Cancer
Universitat de Vic - Universitat Central de Catalunya (ES), Universitat Autònoma de Barcelona (ES), Universitat de València (ES), Universitat Pompeu Fabra (ES), University of Milan (IT), Mario Negri Institute for Pharmacological Research (IT), University of Perugia (IT), Instituto de Salud Carlos III (ES), Azienda Ospedaliera di Perugia (IT), Ospedale "Santa Maria delle Croci" di Ravenna (IT), Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), Vall d'Hebron Institut de Recerca (ES), Institut Català d'Oncologia (ES), Istituto Oncologico Veneto (IT), IFOM (IT), Ospedale Santa Maria (IT), Hospital Del Mar (ES), Candiolo Cancer Institute (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Fondazione IRCCS Istituto Nazionale dei Tumori (IT), INCLIVA Health Research Institute (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), University of Turin (IT), European Institute of Oncology (IT)
Università degli Studi di Milano, Istituto di Ricerche Farmacologiche Mario Negri - IRCCS, Universitat Pompeu Fabra, European Commission, Universitat de València, Associazione Italiana per la Ricerca sul Cancro, Universitat de Barcelona, Istituto Oncologico Veneto, Università degli Studi di Perugia, Centro de Investigación Biomédica en Red de Cáncer, INCLIVA Instituto de Investigación Sanitaria, Instituto de Salud Carlos III
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Cancer Genomics and Diagnostics
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