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

Abstract

TPS4124 Background: Moving stage III Colon Cancer (CC) into the precision medicine space is a priority in view of the lack of molecular markers driving adjuvant treatment. Retrospective studies have demonstrated the tremendous prognostic impact of circulating tumor DNA (ctDNA) analysis after curative intent surgery, and suggested that lack of conversion of ctDNA from detectable to undetectable after adjuvant chemotherapy reflects treatment failure. With these premises, we have designed the PEGASUS trial (NCT04259944). Methods: PEGASUS is a prospective multicentric study designed to prove the feasibility of using liquid biopsy (LB) to guide the post-surgical and post-adjuvant clinical management in 140 microsatellite stable Stage-III and T4N0 Stage-II CC patients. The LUNAR1 test (Guardant Health, Redwood City, CA, USA) will be used for ctDNA determination. For the efficacy analysis, the PEGASUS cohort will be compared with a 3:1 matched cohort of 420 patients from the TOSCA trial (NCT00646607). A LB executed 2-4 weeks post-surgery will guide a “Molecular Adjuvant” treatment: i) ctDNA+ patients will receive CAPOX for 3 months and ii) ctDNA- patients will receive capecitabine (CAPE) for 6 months but will be retested after 1 cycle, and if found ctDNA+ will be switched to CAPOX treatment. At the end of the “Molecular Adjuvant” treatment a further LB will be performed and instruct subsequent treatment. Positive patients (ctDNA+/+ and ctDNA-/+) will receive an up-scaled “Molecular Metastatic” systemic treatment for 6 months or until radiological progression or toxicity: i) ctDNA+/+ patients will be treated with FOLFIRI; ii) ctDNA-/+ patients with CAPOX. These patients will be subjected to a LB after 3 months and at the end of treatment: in case of positivity will be switched to FOLFIRI. ctDNA+/- patientswill receive a de-escalated treatment with CAPE for 3 months. 3 LB will be performed within 3 months and in case of positivity the patient will be switched to FOLFIRI. Patients with ctDNA-/- will be subjected to an interventional follow-up comprising 2 further LB and in case of positivity they will be switched to CAPOX treatment. PEGASUS is piggybacked to AlfaOmega (NCT04120935), a Master Observational Protocol that will follow patients from diagnosis to 5 years or recurrence/death (whichever comes first), collecting clinical data, radio-images and biological samples. AlfaOmega provides a clinical and logistic ecosystem for the seamless integration of PEGASUS clinical results with the biological underpinning of colon cancer. Clinical trial information: NCT04259944 .

Circulating Tumor DNA in Stage III Colorectal Cancer, beyond Minimal Residual Disease Detection, toward Assessment of Adjuvant Therapy Efficacy and Clinical Behavior of Recurrences

“…Potentially, ctDNA-positive patients will benefit more from future adjuvant regimens (28). To determine the optimal regimen and associated benefit, prospective randomized studies are needed (25,30).…”

ctDNA and Adjuvant Therapy for Colorectal Cancer: Time to Re-Invent Our Treatment Paradigm

“…The ALTAIR study will assess the efficacy of second-line adjuvant trifluridine/tipiracil in patients with ctDNA that remain positive after 3 months of adjuvant CAPOX. The PEGASUS study (NCT04259944) is a Italian/Spanish non-randomised ctDNA-guided interventional trial to explore the feasibility of a ctDNA-guided treatment strategy which also includes the use of second-line adjuvant FOLFIRI in patients with persistently positive ctDNA after standard CAPOX treatment [ 88 ]. One potential challenge with the second-line adjuvant therapy approach may be the relatively short time interval between ctDNA detection at the end of treatment and clinical recurrence, limiting the opportunity for therapeutic intervention.…”

Liquid Biopsy for Prognosis and Treatment in Metastatic Colorectal Cancer: Circulating Tumor Cells vs Circulating Tumor DNA

“…As a future prospective, “molecular” progression will complement radiological evaluation, while computational mathematics already proved capable of predicting time-to-treatment failure in patients with mCRC through clonal tracking forecast [ 78 , 122 ]. Finally, although not a focus of the present review, LB may have a role as a screening tool in CRC and is currently under intense investigation aiming to guide decisions about adjuvant treatment for patients with stage II–III surgically resected CRC [ 123 , 124 ]. In conclusion, LB represents a major opportunity for better tailoring the whole patient care in mCRC, with ctDNA especially demonstrating, from initial pioneering studies in this tumor type [ 11 ], an ever-increasing acceleration toward multiple clinical applications.…”