Evaluating novel therapies and circulating tumor DNA (ctDNA) as a marker of response in curatively treated gastrointestinal cancers with microscopic residual disease.
Authors: Mukherji Reetu , Noel Marcus Smith , He Aiwu Ruth , Weinberg Benjamin Adam , Weiner Louis M. , Marshall John 
Published: January 2024

TPS765

Background: ctDNA has emerged as a novel tool that can identify the earliest sign of relapse (MRD) after curative therapies with specificities of 93-100%, positive predictive values over 98%, and median lead times of 8-9 months before radiographic relapse. ctDNA has allowed us to identify a "new stage" of high-risk patients (pts) with no evidence of disease radiographically (rNED) and MRD who lack guideline-directed treatment (tx) strategies as, traditionally, they wait for radiographic progression of disease (POD) before starting therapies. Treating MRD is a promising strategy supported by observational studies where ctDNA clearance is linked with improved survival and on-tx ctDNA kinetics predict drug efficacy. We designed a pilot investigator-initiated trial to 1) determine the feasibility of using a surrogate marker, ctDNA, as a rapid signal for positive therapeutic activity and 2) obtain pilot data on the efficacy of a novel combination therapy (atezolizumab [A] + bevacizumab [B]) in eradicating MRD in previously curatively treated pts with GI cancers. Methods: We will enroll 20 pts with any-stage GI cancers divided over 4 cohorts (n=5 colorectal [CRC], n=5 hepatocellular/biliary tract carcinoma, n=5 gastric, n=5 pancreatic adenocarcinoma) who have a positive Signatera ctDNA test and rNED any time after completing standard curative-intent therapies. Pts are treated with A 1200 mg IV + B 15 mg/kg IV on day 1 of a 21-day cycle for up to 1 year with imaging every 12 weeks and serial ctDNA testing every 3 weeks. Co-primary endpoints are rates of pt enrollment in 12 months and rates of ctDNA responses at a 12-week landmark after tx initiation. Pts with ctDNA POD (ctDNA doubling on each of 2 sequential tests, any rate of rise in 3 sequential tests, or radiographic relapse) will stop while those with ctDNA complete response (CR; clearance on 2 sequential tests + ongoing rNED) or ctDNA partial/stable response (PR; not ctDNA CR or POD + ongoing rNED) will continue tx. Each cohort's Bayesian predictive probability of positive therapeutic activity will be calculated. If at least 60% of a cohort experiences ctDNA CR, it will be expanded by 5 pts. This scenario is equivalent to Simon's 2-stage Minimax design testing a null hypothesis of 20% CR vs. an alternative hypothesis of at least 60% CR at 5% alpha with 80% power. If at least 5/10 pts in an expanded cohort experience ctDNA CR, this will generate interest in developing a larger confirmatory trial to evaluate pt survival outcomes with A+B and ctDNA as a surrogate for survival. Secondary endpoints are toxicity and reasons for enrollment failure. Exploratory endpoints are associations between ctDNA conversion and disease-free survival, tumor whole exome sequencing data, and peripheral blood immune profiles collected at baseline and on tx. Enrollment began in Q1 2023. 4 pts are enrolled in the CRC cohort. Clinical trial information: NCT05482516 .