Lieu, Christopher

TPS3686 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA–) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk-stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage IIB, IIC, and III CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor-informed assay (Signatera, bespoke assay), those who are ctDNA– (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP)+oxaliplatin (Ox) for 3-6 mos per established guidelines v serial ctDNA monitoring. Patients who are ctDNA+ post-operatively, or with serial monitoring (Cohort B), will be randomized to FP+Ox v more intensive AC with addition of irinotecan (I) for 6 mos. One cycle of chemotherapy is allowed while awaiting ctDNA testing results for cohort assignment. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) (phase III) in the immediate v delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox v FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, as well as post-operative plus serial matched/normal blood samples, will be collected for exploratory correlative research. Active enrollment across the NCTN started in June 2022 with CCTG sites joining in August 2023. Accrual is 1,123/1,912 (as of 1/20/2026). *Drs. Dasari and Lieu contributed equally to the development of this trial. Clinical trial information: NCT05174169 .

3626 Background: For patients (pts) with dMMR stage III colon cancer, the addition of atezolizumab (atezo) to adjuvant 5-fluorouracil, leucovorin plus oxaliplatin (mFOLFOX6) significantly improved disease-free survival in ATOMIC (NCT02912559). Here we present HRQOL data. Methods: Pts with surgically resected stage III dMMR colon cancer were randomized (1:1) to receive mFOLFOX6 + atezo (840 mg IV q2 weeks) for 12 cycles (6 months [mo]) followed by atezo monotherapy for 13 cycles (12 mo total) versus mFOLFOX6 for 12 cycles. HRQOL was an exploratory endpoint measured using the FACT-C (includes FACT-G), FACT/GOG-NTX, EQ5D-5L, and PRO-CTCAE. Optional participation was by paper surveys at trial registration, prior to treatment cycles 4 and 7, and at 6, 12, and 36 mo after registration. Mean changes from baseline (BL) were compared between treatment arms using general linear mixed models (negative mean changes indicate worsening). At 6 mo, a two-sided 95% confidence interval excluding a difference of 1.9 points (FACT/GOG-NTX) and 6 points (FACT-C Trial Outcome Index [TOI]) favoring the mFOLFOX6 arm would indicate non-inferiority of the addition of atezo. Rates of side effect bother (FACT-G item GP5) and pt-reported adverse events (AEs) by PRO-CTCAE (composite scores, baseline adjusted) were compared using Fisher’s exact tests. Results: Of 712 randomized pts, 581 (285 atezo+mFOLFOX6; 296 mFOLFOX6) consented to participate in the survey. Pts completed 2398/3021 (79%) of expected surveys across all time points (1218/1489 [82%] atezo+mFOLFOX6; 1180/1532 [77%] mFOLFOX6). The difference in mean changes from BL between arms indicated non-inferiority of the addition of atezo at 6 mo (table); differences remained small at 12 and 36 mo. No significant differences in mean changes from BL between arms were found at 6, 12, or 36 mo for any scale. At 6 mo, 16% vs 20% of pts in each arm reported at least “quite a bit” of side effect bother (p=0.34), favoring atezo. Across cycles, atezo was associated with higher rates of pt-reported itchy skin (62% vs 48%), cough (53% vs 43%), and shortness of breath (51% vs 41%) [all p<0.05]. Conclusions: Addition of atezo to mFOLFOX6 slightly increases pt-reported AEs, but its effect on HRQOL is minimal and not clinically meaningful. Results support tolerability of atezo+mFOLFOX6 as standard of care adjuvant treatment for pts with dMMR stage III colon cancer. Support: UG1CA189823, U10CA180821, U10CA180882; Genentech, a member of the Roche group; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02912559 . Scale Mo Mean change from BL – atezo+mFOLFOX6 Mean change from BL – mFOLFOX6 Diff (95% CI) FACT/GOG-NTX 6 -10.0 -10.6 0.6 (-0.8, 2.1) 12 -8.0 -9.4 1.4 (-0.2, 2.9) 36 -7.2 -6.9 -0.4 (-2.1, 1.4) FACT-C TOI 6 -4.1 -2.5 -1.6 (-3.7, 0.6) 12 2.1 1.8 0.3 (-1.9, 2.6) 36 0.7 1.8 -1.1 (-3.7, 1.5)

3516 Background: ICIs produce durable benefit in MSI-H CRC, yet optimal treatment duration and monitoring strategies remain unclear. ctDNA enables minimally invasive assessment of molecular response during and after ICI. We evaluated real-world treatment patterns, outcomes, and longitudinal ctDNA dynamics in pts with MSI-H CRC treated with ICI. Methods: Pts with MSI-H mCRC treated with first-line ICI were identified from Natera’s Real-World Database with linked longitudinal ctDNA results (Signatera, Natera, Inc.) and commercial claims data (Forian’s Hybrid data ecosystem, CHRONOS). Overall survival (OS) was estimated using available mortality data (Veritas Data Research, Fact of Death Mortality Data Index). ctDNA status was assessed pre-ICI when available and longitudinally following ICI initiation. Outcomes included OS and time to next trmt (TTNT); ctDNA dynamics following ICI discontinuation were descriptively evaluated. Results: Among 559 pts treated with first line ICI (pembrolizumab [70.1%], ipilimumab+nivolumab [15.7%], and nivolumab [11.8%]), the median duration of ICI was 266 days. Baseline (pre-ICI) ctDNA results were available for 180 pts, including 38% who were treated with chemotherapy, and most pts (71.7%, 129/180) were ctDNA-positive (ctDNA(+)) prior to ICI initiation. Of these, 89.9% (116/129) had ctDNA-timepoints after the start of ICI, and 81.0% (94/116) achieved anytime ctDNA clearance (from ctDNA(+) to negative), while 19.0% (22/116) remained ctDNA(+). ctDNA(+) at anytime after the start of ICI (HR: 8.0, p < 0.0001) or on first result after the start of ICI (HR: 3.4, p < 0.0001) was associated with inferior OS compared ctDNA-negativity (ctDNA(-)) at these time points. Among pts whose first post-ICI test was ctDNA(+), 32% switched treatments, with a median TTNT of 302 days, compared to only 6.6% of pts (median TTNT 683 days) whose first post-ICI test was ctDNA(-). First post-ICI ctDNA status was associated with longer ICI duration (median 192 days for ctDNA(+) vs 303 days for ctDNA(-)), and ctDNA(+) was predictive of inferior OS (HR: 4.9; p < 0.001). ctDNA after the end of ICI was available for 392 patients; it was persistently negative in 77.2% (303/392), persistently positive in 12.8% (50/392), cleared after the end of ICI (positive to persistently negative) in 4.1%, and the remaining 5.9% had variable patterns (e.g. positive to negative to positive). Conclusions: In this large real-world cohort of MSI-H mCRC treated with ICI, longitudinal ctDNA dynamics strongly correlated with treatment durability, time to subsequent therapy, and OS. These findings support further evaluation of ctDNA to inform treatment duration and surveillance strategies in MSI-H mCRC.