Five Major Colorectal and GI Cancer Abstracts From 2025 ASCO
Key Points
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DYNAMIC-III: Circulating tumor DNA (ctDNA) positivity is not an effective marker for guiding treatment escalation in stage III colon cancer.
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ATOMIC: Atezolizumab added to FOLFOX improves disease-free survival (DFS) in stage III deficient DNA mismatch repair (dMMR) colon cancer.
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BREAKWATER: Encorafenib plus cetuximab doubles overall survival (OS) for patients with BRAF V600E–mutated metastatic colorectal cancer.
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MATTERHORN: Perioperative durvalumab improves event-free survival (EFS) and OS in gastric and gastroesophageal junction (GEJ) cancer.
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DESTINY-Gastric04: Trastuzumab deruxtecan (T-DXd) is superior to the second-line standard of care in HER2-positive upper gastrointestinal (GI) cancers.
The hosts of the Oncology Brothers podcast—Rahul Gosain, MD, MBA, and Rohit Gosain, MD—met with Cathy Eng, MD, FACP, FASCO, of Vanderbilt-Ingram Cancer Center, to discuss major abstracts on colorectal and upper GI cancers that were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.
The doctors covered the BREAKWATER study, which Dr. Eng helped author, as well as data from the DYNAMIC-III, ATOMIC, MATTERHORN, and DESTINY-Gastric04 trials.
Using Circulating Tumor DNA to Guide Adjuvant Treatment in Colon Cancer
The DYNAMIC III trial evaluated the use of ctDNA to guide treatment escalation after resection surgery in patients with stage III colon cancer. Participants were randomized to ctDNA-informed management or standard of care.
Patients in the ctDNA-informed arm who were ctDNA positive had their preplanned adjuvant chemotherapy escalated to one of the following: 5-fluorouracil (5-FU) or capecitabine, 3 months or 6 months of oxaliplatin-based doublet, or at least 3 months of FOLFOXIRI (leucovorin [folinic acid], 5-FU, oxaliplatin, and irinotecan).
The primary analysis presented at the 2025 ASCO Annual Meeting was the 2-year recurrence-free survival (RFS) in ctDNA-positive patients. Notably, therapy escalation did not appear to improve RFS, as the ctDNA-positive arm had a 2-year RFS of 52% (90% CI, 44-59) compared with 61% (90% CI, 54-68) in the standard of care arm (hazard ratio [HR], 1.11; 90% CI, 0.83-1.45; P = .57).
The negative finding still raised some pertinent questions for researchers, Dr. Eng said, including whether the available treatment options for stage III colon cancer are inadequate. She also noted that the DYNAMIC III data may impact the ongoing phase 3 CIRCULATE-US trial.
Combining Atezolizumab With FOLFOX in Stage III DNA Mismatch Repair Colon Cancer
The ATOMIC trial enrolled patients with stage III deficient dMMR colon cancer to evaluate the addition of atezolizumab to standard adjuvant FOLFOX after resection. Patients in the atezolizumab arm received FOLFOX (leucovorin, 5-FU, and oxaliplatin) plus atezolizumab for 6 months followed by another 6 months of atezolizumab alone.
The study fulfilled its primary end point, as the atezolizumab arm had a 3-year DFS rate of 86.4% (95% CI, 81.8-89.9) compared with 76.6% (95% CI, 71.3-81.0) in the standard FOLFOX arm (HR, 0.50; 95% CI, 0.34-0.72; P < .0001). The benefit was seen across subgroups including age, sex, race, tumor location, T stage, N stage, and risk stratification.
“I think [ATOMIC] is a very pivotal trial. It provides us the answer that immunotherapy has a role in the adjuvant setting for this patient population,” Dr. Eng said. She noted that ATOMIC doesn’t answer whether immunotherapy alone is a viable adjuvant option.
For practical purposes, Dr. Eng suggested community oncologists stratify patients with stage III dMMR colon cancer by low- or high-risk disease to determine the appropriate duration of FOLFOX.
Adding Encorafenib and Cetuximab to FOLFOX in Metastatic Colorectal Cancer
For the final colorectal cancer trial from the ASCO meeting, the doctors discussed the phase 3 BREAKWATER trial, which evaluated adding encorafenib plus cetuximab to standard first-line FOLFOX in patients with BRAFV600E–mutated metastatic colorectal cancer.
The trial initially included a third arm to evaluate first-line encorafenib plus cetuximab, but that arm was discontinued based on data from the ANCHOR trial, Dr. Eng said.
According to the ASCO report, the median progression-free survival (PFS) was 12.8 months (95% CI, 11.2-15.9) in the encorafenib-plus-cetuximab arm compared with 7.1 months (95% CI, 6.8-8.5) in the FOLFOX arm. Additionally, OS was 30.3 months (95% CI, 21.7–not estimable) with encorafenib plus cetuximab versus 15.1 months (95% CI, 13.7-17.7) with FOLFOX.
The doctors noted that encorafenib plus cetuximab has a toxicity profile comparable with other EGFR inhibitor combinations, so oncologists should be prepared to manage rash, diarrhea, myelosuppression, and fatigue.
Overall, the BREAKWATER trial “really gives a lot of hope to this patient population, which always had such a poor prognosis,” Dr. Eng said. “Even with FOLFOXIRI, they historically still only had an overall survival of 12 to 14 months.”
Perioperative Durvalumab and FLOT in Resectable Upper GI Cancers
Moving on from colorectal cancer abstracts, the doctors discussed the phase 3 MATTERHORN trial on adding durvalumab to perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) in patients with gastric or GEJ cancer.
Patients randomized to the durvalumab arm received 2 doses of durvalumab and 4 doses of FLOT both before and after surgery, plus up to 10 subsequent doses of durvalumab. The primary end point was EFS, and the secondary end point was OS.
The median EFS was not reached (NR; 95% CI, 40.7-NR) in the durvalumab arm compared with 32.8 months (95% CI, 27.9-NR) in the standard of care arm (HR, 0.71; 95% CI, 0.58-0.86; P < .001). Additionally, the median OS was NR (95% CI, NR-NR) in the durvalumab arm compared with 47.2 months (95% CI, 45.1-NR) in the FLOT arm (HR, 0.78; 95% CI, 0.62-0.97; P = .025).
While the survival benefits are meaningful, Dr. Rahul Gosain noted that the MATTERHORN data do not answer how valuable the adjuvant immunotherapy component is, a question raised in many perioperative immunotherapy trials in other cancers.
Second-Line Trastuzumab-Deruxtecan Versus Ramucirumab Plus Paclitaxel in HER2-Positive GI Cancer
The phase 3 DESTINY-Gastric04 compared T-DXd with standard ramucirumab plus paclitaxel in second-line treatment of patients with HER2-positive unresectable or metastatic gastric or GEJ cancer. The primary end point was OS, and the key secondary end point was PFS.
The T-DXd arm had a median OS of 14.7 months (95% CI, 12.1-16.6) versus 11.4 months (95% CI, 9.9-15.5) in the ramucirumab-plus-paclitaxel arm (HR, 0.70; 95% CI, 0.55-0.90; P = .0044). Median PFS was 6.7 months (95% CI, 5.6-7.1) and 5.6 months (95% CI, 4.9-5.8) with T-DXd and ramucirumab plus paclitaxel, respectively (HR, 0.75; 95% CI, 0.59-0.92; P = .0074).
“I think these findings are going to change our approach to the second-line setting for this patient population,” Dr. Eng said, adding that it was surprising to see no reports of grade 5 interstitial lung disease.
Dr. Rohit Gosain cited recent data from breast cancer trials showing a survival benefit moving T-DXd to the first-line setting and suggested it wouldn’t be surprising to see T-DXd investigated in earlier lines of treatment for GI cancer.