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GI Highlights From ASCO
Changing Gastrointestinal Cancer Care—Highlights From the 2025 ASCO Annual Meeting

Released: August 26, 2025

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Key Takeaways
  • The ATOMIC trial results establish mFOLFOX6 plus atezolizumab as the new adjuvant standard of care for stage III mismatch repair–deficient colon cancer, reducing recurrence risk by 50% with manageable toxicity. 
  • The MATTERHORN trial demonstrates that adding durvalumab to perioperative FLOT chemotherapy (DFLOT) significantly improves event-free survival and pathologic complete response in resectable gastric and gastroesophageal junction adenocarcinoma. 
  • The phase 3 randomized CHALLENGE trial shows a clear cancer survival benefit from a structured exercise program following adjuvant chemotherapy in patients with  high-risk stage II and stage III colon cancer resected colon cancer. 

In this commentary, I discuss 3 practice-changing clinical trials for gastrointestinal cancers that featured prominently at the ASCO 2025 annual meeting. These trials  are paradigm-shifting studies demonstrating a new standard of care for patients with  resectable colon cancer and patients with resectable stage II/III gastric cancer and gastroesophageal junction (GEJ) adenocarcinoma.

ATOMIC Trial
First, the phase III ATOMIC trial evaluated adding atezolizumab to adjuvant modified 5-fluorouracil/leucovorin/oxaliplatin (mFOLFOX6) chemotherapy in patients with resected stage III mismatch repair–deficient (dMMR) colon cancer. Previously, PD-1/PD-L1 inhibitors demonstrated efficacy, durable responses, and treatment-free remissions in metastatic dMMR colon cancer. The ATOMIC trial was designed to answer the question of whether these benefits extended to the approximately 15% of our patients with stage III disease and dMMR status. This question was of particular importance since there is concern that patients with MSI-High colon cancer do not respond well to chemotherapy (previous data has shown that 5-FU monotherapy is ineffective MSI-High colon cancer).

This multicenter, open-label phase III clinical trial randomized more than 700 patients with stage III dMMR colon cancer to receive either 6 months of mFOLFOX6 alone or mFOLFOX6 combined with atezolizumab, followed by maintenance atezolizumab (840 mg every 2 weeks) for up to 1 year of treatment. The results showed a clear benefit in DFS with the addition of atezolizumab. At 3-years, 86.4% of patients who received atezolizumab remained free of any signs or symptoms of their cancer compared with  76.6 % of patients treated with mFOLFOX6 alone (HR 0.5, P <0.0001). This DFS benefit with the addition of atezolizumab was seen across all patient subgroups examined including low-risk and high-risk stage III disease, proximal and distal tumors, and older or younger patients.

In general, this trial showed manageable side effects with slight increases seen with the addition of atezolizumab to adjuvant chemotherapy. About 72% of patients had a grade 3/4 treatment-related AE in the adjuvant chemotherapy plus atezolizumab arm compared with 59% in the adjuvant chemotherapy alone arm. The immune-mediated AEs were what one would expect from adding PD‑1/PD-L1–directed therapy to chemotherapy. Treatment-related mortality remained low with 6 deaths in the combination arm and 2 in the chemotherapy-only arm.

My takeaway from the ATOMIC trial is that going forward, adjuvant mFOLFOX6 plus atezolizumab should be considered the standard of care for patients with resected stage III dMMR colon cancer. Looking forward, I think 2 important questions will need to be addressed in the future 1) whether patients with low-risk stage III colon cancer really need 6 months of adjuvant chemotherapy or could just do 3 months of adjuvant chemotherapy and (2) whether a neoadjuvant immunotherapy strategy, which has been looked at in phase II trials, might be an even better approach.

MATTERHORN Trial
Next, the MATTERHORN trial evaluated the addition of durvalumab to perioperative fluorouracil/leucovorin/oxaliplatin/docetaxel (FLOT) chemotherapy in resectable gastric and GEJ adenocarcinomas. This was a very important study because a major challenge facing our patients with gastroesophageal cancer is the high rate of recurrence. Following the ESOPEC trial results presented at ASCO 2024, perioperative FLOT became the standard of care for patients with stage II and III disease. Building on this, the MATTERHORN trial asked whether outcomes could be improved further by adding durvalumab to perioperative FLOT chemotherapy.

This trial was an international, double-blind, placebo-controlled, randomized phase III trial that enrolled 948 patients who were randomized 1:1 to standard perioperative FLOT or FLOT plus durvalumab 1500 mg every 4 weeks (DFLOT). Both arms received 4 cycles of FLOT before surgery and 4 cycles after surgery with adjuvant durvalumab or placebo continued for up to 1 year. It is important to note that 90% of patients in this trial had a PD‑L1–positive tumor (≥1%).

The primary endpoint was event-free survival, and the data were impressive with a nearly 30% reduction in the risk of a negative event with the addition of durvalumab (HR: 0.71; P <.001). Approximately 73.2% of patients in the DFLOT arm were event free at 18 month, compared with 63.6% in the FLOT arm. At 24 months, the data still held at 67% and 58%, respectively. Also, it is important to remember that the pathologic complete response rate was 19.0% in the DFLOT arm and 7.0% in the control arm, suggesting the increased potency of this regimen. The overall survival data are still maturing.

In terms of safety, the results from this trial were also as expected. The treatment-related AEs were manageable, without a significant difference in the incidence of grade 3/4 AEs between the arms. There were no significant differences in the rates of surgical delay or in patients who were unable to proceed to surgery—a critical concern in perioperative trials. As expected, immune-related AEs were more common in the experimental arm with durvalumab, but again, those were manageable.

In summary, I think that the MATTERHORN trial establishes a new standard of care for stage II and III gastric/GEJ adenocarcinoma. The results suggest that among fit patients, DFLOT should become the preferred perioperative regimen once it is approved. I do think that FLOT is a hard chemotherapy regimen for patients, but for my patients who can tolerate FLOT, I will treat them by giving perioperative DFLOT. However, for my unfit patients who may not tolerate FLOT because of age or comorbidities, I will consider chemoradiation followed by adjuvant nivolumab as an option.

CHALLENGE Trial
Finally, the CHALLENGE trial was a randomized phase III study for patients with high-risk stage II and stage III  resected colon cancer that evaluated the incorporation of a 3-year structured exercise program (SEP) into treatment after completing their adjuvant chemotherapy. Previous observational data suggested an association between exercise and survival in patients with colon cancer. The prospective, randomized CHALLENGE trial evaluated whether exercise has an impact on improving outcomes in patients with colon cancer. The primary endpoint was DFS. 

The CHALLENGE trial randomized 889 patients with resected stage III or high-risk stage II colon cancer who completed adjuvant chemotherapy within 2-6 months. The SEP intervention required patients to gradually increase their physical activity up to 10 units of energy per week over their baseline, which could be accomplished with 45-minute brisk walks 3-4 times per week in the first 6 months on the study. Although the control arm was standard surveillance, both study arms were provided with health education materials.

At 60 months, the DFS for patients in the SEP group was 80.3% compared with 73.9% in the control group (HR: 0.72; P = .017). Participants in the control group were more likely than those in the SEP group to be diagnosed with recurrence in the liver (29 vs 16) or new cases of breast cancer (12 vs 2), prostate cancer (9 vs 5), and colorectal cancer (5 vs 0). For every 16 patients, exercise prevented 1 individual from experiencing a recurrence or a new cancer diagnosis. The overall survival at 96 months was 90.3% in the SEP group and 83.2% in the control group (HR: 0.63; P = .022). Results of the CHALLENGE trial suggest long-term benefits of incorporating exercise as an interventional treatment in colon cancer.

The results were impressive and showed us that exercise can help our patients. Now, I am recommending exercise for all of my patients with colorectal cancer after they finish adjuvant chemotherapy. Even a small amount of exercise, like a 45‑minute walk for 3 or 4 days per week, seems like a big win for our patients.

Summary
In conclusion, in my opinion, these 3 trials produced paradigm-shifting results for our clinical practice and are wonderful news for our patients.

The ATOMIC trial establishes mFOLFOX6 plus atezolizumab as a new standard for patients with stage III dMMR colon cancer. The MATTERHORN trial supports the combination of durvalumab plus FLOT chemotherapy as the optimal regimen for resectable stage II and III gastric and GEJ cancers and we await approval.

Finally, the CHALLENGE trial shows that moderate exercise improved survival in patients with high-risk stage II and stage III resected colon cancer. I am now encouraging my patients to go out and walk to improve their outcomes.

Your Thoughts
What do you think about the findings from these trials? Will you change your practice and how you counsel your patients with gastrointestinal cancers based on these results?

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Do you plan to change your practice based on evidence reported from the ATOMIC, MATTERHORN, or CHALLENGE trials? Please select all that apply.

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