ASCO 2025 Highlights: Breakthroughs in GI Oncology From BREAKWATER, MATTERHORN, ATOMIC & CHALLENGE

Sawyer Bawek, DO University at Buffalo

The 2025 American Society of Clinical Oncology (ASCO) Annual Meeting featured several major developments in gastrointestinal (GI) oncology, showcasing potentially practice-changing findings across four key trials: BREAKWATER, MATTERHORN, ATOMIC, and CHALLENGE.

1. BREAKWATER: encorafenib plus cetuximab (EC) and modified FOLFOX6 (mFOLFOX6; leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin) in BRAF-mutated colorectal cancer (CRC)
2. MATTERHORN: event-free survival (EFS)—durvalumab plus FLOT (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) chemotherapy in resectable gastric cancer/gastroesophageal junction cancer (GC/GEJC)
3. ATOMIC: standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III deficient DNA mismatch repair (dMMR) colon cancer
4. CHALLENGE: structured exercise after adjuvant chemotherapy for colon cancer

Key Takeaways From the BREAKWATER Trial 

Progression-Free Survival 

• Patients who received EC with mFOLFOX6 had a significantly longer progression-free survival (PFS) of 12.8 months versus 7.1 months for standard of care (hazard ratio [HR], 0.53; P < .0001). 

Overall Survival 

• Patients who received EC with mFOLFOX6 had a significantly longer overall survival (OS) of 30.3 months compared with 15.1 months for standard of care (HR, 0.49; P < .0001).

Treatment-Related Adverse Events 

• EC with mFOLFOX6: 46.1%
• Standard of care: 38.9%

Background 

Patients with BRAF V600E–mutant metastatic CRC have poor prognoses and limited treatment options. The BREAKWATER trial is the first phase 3 study to evaluate EC with mFOLFOX6 as a first-line treatment option for this patient population.

BREAKWATER Trial Design

• Population: patients with untreated BRAF V600E-mutated metastatic CRC
• Study arms: randomized 1:1:1 to receive EC, EC with mFOLFOX6, or EC without mFOLFOX6
• Primary end point: PFS

Takeaway for Community Oncologists

The BREAKWATER trial offers a potential first-line standard of care therapy for BRAF V600E–mutant metastatic CRC. The trial showed significant results, with improvements in objective response rate (previously reported), PFS, and OS when using EC plus mFOLFOX6 over standard of care. The significantly improved survival outcomes, along with a manageable safety profile, support an exciting new potential first-line treatment option for patients with BRAF V600E–mutant metastatic CRC. 

Key Takeaways From the MATTERHORN Trial 

2-Year Event-Free Survival

• Durvalumab plus FLOT showed a significant improvement in EFS versus placebo plus FLOT (67.4% vs 58.5%; HR, 0.71; P < .001).

2-Year Overall Survival

• Durvalumab plus FLOT showed improved OS versus placebo plus FLOT (75.7% vs 70.4%).

Pathological Complete Response

• Durvalumab plus FLOT: 19.2%
• Placebo plus FLOT: 7.2%

Treatment-Related Adverse Events 

• Maximum grade 3 or 4 treatment-related adverse event (TRAE) rates were similar between durvalumab plus FLOT (71.6%) and placebo plus FLOT (71.2%).

Delayed Surgery or Delayed Initiation of Adjuvant Treatment

• Percentage of patients with delayed surgery was 10.1% (durvalumab plus FLOT) versus 10.8% (placebo plus FLOT).
• Percentage of patients with delayed initiation of adjuvant treatment was 2.3% (durvalumab plus FLOT) versus 4.6% (placebo plus FLOT).

Background 

Perioperative treatment with FLOT is the standard of care for patients with resectable gastric or GEJ adenocarcinoma. However, most patients have disease recurrence following resection, necessitating an improvement in the standard of therapy. MATTERHORN is the first large, phase 3 trial to evaluate immunotherapy (durvalumab) combined with FLOT in the perioperative setting in this patient population.

MATTERHORN Trial Design

• Population: patients with resectable gastric or GEJ adenocarcinoma
• Study arms: durvalumab (1500 mg) or placebo plus FLOT every 4 weeks for 4 cycles, followed by durvalumab or placebo every 4 weeks for 10 cycles
• Primary end point: EFS

Takeaway for Community Oncologists

Perioperative FLOT is the standard of care in resectable gastric or gastroesophageal junction cancers in Western countries, but recurrence rates remain high. Immunotherapy is not yet approved in neoadjuvant or adjuvant settings but is approved in combination with chemotherapy for metastatic GC/GEJC. The MATTERHORN trial demonstrated improved EFS with the addition of perioperative durvalumab to FLOT for patients with resectable GC/GEJC without new safety concerns. These findings support perioperative durvalumab plus FLOT as a potential new first-line treatment in this setting. However, it remains to be seen whether the study will meet the OS end point.

Key Takeaways From the ATOMIC Trial 

Disease-Free Survival 

• The 3-year disease-free survival (DFS) rate was 86.4% for patients treated with mFOLFOX6 plus atezolizumab compared with 76.6% for mFOLFOX6 alone (HR, 0.50; P < .0001).

Overall Survival

• OS data are not yet mature.

Treatment-Related Adverse Events 

• Grade 3 or higher TRAES occurred in 71.7% of patients who received mFOLFOX6 plus atezolizumab compared with 62.1% in the mFOLFOX6 arm.
• The safety profile was in line with known safety profiles of each approach, with an increase in nonfebrile neutropenia.

Background

Current standard adjuvant chemotherapy for stage III colon cancer consists of fluoropyrimidine plus oxaliplatin. The ATOMIC trial evaluated the use of immunotherapy combined with adjuvant chemotherapy for patients with stage III dMMR colon cancer.

ATOMIC Trial Design

• Population: patients with stage III dMMR colon cancer
• Study arms: randomized 1:1 to receive mFOLFOX6 plus atezolizumab for 12 cycles, followed by atezolizumab monotherapy for 13 cycles, versus mFOLFOX6 alone for 12 cycles
• Primary end point: DFS

Takeaway for Community Oncologists

ATOMIC is another practice-changing trial that offers a potential new adjuvant standard of care for patients with stage III dMMR colon cancer. Participants who received mFOLFOX6 plus atezolizumab showed significantly improved DFS compared with mFOLFOX6 alone with known safety profiles.

Key Takeaways From the CHALLENGE Trial 

Disease-Free Survival 

• DFS was significantly longer in the exercise group compared with the health education group (HR, 0.72; P = .017). The 5-year DFS was 80.3% in the exercise group versus 73.9% in the health education group. 

Overall Survival

• Patients in the exercise group had longer OS than the health education group (HR, 0.63). 
• The 8-year OS was 90.3% in the exercise group compared with 83.2% in the health education group.

Musculoskeletal Adverse Events 

• Exercise group: 18.5%
• Health education group: 11.5%

CHALLENGE Trial Design

• Population: patients with resected colon cancer post-adjuvant chemotherapy
• Study arms: randomized 889 patients to exercise (445) or health education (444)
• Primary end point: DFS

Takeaway for Community Oncologists

The CHALLENGE trial provides strong evidence for the benefit of a structured exercise program for patients with resected colon cancer post-adjuvant chemotherapy. This nonpharmacologic intervention showed significant improvement in both DFS and OS and also demonstrated other benefits, including a decrease in new primary cancers and improved cardiorespiratory fitness. Most of the increased musculoskeletal adverse events were mild, with no major safety concerns. The results underscore the importance of educating patients on the benefits of exercise. Oncologists can consider integrating referrals for supervised exercise and incorporating exercise counseling in follow-up care.