ISGIO Conference Highlights Emerging Trial Results Shaping GI Cancer Care

Despite being among the most frequently mutated oncogenes in cancer, RAS mutations have long eluded effective therapeutic strategies. However, recent advances in direct RAS targeting are yielding promising outcomes, particularly in gastrointestinal (GI) cancers. Breakthroughs in clinical trials, novel drug approvals, and innovative therapeutic combinations are reshaping treatment paradigms for clinicians and patients alike.

“There is significant excitement around targeting RAS mutations fueled by recent approvals and emerging clinical trial results,” Tanios S. Bekaii-Saab, MD, the David F. and Margaret T. Grohne Professor of Novel Therapeutics for Cancer Research I; professor, Mayo Clinic College of Medicine and Science; and program leader, Advanced Clinical Trials and Translational Science, Mayo Clinic, Phoenix, Arizona, said during an interview with Targeted Therapies in Oncology.

He also highlighted trials such as BREAKWATER (NCT04607421) that evaluated the combination of cetuximab (Erbitux) and encorafenib (Braftovi) plus chemotherapy that resulted in FDA approval.¹

“We’re now evaluating RAS inhibitors in both first- and second-line settings, with activity driven by targeted therapies tailored to specific mutations,” Bekaii-Saab said.

With major conferences, such as the American Society of Clinical Oncology Gastrointestinal Cancers Symposium and the European Society for Medical Oncology Gastrointestinal Cancers Congress, presenting a deluge of trial data, community oncologists need dedicated opportunities to digest findings, discuss implications, and integrate them into clinical practice.

The upcoming 2025 International Symposium of Gastrointestinal Oncology (ISGIO), sponsored by Physicians’ Education Resource (PER), LLC, on September 12 and 13, 2025, in Austin, Texas, aims to do just that. “ISGIO offers clinicians the chance to learn about what’s new, what’s exciting, and what’s practice changing,” said Bekaii-Saab, who will co-chair the meeting with Eileen M. O’Reilly, MD, FASCO. Given the breakthroughs in the field, he hopes attendees at ISGIO will gain clarity on the evolving treatment landscape, including its impact on patient outcomes and emerging therapies to watch.

There are a number of trials in the GI setting that will be important for clinicians to be aware of. Specifically, in the colorectal setting, one subgroup of patients being watched closely includes the microsatellite instability-high (MSI-H) or the mismatch repair deficient (dMMR) group.

CheckMate-8HW Trial

The CheckMate 8HW trial (NCT04008030)² evaluated the combination of nivolumab (Opdivo) with ipilimumab (Yervoy) as a first-line treatment for adult and pediatric patients aged 12 years and older with MSI-H or dMMR colorectal cancer.

Based on the efficacy data from the trial, the combination was approved by the FDA on April 8, 2025.³

In the trial, the combination demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) vs the investigator’s choice of chemotherapy. Among 255 patients with centrally confirmed MSI-H or dMMR tumors, the median PFS was not reached (95% CI, 38.4-not evaluable [NE]) in the frontline nivolumab/ipilimumab arm (n = 171) vs 5.8 months (95% CI, 4.4-7.8) in the frontline chemotherapy arm (n = 84; HR, 0.21; 95% CI, 0.14-0.32; P <.0001).

In a broader subset of 582 patients with centrally confirmed MSI-H/dMMR status (from an initial 707 identified via local testing), outcomes were compared between nivolumab plus ipilimumab and nivolumab monotherapy across all lines of therapy.

The median PFS was not reached in the combination arm (95% CI, 53.8-NE) vs 39.3 months in the nivolumab arm (95% CI, 22.1-NE), with an HR of 0.62 (95% CI, 0.480.81; P =.0003). The objective response rate (ORR) was 71% (95% CI, 65%-76%) with the combination and 58% (95% CI, 52%-63%) with monotherapy (P =.0011).

“We’re still determining the value of adding a CTLA-4 inhibitor to a PD-1 inhibitor, but these findings are intriguing and seem promising,” Bekaii-Saab said. “We’re waiting on the first-line comparative data for nivolumab vs ipilimumab plus nivolumab, and that may actually change practice,” Bekaii-Saab continued.

ATOMIC Trial

“We’re eagerly awaiting the results of the ATOMIC trial [NCT02912559],⁴ which is evaluating the combination of chemotherapy and atezolizumab [Tecentriq] in the adjuvant setting in patients with MSI-H,” Bekaii-Saab said.

Patients with curatively resected stage III colon cancer with evidence of dMMR will be randomly assigned to receive atezolizumab combined with FOLFOX (oxaliplatin, leucovorin calcium, and fluorouracil) and atezolizumab monotherapy compared with FOLFOX alone (FIGURE). The primary end point is disease-free survival, and the second end points are overall survival (OS), safety, and quality of life.

Investigators have identified a targeted accrual goal of 700 patients with 165 disease-free survival events for 90% power.

“The ATOMIC trial may shed some light on the role of adjuvant therapy, including immunotherapy-based therapy for patients with resectable MSI-H colon cancer,” Bekaii-Saab added.

BREAKWATER Trial

In BRAF V600E disease, findings from the phase 3 BREAKWATER trial showed encouraging response rates and trends in improvement in OS for the combination of encorafenib (Braftovi) and cetuximab (Erbitux) compared with mFOLFOX6.⁵

In the encorafenib plus cetuximab and chemotherapy arm (n = 110), the ORR was 60.9% (95% CI, 51.6%-69.5%) per blinded independent central review compared with 40.0% (95% CI, 31.3%-49.3%) in the chemotherapy alone arm (n = 110; OR, 2.443; 95% CI, 1.403-4.253; 1-sided P =.0008).⁵

Schema for ATOMIC trial (NCT02912559)

The best responses in the experimental arm were complete response (CR; 2.7%), partial response (58.2%), stable disease (28.2%), progressive disease (PD; 2.7%), non-CR/ non-PD (2.7%), and NE (5.5%) compared with rates of 1.8%, 38.2%, 30.9%, 3.6%, 8.2%, and 17.3% in the control arm, respectively.⁵

The median time to response in the triplet arm was 7.1 weeks (range, 5.753.7) vs 7.3 weeks (range, 5.4-48.0) in the chemotherapy arm, and the estimated durations of response (DOR) across groups were 13.9 months (range, 8.5-NE) and 11.1 months (range, 6.7-12.7), respectively.

The 6- and 12-month DOR rates were 68.7% and 22.4%, and 34.1% and 11.4%, respectively. The interim OS showed a median follow-up of 10.3 months (95% CI, 8.6-11.6) in the treatment arm and 9.8 months (95% CI, 7.5-11.3) in the control arm.

The median OS was not evaluable (95% CI, 19.8-NE) in the treatment arm vs 14.6 months (95% CI, 13.4-NE) in the control arm, respectively (HR, 0.47; 95% CI, 0.318-0.691; P =.0000454). The OS difference was not statistically significant.

“We still need the final data, including PFS data, to make full sense of the findings as this disease is very aggressive. It’s important to expose these patients to biologic therapies sooner, rather than later, and the findings from BREAKWATER demonstrate this,” Bekaii-Saab said.

Microsatellite Stable

In patients with microsatellite stable (MSS) colorectal cancer, preliminary data from a phase 2 trial (NCT05608044)⁶ evaluating botensilimab with or without balstilimab has some interesting findings, according to Bekaii-Saab.

In the study, 234 patients with MSS metastatic colorectal cancer with no liver metastases were randomly assigned to receive 75 mg or 150 mg of botensilimab, 75 mg or 150 mg of botensilimab plus 240 mg of balstilimab, or standard of care regorafenib (Stivarga) or trifluridine/tipiracil (Lonsurf). The primary end point was ORR.

The investigators reported that the overall ORR was higher with the combination of botensilimab and balstilimab vs botensilimab alone.

The highest ORR was observed in patients who received the 75 mg botensilimab/ 240 mg balstilimab regimen.

“I think the data are intriguing, but at this point, I don’t think it’s powerful enough to change practice,” Bekaii-Saab said.

As ISGIO approaches, these trials underscore the rapid progress in GI oncology, offering clinicians new tools to improve patient outcomes. To register for the upcoming ISGIO conference, visit https://tinyurl.com/2cr6why3.

REFERENCES:
1. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. FDA. December 20, 2024. Accessed April 29, 2025. https://tinyurl.com/57w3ze2h

2. Andre T, Elez E, Van Cutsem E, et al. Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer. N Engl J Med. 2024;391(21):2014-2026. doi:10.1056/ NEJMoa2402141

3. FDA approves nivolumab with ipilimumab for unresectable or metastatic MSI-H or dMMR colorectal cancer. FDA. April 8, 2025. Accessed April 30, 2025. https://tinyurl.com/yetefxs4

4. Sinicrope FA, Ou FS, Zemla T, et al. Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III colon cancer and deficient mismatch repair (ATOMIC, Alliance A021502). J Clin Oncol. 2019;37(supp 15):e15169. doi:10.1200/ JCO.2019.37.15_suppl.e15169

5. Kopetz S, Yoshino T, Van Cutsem E, et al. BREAKWATER: analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer. J Clin Oncol. 2025;43(supp 4):16. doi:10.1200/JCO.2025.43.4_suppl.16

6. Fakih M, Segal NH, Schlechter BL, et al. Preliminary results from a randomized, open-label, phase 2 study of botensilimab (BOT) with or without balstilimab (BAL) in refractory microsatellite stable metastatic colorectal cancer with no liver metastases (MSS mCRC NLM). J Clin Oncol. 2025;43(suppl 4):23. doi:10.1200/JCO.2025.43.4_suppl.2