Gastrointestinal Cancer Experts Spotlight the Most Exciting Abstracts Ahead of the 2025 ASCO Annual Meeting

Tanios S. Bekaii-Saab, MD

As the 2025 ASCO Annual Meeting comes into focus, OncLive® spoke with expert investigators in the field of gastrointestinal (GI) cancers to gain their insights on the research updates they are most excited to see presented during the meeting.

We gathered expert commentary from:

• Tanios S. Bekaii-Saab, MD, leader, Gastrointestinal Cancer Program, Mayo Clinic Comprehensive Cancer Center, medical director, Cancer Clinical Research Office, and vice chair and section chief, medical oncology at Mayo Clinic in Phoenix, Arizona
• Christine M. Parseghian, MD, associate professor, Department of Gastrointestinal Medical Oncology, Division of Medicine at The University of Texas MD Anderson Cancer Center in Houston
• Enrique Velazquez Villarreal, MD, PhD, MPH, MS, assistant professor, Department of Integrative Translational Sciences at City of Hope in Duarte, California
• Amit Mahipal, MD, Ruth and Donald Goodman Chair in GI Oncology at the University Hospitals Seidman Cancer Center in Cleveland, Ohio.

The investigators highlighted over 10 studies in the GI space to be on the lookout for during the meeting and explained their potential effects on clinical practice.

Abstract LBA1: Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III deficient DNA mismatch repair (dMMR) colon cancer (Alliance A021502; ATOMIC).

Session time: June 1, 1:05-1:17 pm CDT

Amit Mahipal, MD

Bekaii-Saab: If positive, this study may change the landscape of how we treat [patients with] mismatch repair–deficient [dMMR]/microsatellite instability–high [MSI-H] stage III, and potentially high-risk stage II, colon cancer in the adjuvant setting. [The questions] this study will not help answer are: Do we need chemotherapy? [What is the] optimal duration [of chemotherapy]? Do we need to expose patients for more than 6 months given what we know from neoadjuvant studies? Will there be an overall survival [OS] benefit? The latter is very important given the cost implications of adjuvant immuno-oncology [IO] therapy. [It will also not address the question of] whether we can better select patients who may benefit from IO.

Mahipal: This study could change the standard of care [SOC] for [patients with] resected dMMR/MSI-H colon cancer.

Abstract LBA3500: First-line encorafenib + cetuximab + mFOLFOX6 in BRAF V600E-mutant metastatic colorectal cancer (BREAKWATER): Progression-free survival and updated overall survival analyses.

Session time: May 30, 2:45-2:57 pm CDT

Christine M. Parseghian, MD

Parseghian: I am looking forward to seeing the updated survival data coming out of the phase 3 BREAKWATER trial [NCT04607421] of first-line encorafenib [Braftovi] plus cetuximab [Erbitux] and mFOLFOX6 [fluorouracil, leucovorin, and oxaliplatin] in [patients with] BRAF V600E–mutated metastatic colorectal cancer [CRC]. This study previously met one of its primary end points with an improvement in objective response rate [(ORR) vs chemotherapy with or without bevacizumab (Avastin)], resulting in accelerated approval from the FDA of the regimen in the frontline setting for this very aggressive subpopulation of patients with metastatic CRC.1 Further survival data will hopefully solidify the consistent use of this regimen in patients with treatment-naive disease.

Bekaii-Saab: This regimen was recently approved by the FDA through its accelerated mechanism based on the ORR benefit. Data to be presented at ASCO will include progression-free survival and updated OS data which may allow for a full approval if meaningfully positive. We also await the results of the FOLFIRI [5-fluorouracil, leucovorin, and irinotecan]-based combination in the near future.

Abstract LBA5: Event-free survival (EFS) in MATTERHORN: A randomized, phase 3 study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel chemotherapy (FLOT) in resectable gastric/gastroesophageal junction cancer (GC/GEJC).

Session time: June 1, 3:13-3:25 pm CDT

Bekaii-Saab: A recent press release disclosed that the primary end point of EFS was met and OS was improved, as a trend at least.2 The relevance of an end point such as EFS remains controversial, especially in the absence of a strong OS benefit, and as such it is best to interpret the results of this study with caution until the final OS analysis is disclosed.

Mahipal: Although OS data will be pending, if this is a positive trial and depending on magnitude of benefit, FLOT [fluorouracil, leucovorin, oxaliplatin, and docetaxel] plus durvalumab [Imfinzi] could become a new SOC for [patients with] localized gastroesophageal junction cancer.

Abstract 4000: Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiotherapy (CRT): First results of overall survival (OS) from CheckMate 577.

Session time: May 31, 3:00-3:12 pm CDT

Bekaii-Saab: Previous [data from] this study suggested a positive outcome from administration of nivolumab [Opdivo] in the adjuvant setting. Questions that remain include [the magnitude of the] OS benefit. If [the data are] positive, and with data from the [phase 3] MATTERHORN trial [NCT04592913] also being presented, will the strategy of the [phase 3] CheckMate 577 trial [NCT02743494] make further sense vs chemoimmunotherapy?

Abstract 4006: Preliminary results from the randomized phase 2 study (1801 part 3B) of elraglusib in combination with gemcitabine/nab-paclitaxel (GnP) versus GnP alone in patients (pts) with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC).

Session time: May 31, 4:36-4:48 pm CDT

Bekaii-Saab: This was a positive large phase 2 randomized study. A recent press release suggested positive OS outcomes and as such it met its primary [end point].3 The goal will be to confirm these results in a phase 3 randomized clinical trial that, if positive, will create a new SOC in this disease that desperately needs better ones.

Abstract LBA4005: PANOVA-3: Phase 3 study of tumor treating fields (TTFields) with gemcitabine and nab-paclitaxel for locally advanced pancreatic ductal adenocarcinoma (LA-PAC).

Session time: May 31, 4:24-4:36 pm CDT

Bekaii-Saab: A recent press release announced positive results with the study [achieving] OS benefit.4 With these positive results we may have an approval in [patients with] locally advanced pancreatic ductal adenocarcinoma.

Abstract 3506: Long-term safety and efficacy of sotorasib plus panitumumab and FOLFIRI for previously treated KRAS G12C-mutated metastatic colorectal cancer (mCRC): CodeBreaK 101 (phase 1b).

Session time: May 30, 4:45-4:57 pm CDT

Parseghian: I am anticipating the long-term safety and efficacy results from the phase 1b CodeBreaK 101 trial [NCT04185883] in patients with previously treated KRAS G12C–mutated metastatic CRC receiving sotorasib [Lumakras] plus panitumumab [Vectibix] and FOLFIRI. We saw in the phase 3 CodeBreaK 300 trial [NCT05198934] that the combination of sotorasib and panitumumab improved clinical outcomes, resulting in the FDA approval of this regimen in the chemotherapy-refractory setting.5 However, CodeBreaK 101 was the first study to evaluate the combination with FOLFIRI. If these data remain promising, then the ongoing phase 3 CodeBreaK 301 study [NCT06252649] evaluating this combination vs SOC in the first-line setting may be practice changing.

Abstract 3534: Open-label phase Ib/II study of cetuximab (CET) plus LY3214996 with or without abemaciclib in patients (pts) with anti-EGFR-refractory metastatic colorectal cancer (mCRC).

Session time: May 31, 9:00 am-12:00 pm CDT

Enrique Velazquez Villarreal, MD, PhD, MPH, MS

Velazquez Villarreal: This is one of the important studies where we are addressing an unmet need in [patients with] refractory CRC. We know that patients with anti–EGFR-refractory metastatic CRC have limited treatment options and a poor prognosis once tumors develop resistance to EGFR inhibitors such as cetuximab. Therapeutic alternatives are scarce. This study explores new combinations that could overcome resistance mechanisms and improve outcomes.

Abstract 3536: Survival of patients (pts) with microsatellite stable/mismatch repair proficient (MSS/pMMR) metastatic colorectal carcinoma (mCRC) treated with EO4010 + nivolumab (EO/N).

Session time: May 31, 9:00 am-12:00 pm CDT

Velazquez Villarreal: This is a study of a major group of patients with CRC who are resistant to immunotherapy. MSS/pMMR disease accounts for [approximately] 90% of cases of CRC. [This study] is largely looking at [patients who] are not responsive to immune checkpoint inhibitors, such as nivolumab, and there is a pressing need to unlock immune sensitivity in this large patient population. This study explores a novel immunomodulatory combination [consisting of] EO4010, a next-generation immunomodulatory agent, and nivolumab. This [approach] aims to prime the immune system and enhance T-cell activation in immune-cold tumors.

Abstract 3549: Outcomes of young-onset colorectal cancer vs late-onset colorectal cancer patients on phase 1 matched and non-matched therapies.

Session time: May 31, 9:00 am-12:00 pm CDT

Velazquez Villarreal: This [study] is important because it's highlighting the rising incidence of CRC in young adults. Young-onset CRC, which is diagnosed before the age of 50 [years old], has been increasing globally, whereas overall rates of CRC diagnosis have declined. [There are] questions about whether younger patients respond differently to treatment compared with older patients, and I believe there's a difference in tumor biology. There is emerging evidence that suggests that young-onset CRC may involve distinct molecular features [such as] MSI-H, germline mutations, or hypermethylation compared with late-onset CRC. Understanding whether these biological differences translate into viable responses to therapy is essential for tailoring treatment.

Abstract 3553: Vilastobart (XTX101), a tumor-activated, Fc-enhanced anti–CTLA-4 monoclonal antibody, in combination with atezolizumab in patients with MSS CRC.

Session time: May 31, 9:00 am-12:00 pm CDT

Velazquez Villarreal: This is a disease subtype that is highly resistant to current immunotherapies, including immune checkpoint inhibitors. MSI-H tumors often respond [well to] anti–PD-1 and anti–PD-L1 agents, but MSS tumors have remained largely unresponsive.

[Vilastobart has] an innovative mechanism of action that is basically tumor activated. [It is] an Fc-enhanced anti–CTLA-4 monoclonal antibody. This design allows for localized activation within the tumor microenvironment, potentially minimizing systemic toxicities, which are a major limitation of conventional CTLA-4 blockade, and enhanced antitumor immune activity. This research is important because it investigates a novel immunotherapy combination for [patients with] MSS CRC, a subtype that currently lacks effective immunotherapy options.

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 May 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf
2. IMFINZI (durvalumab)-based regimen demonstrated statistically significant and clinically meaningful improvement in event-free survival in resectable early-stage gastric and gastroesophageal junction cancers. News release. AstraZeneca. March 7, 2025. Accessed May 19, 2025. https://www.astrazeneca-us.com/media/press-releases/2025/IMFINZI-durvalumab-based-regimen-demonstrated-statistically-significant-and-clinically-meaningful-improvement-in-event-free-survival-in-resectable-early-stage-gastric-and-gastroesophageal-junction-cancers.html
3. Actuate Therapeutics announces statistically significant topline results from global phase 2 trial of elraglusib in first-line treatment of metastatic pancreatic cancer. News release. Actuate Therapeutics. May 6, 2025. Accessed May 19, 2025. https://actuatetherapeutics.com/press_releases/actuate-therapeutics-announces-statistically-significant-topline-results-from-global-phase-2-trial-of-elraglusib-in-first-line-treatment-of-metastatic-pancreatic-cancer/
4. Novocure announces positive topline results from phase 3 PANOVA-3 clinical trial of tumor treating fields (TTFields) therapy for pancreatic cancer. News release. Novocure. December 2, 2024. Accessed May 19, 2025. https://www.novocure.com/novocure-announces-positive-topline-results-phase-3-panova-3-clinical-trial-tumor-treating-fields
5. FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer. FDA. January 16, 2025. Accessed May 19, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sotorasib-panitumumab-kras-g12c-mutated-colorectal-cancer