ESMO 2025 Will See Novel Agents Emerge and Standard Strategies Shift in GI Oncology

From further clarifying the role of PD-(L)1 inhibition in gastric cancer and colorectal cancer (CRC), to demonstrating the potential predictive value of minimal residual disease (MRD) negativity in late-stage colon cancer, gastrointestinal oncology data presented at the 2025 ESMO Congress are anticipated to challenge current standards of care (SOCs) and bring new questions to the forefront of research in the field. Additionally, data with KRAS inhibitors in pancreatic cancer are expected to further refine a treatment paradigm that has undergone much evolution in recent years.

OncLive® collected exclusive commentary from:

• Tanios S. Bekaii-Saab, MD, the David F. and Margaret T. Grohne Professor of Novel Therapeutics for Cancer Research I at the Mayo Clinic College of Medicine and Science, chairman for the Division of Hematology/Medical Oncology at Mayo Clinic, and co-leader of the Advanced Clinical and Translational Science Program and the Disease Group leader for Gastrointestinal Cancers for the Mayo Clinic Cancer Center in Phoenix, Arizona
• Suneel Kamath, MD, an assistant professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, as well as a gastrointestinal (GI) medical oncologist at Cleveland Clinic in Ohio
• Kanwal P. S. Raghav, MBBS, MD, a professor in the Department of Gastrointestinal Medical Oncology in the Division of Cancer Medicine, associate vice president of the Department of Ambulatory Medical Operations, and executive medical director of the Department of Ambulatory Treatment Centers at The University of Texas MD Anderson Cancer Center in Houston

“We’re all looking forward to data with immuno-oncology [IO] and VEGF [inhibitor] combinations that might be coming out,” Raghav said. “There are data on multiple antibody-drug conjugates with colorectal expansions that are coming forward, [including] data on HER2 and the long-term outcomes for the now FDA-approved fam-trastuzumab deruxtecan-nxki [Enhertu] in CRC. It’s going to be an exciting ESMO.”

Read on for exclusive insights about the most anticipated presentations and their potential future implications for the field of GI oncology.

LBA81 - Final overall survival (OS) and the association of pathological outcomes with event-free survival (EFS) in MATTERHORN: A randomised, phase III study of durvalumab (D) plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric / gastroesophageal junction (G / GEJ) adenocarcinoma

Presentation time: Friday, October 17, 2025, 14:00-14:10 CEST

Bekaii-Saab: The phase 3 MATTERHORN trial [NCT04592913] is a study that looked at perioperative FLOT plus or minus durvalumab [Imfinzi] for patients with resectable gastric or GEJ cancer.1 The primary outcome of this [trial] was EFS, and the secondary end points included [OS], as well as pathologic outcomes. The study met its primary end point of EFS. [Those data were] presented at the 2025 ASCO Annual Meeting. [Perioperative FLOT plus durvalumab] was integrated into the National Comprehensive Cancer Network [NCCN] guidelines for patients with [gastric/GEJ cancer with a PD-L1] combined positive score [CPS] of at least 1.2,3

The study included patients with both PD-L1–positive and –negative disease, but we haven’t seen the data [in the PD-L1–negative population yet]. What we will see at ESMO 2025 is an update to see if there are further data about CPS as it correlates with EFS. One of the limiting factors with EFS is that it’s not a well-validated end point. It’s validated enough to be included as a primary end point, but we don’t know how well it correlates with OS or other outcomes. We’re hoping to gather a bit more information as more data are presented from this study.

The study may end up being positive for EFS, but negative for OS. Then the question is: Is it worth using durvalumab in this setting? [The study may also] confirm that PD-L1–positive patients are the only ones who have improved outcomes. But if PD-L1–negative patients also do well, then we would consider expanding the indication for durvalumab. It is not approved by the FDA, although it’s on the NCCN guidelines.

LBA84 - Efficacy and safety of GFH375 monotherapy in previously treated advanced KRAS G12D-mutant pancreatic ductal adenocarcinoma (PDAC)

Presentation time: Sunday, October 19, 2025, 10:15-10:25 CEST

Bekaii-Saab: Pancreas cancer is always the forgotten cancer. The field of targeting RAS in pancreas cancer continues to evolve. Pancreas cancer was one of those diseases where we didn’t have any targeted options. The primary driver is RAS; 93% of patients [have] KRAS G12D mutations, and few have KRAS G12C, KRAS G12V, or other mutations. In KRAS G12C–mutated [disease], we had on the horizon adagrasib [Krazati] and sotorasib [Lumakras]; those looked promising because approximately one-third of patients will respond. Several other KRAS G12C inhibitors confirmed that [benefit in patients with KRAS G12C–mutated disease], but [that represents] only 1% or less of the population. Can we expand on this with targeting more RAS alleles? KRAS G12D would be the prime target, because it’s the most common, as well as KRAS G12V and others. We also have a whole field emerging around pan-RAS and -KRAS [inhibitors], which are showing significant responses.

[One phase 2 study (NCT07026916) being presented at ESMO 2025] is [investigating] GFH375 [VS-7375] as a single agent in patients with refractory KRAS G12D–mutated pancreatic cancers. We’ve already seen preliminary data as part of a phase 1/2 basket trial [(NCT06500676) in patients with KRAS G12D–mutated advanced solid tumors] that suggests that perhaps approximately one-third of the patients will respond.4

Kamath: Some data were presented [from the basket trial] at the 2025 ASCO Annual Meeting. There were only 7 patients with pancreatic ductal adenocarcinoma [included] in the ASCO presentation, but there were 3 partial responses, and 4 patients had stable disease. [This is] a strong signal in a cancer that we don’t usually see much response in. I’m excited to see data with more patients and more follow-up [with this agent] to see whether it proves to be effective.

2215O - HRS-4642 combined with gemcitabine and nab-paclitaxel in KRAS-G12D mutant advanced pancreatic cancer: A phase Ib/II study

Presentation time: Sunday, October 19, 2025, 10:25-10:35 CEST

Bekaii-Saab: We’ll have data with HRS-4642 combined with gemcitabine and nab-paclitaxel [(Abraxane) in patients with] KRAS G12D–mutant advanced pancreatic cancer. This is a phase 1b/2 study [NCT07131514].

We’re seeing a transformation in managing pancreas cancer. [It has evolved] from one of the least druggable and targetable cancers to one of the most targetable and druggable cancers. All these studies are looking so promising that I have a strong feeling that all these agents will ultimately make it to the clinic. It’s an exciting time for [patients with] pancreatic cancer.

LBA50 - IMbrave152/SKYSCRAPER-14: a phase 3 study of first-line tiragolumab (tira) + atezolizumab (atezo) + bevacizumab (bev) vs placebo (pbo) + atezo + bev for patients (pts) with untreated locally advanced or metastatic hepatocellular carcinoma (HCC)

Presentation time: Sunday, October 19, 2025, 11:00-11:10 CEST

Kamath: I think this trial [NCT05904886] is going to turn out to be negative, unfortunately. The TIGIT-directed antibodies have largely been somewhat disappointing, as we’ve seen repeatedly in lung cancer and several other [disease states].

LBA29 - Nivolumab plus ipilimumab vs nivolumab monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): new results from CheckMate 8HW

Presentation time: Monday, October 20, 2025, 8:30-8:40 CEST

Bekaii-Saab: [One cohort of] the phase 3 CheckMate-8HW trial [(NCT04008030) enrolled] patients with MSI-H CRC in the first-line setting.5 This [trial investigated] nivolumab [Opdivo] plus ipilimumab [Yervoy] vs chemotherapy [in the first-line setting]. [That portion of the study] study was positive for its primary end point, meaning nivolumab plus ipilimumab [improved progression-free survival vs] chemotherapy. That’s what would be expected, since we already have positive results with pembrolizumab [Keytruda] vs chemotherapy [in microsatellite instability–high (MSI-H) CRC]. Then, nivolumab plus ipilimumab was compared with nivolumab monotherapy across all lines of therapy, and the trial showed that nivolumab plus ipilimumab was [more effective] than nivolumab monotherapy across all lines of therapy.6 That, unfortunately, does not give us the answer of [the activity of nivolumab plus ipilimumab vs nivolumab monotherapy] for first-line treatment.

From what we’ve seen, at least with pembrolizumab in early studies, there is a big difference in how well single-agent PD-1 inhibition performs in later lines vs earlier lines. [It performs] much better in earlier lines. The line of therapy makes a difference. It is possible that a dual checkpoint inhibitor works better in later lines than nivolumab alone.

We want to see survival data with nivolumab plus ipilimumab vs nivolumab monotherapy in the first-line setting before we consider adding ipilimumab—a toxic and more expensive agent—to nivolumab. We have to show that [the combination is] more effective than nivolumab alone in the first-line setting. I’m excited to see the new results. If they’re positive, we’re going to shift our practice to ipilimumab plus nivolumab. If they are not positive, then the argument remains against adding a CTLA-4 inhibitor to a PD-1 inhibitor for most patients [with MSI-H CRC], given the added toxicity and cost with no added benefit. We’ll see what this study shows us.

LBA30 - Zanzalintinib plus atezolizumab (zanza + atezo) vs regorafenib (rego) in patients (pts) with previously treated metastatic colorectal cancer (mCRC): Primary overall survival (OS) analysis from the randomized, open-label, phase 3 STELLAR-303 study

Presentation time: Monday, October 20, 2025, 9:25-9:35 CEST

Kamath: [This trial is investigating] zanzalintinib [XL092], which is the sort of newer version of cabozantinib [Cabometyx], combined with atezolizumab [Tecentriq], so an immunotherapy plus a TKI. This is in refractory metastatic CRC [mCRC]. A news release [from June 2025] suggested this was a positive study that showed an improvement in OS.7 We’re excited to hear the data, how much of an OS improvement there was, if there were any subgroups that benefitted the most, or [if there is a] biomarker we could figure out how to use. It would be an advance to bring immunotherapy plus another TKI into microsatellite-stable [MSS] CRC.

Bekaii-Saab: If truly positive, this study will potentially add an option for patients with MSS disease. Earlier data suggest that zanzalintinib on its own may not do as well as zanzalintinib plus atezolizumab. Unfortunately, the study does not address the separation of components. What if zanzalintinib monotherapy is [more effective] that regorafenib [Stivarga]? Do we need to add atezolizumab? Those data will probably not be provided by the study, and that’s a weakness. How this will be received by regulatory authorities will be interesting to see. Although, a lot of these studies get developed with the blessing of the regulatory authorities when they have a registrational end point, so we know that survival is likely going to be positive for all patients.

Historically, we think that [patients with mCRC without liver metastases] are the ones who benefit the most from these types of strategies. Those data are not available yet and are unlikely to be presented. Why is this important? If [the population without liver metastases] is driving most of the benefit [we see], then zanzalintinib plus atezolizumab will probably be primarily [used] for patients without liver metastases. If that does not seem to be the case, then that’s intriguing, because traditionally, the thought has been that this is the patient population that’s going to benefit from the addition of IO. That goes back to questioning the design of the study, which excluded a zanzalintinib monotherapy arm. A lot of assumptions have been made that may not be confirmed by that study and may be problematic for ultimately adopting [zanzalintinib plus atezolizumab] as a SOC for patients [with mCRC].

LBA9 - ctDNA-Guided Adjuvant Chemotherapy De-Escalation in Stage III colon Cancer: Primary Analysis of the ctDNA-Negative Cohort from the Randomized AGITG DYNAMIC-III Trial (Intergroup Study of AGITG and CCTG)

Presentation time: Monday, October 20, 2025, 16:52-17:04 CEST

Bekaii-Saab: The phase 2/3 DYNAMIC-III trial [ACTRN12617001566325] is investigating circulating tumor DNA–guided adjuvant chemotherapy de-escalation in patients with stage III colon cancer.8 This will be one of the first studies to, in a randomized fashion, show us the value of MRD assessment, specifically for the subgroup of patients with MRD-negative disease, and whether MRD negativity is predictive of less benefit from intensive chemotherapy or chemotherapy overall. We know from prospective, observational studies like CIRCULATE-Japan [UMIN000039205] and BESPOKE [NCT04264702] that patients with MRD-negative disease may not benefit from adjuvant chemotherapy. The problem is, those were not randomized studies, and they’re riddled with biases. [DYNAMIC-III] may help us get a bit closer to an answer about whether MRD assessment has predictive value, and more specifically, whether MRD-negative disease is predictive of less benefit or no benefit from chemotherapy.

References

1. Janjigian YY, Al-Batran SE, Wainberg ZA, et al. Perioperative durvalumab in gastric and gastroesophageal junction cancer. N Engl J Med. 2025;393(3):217-230. doi:10.1056/NEJMoa2503701
2. NCCN. Clinical Practice Guidelines in Oncology. Gastric cancer, version 3.2025. August 22, 2025. Accessed October 8, 2025. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf
3. NCCN. Clinical Practice Guidelines in Oncology. Esophageal and esophagogastric junction cancers, version 4.2025. August 22, 2025. Accessed October 8, 2025. https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf
4. Ai X, Zhou A, Wu L, et al. A first-in-human phase I/II study of GFH375, a highly selective and potent oral KRAS G12D inhibitor in patients with KRAS G12D mutant advanced solid tumors. J Clin Oncol. 2025;43(suppl 16):3013. doi:10.1200/JCO.2025.43.16_suppl.3013
5. 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
6. André T, Elez E, Lenz HJ, et al. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. Lancet. 2025;405(10476):383-395. doi:10.1016/S0140-6736(24)02848-4
7. Exelixis announces zanzalintinib in combination with an immune checkpoint inhibitor improved overall survival in STELLAR-303 phase 3 pivotal trial in patients with metastatic colorectal cancer. News release. Exelixis. June 22, 2025. Accessed October 9, 2025. https://ir.exelixis.com/news-releases/news-release-details/exelixis-announces-zanzalintinib-combination-immune-checkpoint
8. Tie J, Wang Y, Loree JM, et al. ctDNA-guided adjuvant chemotherapy escalation in stage III colon cancer: primary analysis of the ctDNA-positive cohort from the randomized AGITG dynamic-III trial (intergroup study of AGITG and CCTG). J Clin Oncol. 2025;43(suppl 16):3503. doi:10.1200/JCO.2025.43.16_suppl.3503