A Preview of Transformational Presentations at ASCO GI 2025

According to Tanios S. Bekaii-Saab, MD, the results from the BREAKWATER trial (NCT04607421) may “transform practice by establishing doublet chemotherapy plus encorafenib and cetuximab as the standard of care for patients with metastatic CRC and a BRAF V600E mutation.”

With the 2025 Gastrointestinal Cancers Symposium rapidly approaching, researchers and investigators from around the world are preparing to convene in San Francisco, CA, to highlight the latest advances in the gastrointestinal (GI) cancer field. This year’s meeting will see several presentations on updated clinical trial reports, novel targeted agents, surgical modalities, and biomarker testing, among other focuses.

Here are just some of the notable abstracts that have the potential to shape clinical practice across multiple disease types and disciplines.

LBA143: First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW.

Noted on X¹ as one of the “Top Abstract Titles” by Mike J. Pishvaian, MD, PhD, director of Gastrointestinal, Developmental Therapeutics and Clinical Research Programs and an associate professor of Oncology at Johns Hopkins Medicine (@MPishvaian), the meeting will feature a readout of initial data from one of the experimental arms of the phase 3 CheckMate 8HW trial (NCT04008030).²

In one of the symposium’s many late-breaking abstracts, Thierry André, MD, a professor of medical oncology at the Sorbonne Université in Paris and head of the Medical Oncology Department at the Saint Antoine Hospital, Assistance Publique Hôpitaux de Paris, France, will present findings on the use of nivolumab (Opdivo) plus ipilimumab (Yervoy) compared with nivolumab alone in those with microsatellite instability-high (MSI-H), mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC). As part of one of the trial’s primary end points, investigators have sought to determine how progression-free survival (PFS) outcomes differ with the addition of ipilimumab to nivolumab in this patient population.

These updated findings may build upon data that Andre presented in a session at the 2024 Gastrointestinal Cancers Symposium, in which outcomes in the nivolumab/ipilimumab arm compared with those in the chemotherapy arm were the primary focus.³

Data from the prespecified interim analysis showed that the median PFS was not reached (NR; 95% CI, 38.4 months to not evaluable [NE]) with the combination regimen vs 5.9 months (95% CI, 4.4-7.8) with chemotherapy (HR, 0.21; 95% CI, 0.13-0.34; P <.0001). The PFS benefit observed with nivolumab/ipilimumab extended across all subgroups, including those with KRAS- or NRAS-mutated disease and patients with liver, lung, or peritoneal metastases at baseline.

“The first results from this study showed a significant improvement in PFS for nivolumab plus ipilimumab over chemotherapy. It is unclear whether the results that will be discussed at ASCO GI will include a comparison of ipilimumab/nivolumab vs nivolumab [across] all lines or the first line only,” Tanios S. Bekaii-Saab, MD, David F. and Margaret T. Grohne Professor of Novel Therapeutics for Cancer Research and Chair and Consultant in the Division of Hematology and Medical Oncology at Mayo Clinic in Arizona as well as a gastrointestinal editorial advisory board member of ONCOLOGY^®, stated in a written comment to CancerNetwork^® about this presentation.

“If ipilimumab/nivolumab shows improved outcomes vs nivolumab alone in the first line, then this is transformational in the sense that ipilimumab/nivolumab will become the preferred [first-line option] for MSI-H metastatic CRC,” Bekaii-Saab added.

Abstract 16: BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer

Another presentation will highlight results from the phase 3 BREAKWATER trial (NCT04607421) assessing encorafenib (Braftovi) in combination with cetuximab and modified leucovorin calcium, fluorouracil, and oxaliplatin (mFOLFOX6) for patients with metastatic CRC harboring BRAF V600E mutations.⁴

Of note, the FDA granted accelerated approval to encorafenib plus cetuximab and chemotherapy for this patient population in December 2024 based on data from the BREAKWATER trial.⁵ Topline data at the time of the approval showed an objective response rate (ORR) of 61% (95% CI, 52%-70%) with encorafenib plus cetuximab and chemotherapy vs 40% (95% CI, 31%-49%) with chemotherapy alone. Additionally, the median duration of response (DOR) was 13.9 months (95% CI, 8.5-not estimable [NE]) and 11.1 months (95% CI, 6.7-12.7) in each respective arm.

The FDA indicated that post-marketing confirmatory evidence for the accelerated approval status of this encorafenib-based regimen may be based on an analysis of PFS and overall survival (OS) data from the BREAKWATER trial.

According to Bekaii-Saab, the results from BREAKWATER may “transform practice by establishing doublet chemotherapy plus encorafenib and cetuximab as the standard of care for patients with metastatic CRC and a BRAF V600E mutation.”

LBA329: Preliminary results from the multicenter, randomized phase III trial (SCIENCE): Comparing chemotherapy plus sintilimab and chemoradiotherapy plus sintilimab versus chemoradiotherapy for neoadjuvant treatment in resectable locally advanced esophageal squamous cell carcinoma

On X,⁶ Sharlene Gill, MD, MPH, MBA, FASCO, a professor of Medicine and medical oncologist at the University of British Columbia (BC) BC Cancer – Vancouver (@GillSharlene), identified the upcoming readout of initial data from the phase 3 SCIENCE trial (NCT05244798) as a key abstract in esophagogastric cancer.⁷

Investigators of this multicenter phase 3 study are conducting a comparative analysis of sintilimab (Tyvyt) plus chemotherapy, sintilimab plus chemoradiotherapy, and chemoradiotherapy alone as neoadjuvant treatment for patients with resectable locally advanced esophageal squamous cell carcinoma. The trial’s primary end point is the pathologic complete response (pCR) rate, with secondary end points including major pathological remission rate, event-free survival, OS, disease-free survival, and ORR.

In the past, sintilimab plus chemotherapy has demonstrated improved outcomes in frontline unresectable locally advanced, recurrent, or metastatic esophageal squamous cell carcinoma as part of the phase 3 ORIENT-15 study (NCT03748134). Investigators announced final analysis results from ORIENT-15 in April 2023.⁸

Prior data showed that sintilimab plus chemotherapy produced a median OS of 17.4 months vs 12.8 months with placebo plus chemotherapy among all randomly assigned patients (HR, 0.661; P <.0001). Among patients with PD-L1–positive disease, the median OS was 18.4 months and 14.5 months in each respective arm (HR, 0.635; P = .0001).

The safety profile of sintilimab in the ORIENT-15 study was comparable with prior reports of the agent.

“In this final analysis, sintilimab in combination with chemotherapy demonstrated continued significant OS benefits, further supporting the use of sintilimab plus chemotherapy as a standard of care for first-line treatment in these patients,” lead investigator Shen Lin, MD, a professor and vice president of Peking University Cancer Hospital and Institute, stated in a press release at the time of these findings.⁶

Preliminary findings from the SCIENCE trial may build upon prior results achieved with sintilimab-based treatment in esophageal squamous cell carcinoma by demonstrating whether the agent can produce efficacy in the neoadjuvant setting among patients with resectable disease.

Abstract 722: Safety, efficacy, and on-treatment circulating tumor DNA (ctDNA) changes from a phase 1 study of RMC-6236, a RAS(ON) multi-selective, tri-complex inhibitor, in patients with RAS mutant pancreatic ductal adenocarcinoma (PDAC)

Regarding novel therapeutics in the GI cancer space, Pishvaian⁹ listed a presentation on a phase 1 study (NCT05379985) evaluating the RAS(ON) inhibitor RMC-6236 as an abstract to look out for at this year’s symposium.¹⁰

Developers designed RMC-6236 as an orally available, direct multi-selective inhibitor of RAS(ON) to help manage a variety of cancers driven by oncogenic RAS mutations.¹¹ The agent suppresses RAS signaling by harnessing downstream effectors to block the interaction of RAS(ON) across oncogenic mutations G12X, G13X, and Q61X in diseases such as pancreatic ductal adenocarcinoma (PDAC), non–small cell lung cancer, and CRC.

Previous findings from the phase 1 trial assessing RMC-6236 in RAS-mutated PDAC showed a median PFS of 8.5 months (95% CI, 5.3-11.7) and a median OS of 14.5 months (95% CI, 8.8-NE) among patients in the second-line setting with KRAS G12X mutations.¹¹ Additionally, the ORR for patients with a KRAS G12X mutation was 29% in the second-line setting and 22% in the third line and beyond.

At the time of this analysis, treatment with RMC-6236 appeared to be well tolerated at doses ranging from 160 mg to 300 mg once daily. The most common treatment-related adverse effects (TRAEs) included grade 1/2 rash and GI-related toxicities; investigators highlighted no new safety signals.

Shubham Pant, MD, MBBS, a professor in the Department of Gastrointestinal Medical Oncology with a joint appointment in the Department of Investigational Cancer Therapeutics (Phase I Center) at The University of Texas MD Anderson Cancer Center, and gastrointestinal cancer editorial advisory board member for ONCOLOGY, previously spoke with CancerNetwork and highlighted the “encouraging” data related to RMC-6236 in PDAC.

“In a single-arm study, results that were reported showed a PFS north of 8 months [with RMC-6236]. Normally, the PFS with regular chemotherapy is [approximately] 3.1 months,” Pant stated. “This was a single-arm [study], but they were encouraging data.”

Abstract 332: Final analysis of the randomized phase 2 part of the ASPEN-06 study: A phase 2/3 study of evorpacept (ALX148), a CD47 myeloid checkpoint inhibitor, in patients with HER2-overexpressing gastric/gastroesophageal cancer (GC)

Pishvaian highlighted¹² the presentation on final analysis results from the phase 2 portion of the ASPEN-06 study (NCT05002127) as a key presentation in the realm of HER2-targeted trials in upper GI cancers.¹³ Here, investigators will detail outcomes associated with evorpacept (ALX148) in patients with gastric or gastroesophageal cancers harboring HER2 overexpression.

Investigators previously reported topline data from the ASPEN-06 study in July 2024.¹⁴ At the time of analysis, evorpacept in combination with trastuzumab (Herceptin), ramucirumab (Cyramza), and paclitaxel (TRP) yielded an ORR of 40.3% vs 26.6% with TRP alone in the intent-to-treat population (n = 127). Among those with evaluable HER2-positive biopsies (n = 48), the respective ORRs in each arm were 54.8% vs 23.1%.

Data associated with PFS and OS outcomes were not yet mature at the time of this analysis. Additionally, treatment with evorpacept plus TRP appeared to be well tolerated.

Abstract 520: Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line (1L) therapy for unresectable hepatocellular carcinoma (uHCC): CheckMate 9DW expanded analyses

Bekaii-Saab identified a presentation on updated results from the phase 3 CheckMate 9DW trial (NCT04039607) as a potentially notable update in the liver cancer field.¹⁵ Investigators presented first results from this trial assessing nivolumab/ipilimumab vs lenvatinib (Lenvima) or sorafenib (Nexavar) among patients with unresectable hepatocellular carcinoma (HCC) at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.¹⁶

Prior data from CheckMate 9DW showed that nivolumab/ipilimumab produced a median OS of 23.7 months (95% CI, 18.8-29.4) vs 20.6 months (95% CI, 17.5-22.5) with lenvatinib or sorafenib (HR, 0.79; 95% CI, 0.65-0.96; P = .018). In each respective arm, the ORR was 36% vs 13% (P <.0001), and the median PFS was 9.1 months (95% CI, 6.6-10.5) vs 9.2 months (95% CI, 7.9-11.1; HR, 0.87; 95% CI, 0.72-1.06).

The rates of treatment-related AEs (TRAEs) were 84% with nivolumab/ipilimumab vs 91% with lenvatinib or sorafenib. The most common TRAEs in the nivolumab/ipilimumab arm included pruritus (28%), aspartate aminotransferase increases (20%), and alanine aminotransferase increases (19%).

“The landscape of treatment options in unresectable HCC has become very complex with 2 established options: atezolizumab (Tecentriq)/bevacizumab (Avastin) and tremelimumab (Imjudo)/durvalumab (Imfinzi). The combination of nivolumab/ipilimumab showed significant promise vs lenvatinib or sorafenib with concerns regarding more toxicities vs historical expectations, primarily given the higher ipilimumab dose,” Bekaii-Saab wrote.

“The expanded analyses may provide further insight regarding updated efficacy and safety measures. In the absence of head-to-head comparisons vs other [immunotherapy]-based combinations, it will be difficult to consider [nivolumab/ipilimumab] as a preferred standard but only an additional option for patients with a great level of performance,” he added.

References

1. @MPishvaian. #GI25 @ASCO And 3 immunotherapy trials in #MCRC: 1. Thierry Andre🗣️the LBA of Ipi-Nivo vs Nivo of dMMR mCRC, ABS LBA143 2. @mgfakih 🗣️a Ph2 trial of BOT +/- Bal in MSS mCRC (no liver mets), Oral Abs 23 3. Joel R Hecht🗣️a Ph2 trial of a personalized Neo-Ant IO for MSS CRC, Abs LBA13. January 11, 2025. Accessed January 20, 2025. https://x.com/MPishvaian/status/1878169374801952946
2. Andre T, Elez E, Lenz H-J, et al. First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW. J Clin Oncol. 2025;43(suppl 4):LBA143.
3. Andre T, Elez E, Van Cutsem E, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): First results of the CheckMate 8HW study. J Clin Oncol. 2024;42(suppl 3):LBA768. doi:10.1200/JCO.2024.42.3_suppl.LBA768
4. 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(suppl 4):16.
5. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. News release. FDA. December 20, 2024. Accessed January 20, 2025. https://tinyurl.com/4utu3tdr
6. @GillSharlene. 🚨Its that time of year again - #GI25 @ASCO is just 2 weeks away! #SanFrancisco #HPBsm #CRCsm #STCsm #PCsm Abstracts drop on Jan 21st 👇List of key studies I will be watching out for 👀 See you there 👋 @OncoAlert. January 9, 2025. Accessed January 15, 2025. https://x.com/GillSharlene/status/1877423787307671709
7. Leng X, He W, Lyu J, et al. Preliminary results from the multicenter, randomized phase III trial (SCIENCE): comparing chemotherapy plus sintilimab and chemoradiotherapy plus sintilimab versus chemoradiotherapy for neoadjuvant treatment in resectable locally advanced esophageal squamous cell carcinoma. J Clin Oncol. 2025;43(suppl 4):LBA329.
8. Innovent releases final analysis results of ORIENT-15: the phase 3 study of sintilimab plus chemotherapy for the first-line treatment of esophageal squamous cell carcinoma at the AACR Annual Meeting 2023. News release. Innovent Biologics. April 16, 2023. Accessed January 20, 2025. https://tinyurl.com/36mts42d
9. @MPishvaian. #GI25 @ASCO Starting with #PancreaticCancer and Ras⛔️ Actually only 2 titles I saw: 1. @GarridoLagunaMD 🗣️ctDNA🩸changes in the Ph1 trial of the Ras(on)⛔️RMC-6236 Abs 722; Poster#H10 2. @AlexSpiraMDPhD 🗣️a Ph1 trial of the G12D specific⛔️RMC-9805 Abs 724; Poster#H12. January 11, 2025. Accessed January 15, 2025. https://x.com/MPishvaian/status/1878153047290806759
10. Garrido-Laguna I, Wolpin B, Park W, et al. Safety, efficacy, and on-treatment circulating tumor DNA (ctDNA) changes from a phase 1 study of RMC-6236, a RAS(ON) multi-selective, tri-complex inhibitor, in patients with RAS mutant pancreatic ductal adenocarcinoma (PDAC). J Clin Oncol. 2025;43(suppl 4):722.
11. Revolution Medicines presents updated data from RMC-6236 monotherapy study in patients with advanced pancreatic ductal adenocarcinoma. News release. Revolution Medicines, Inc. October 23, 2024. Accessed January 20, 2025. https://tinyurl.com/mtx57rs4
12. @MPishvaian. #GI25 @ASCO Finally, 2 HER2-targeted trials in upperGI cancer: 1. @KoheiShitara 🗣️ASPEN-06, a CD47-targeted immuncheckpoint inhibitor for HER2+ gastric cancer, Oral Abs 332, Post#C24 2. Dr. Frost🗣️a Ph1 trial of a HER2 directed CAR-T cell Tx, Abs 449, Post#F14. January 11, 2025. Accessed January 15, 2025. https://x.com/MPishvaian/status/1878176010689994987
13. Shitara K, Wainberg Z, Tabernero J, et al. Final analysis of the randomized phase 2 part of the ASPEN-06 study: A phase 2/3 study of evorpacept (ALX148), a CD47 myeloid checkpoint inhibitor, in patients with HER2-overexpressing gastric/gastroesophageal cancer (GC). J Clin Oncol. 2025;43(suppl 4):332.
14. ALX Oncology reports topline data from ASPEN-06 phase 2 trial demonstrating evorpacept improves tumor response in patients with HER2-positive gastric cancer. News release. ALX Oncology Holdings Inc. July 31, 2024. Accessed January 20, 2025. https://tinyurl.com/ycyhjczd
15. Kudo M, Yau T, Decaens T, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line (1L) therapy for unresectable hepatocellular carcinoma (uHCC): CheckMate 9DW expanded analyses. J Clin Oncol. 2025;43(suppl 4):520.
16. Galle PR, Decaens T, Kudo M, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): first results from CheckMate 9DW. J Clin Oncol. 2024;42(suppl 17):LBA4008. doi:10.1200/JCO.2024.42.17_suppl.LBA4008