ASCO 2026: All Eyes Are on Daraxonrasib and a Wave of Novel Targeted Therapies in GI Malignancies

As anticipation continues to build for the 2026 ASCO Annual Meeting, a select few presentations have emerged as the ones to watch across the gastrointestinal (GI) cancer continuum.

The biggest story from the meeting is shaping up to be the phase 3 RASolute 302 trial (NCT06625320) in pancreatic ductal adenocarcinoma (PDAC), which already generated significant buzz after topline results revealed a doubling of median overall survival (OS) over standard chemotherapy with the pan-RAS inhibitor daraxonrasib (RMC-6236).¹ Experts agree that if the full data confirm what has been previewed, this could represent the most consequential shift in PDAC treatment in more than a decade—and potentially define a new standard of care (SOC).

"Everyone’s excited about the data with daraxonrasib in pancreatic cancer, which we’ll see in the plenary session,” Zev A. Wainberg, MD, MSc, shared in an exclusive interview with OncLive®. “Beyond that landmark study, there are going to be other KRAS inhibitor studies being presented in…both pancreatic and colorectal [cancer (CRC)]. In gastric cancer, there are some new drugs that look interesting. Antibody-drug conjugates and bispecifics are novel targets in the disease, so we look forward to seeing them too.”

Wainberg is a professor of medicine in the Division of Hematology/Oncology, co-director of the GI Oncology Program, and medical director of the Pancreas Cancer Center at UCLA Health in Los Angeles, California.

In the preview article below, Wainberg’s insights are accompanied by exclusive perspectives from the following experts:

• Tanios Bekaii-Saab, MD, FACP, professor of medicine at the Mayo Clinic College of Medicine and Science; leader of the Gastrointestinal Cancer Program, Mayo Clinic Comprehensive Cancer Center; medical director of the Cancer Clinical Research Office; and vice chair and section chief of Medical Oncology in the Department of Internal Medicine at Mayo Clinic in Phoenix, Arizona.
• Christopher Lieu, MD, professor of medicine and co-director of GI Medical Oncology and Associate Director for Clinical Research at the University of Colorado Cancer Center in Aurora, Colorado.
• Brian Wolpin, MD, MPH, professor of medicine at Harvard Medical School, director of the Hale Family Center for Pancreatic Cancer Research at Dana-Farber Cancer Institute, and principal investigator of the RASolute 302 trial in Boston, Massachusetts.
• Jonathan Lee, MD, MSc, chief hematology/oncology fellow specializing in thoracic and GI oncology at NewYork-Presbyterian/Weill Cornell Medicine in New York, New York.
• Shubham Pant, MD, MBBS, professor in the Department of Gastrointestinal Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas.
• John L. Marshall, MD, director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers; chief medical officer of the Georgetown Lombardi, MedStar Georgetown Cancer Institute; chief of the Division of Hematology and Oncology at MedStar Georgetown University Hospital; and professor of medicine and oncology at Georgetown University School of Medicine in Washington, DC.

Read on to learn which presentations warrant your attention.

How is daraxonrasib set to shake up the pancreatic cancer paradigm?

Featured presentation:

• Abstract LBA5: Daraxonrasib, a RAS(ON) multi-selective inhibitor, vs chemotherapy in previously treated patients with metastatic pancreatic adenocarcinoma: Primary and final analysis from the Phase 3 RASolute 302 study

Presentation time: Saturday, May 31, 2026, 3:21–3:33 PM CDT | Plenary Session

Bekaii-Saab: Having [treated patients with pancreatic cancer] for more than 2 decades, we [saw] pancreatic cancer as one of those cancers that were impossible to target. The main reason for this was that it was driven by RAS [mutations for the majority of patients]. For those [patients], we thought it was non-druggable.

Daraxonrasib, which is a pan-RAS inhibitor, covers the whole gamut of RAS mutations. So far, what we’ve seen does suggest a significant and meaningful benefit for daraxonrasib over chemotherapy. The OS [outcomes appear to be] better than what we see with chemotherapy in the first line, and that’s in refractory patients, [which is] pretty remarkable. We have to learn about the toxicities [with this agent] a bit more…but I think a lot of [that can be addressed] with more education and more hands-on [experience] with this agent. The results [from RASolute 302] are undeniably meaningful. We’re also seeing a lot of other agents specifically targeting KRAS G12D following this path…of rapid development. We’re [about to see] a major shift in pancreatic cancer [management].

Uboha: RASolute 302 enrolled patients with pretreated pancreatic cancer, randomized to SOC [therapy] or [the] pan-RAS inhibitor [daraxonrasib]—and the study is positive, according to a press release from Revolution Medicine. [There is an] impressive improvement in OS over SOC, with a HR of 0.4. We do not see HRs like this in pancreatic cancer, so I’m excited to see the full presentation in the plenary at ASCO.

Lieu: The phase 3 [RASolute 302] trial is a potentially practice-changing moment for metastatic PDAC. The topline results are showing a nearly doubled median OS compared with standard chemotherapy. [This agent could] address one of the most difficult-to-treat populations in GI oncology. It’s a massive step forward in proving that targeting RAS is finally a viable, highly effective strategy for the vast majority of our pancreatic cancer patients.

Wolpin: RASolute-302 is the study that will hopefully define daraxonrasib as an appropriate therapy option in the second-line setting. The advancements in targeting RAS, which is mutated in approximately 20% of all cancers, really have been impressive. The ability to go from having really no good medicines to target that [pathway] to now having dozens of medicines that are being tested in patients that are trying to attack a really important target in cancer is exceptionally impressive.

Pant: We’ve never seen data like these presented in pancreatic cancer. The last [data readout] which was this impactful [for the field] was when FOLFIRINOX was compared against gemcitabine, [which was] more than a decade [ago]. These are going to be practice-changing [results]...not only for us folks in academic medicine but for our community oncologists also, who treat a majority of the patients with pancreatic cancer.

Will data from the CIRCULATE trial provide the evidence needed to guide risk-adapted adjuvant treatment decisions in stage 2 colon cancer?

Featured presentation:

• Abstract LBA3500: Disease-free survival (DFS) and time to recurrence (TTR) with circulating tumor (ct)DNA–based decision for adjuvant treatment in colon cancer Stage II (CIRCULATE): An AIO (KRK-0217)/ABCSG trial

Presentation time: Saturday, May 31, 2026, 8:00–8:12 AM CDT | Rapid Oral Abstract Session

Lee: The impact of circulating tumor DNA [ctDNA] in CRC has been substantial. I’m looking forward to this update of the phase 3 CIRCULATE trial [NCT04089631], which will give valuable clinical information that correlates with the prior data presented at the 2025 ASCO Annual Meeting, which looked at postoperative cell-free DNA and ctDNA levels in stage II colon cancer. These data will help guide conversations with our patients about the potential need and duration of adjuvant treatment in the stage II setting.

Lieu: This study continues to push the envelope on the utility of ctDNA in the adjuvant setting for stage 2 colon cancer. As we move toward more ‘risk-adapted’ treatment strategies, the DFS and TTR data from this trial will provide much-needed evidence on whether we can safely de-escalate treatment in ctDNA-negative patients or must intensify it for those who are ctDNA-positive.

What will FIGHT-302 data mean for the role of pemigatinib in the first-line treatment of FGFR2-rearranged cholangiocarcinoma?

Featured presentation:

• Abstract 4017: Pemigatinib for untreated unresectable/metastatic cholangiocarcinoma (mCCA) with fibroblast growth factor receptor-2 (FGFR2) rearrangement: Phase 3 FIGHT-302 results

Presentation time: Monday, June 1, 2026, 9:45 AM– 12:45 PM CT | Oral Abstract Session

Bekaii-Saab: Although [the phase 3 FIGHT-302 trial (NCT03656536)] stopped early, it remains the largest [dataset] with an FGFR inhibitor in the first line and in a randomized setting. With all the benefits we’ve seen with these FGFR inhibitors in later lines of therapy, whatever the results end up being, they’re going to be meaningful, one way or the other, for us to understand. In the second [and] third line, [we have] pemigatinib [Pemazyre] and futibatinib [Lygtobi] approved in the United States on an accelerated basis,^2,3 and a number of other [agents] are being developed. A phase 3 study is essential for permanent approval. Also, at the end of the day, we haven’t had any first-line data, and this is the first large study at that scale.

We’re excited about presenting these data. We’ll see where it goes. If positive, it could at least create a pathway for [pemigatinib’s use in] earlier lines. The fact that it wasn’t completed may limit us somewhat, but the results will either confirm the role of pemigatinib in FGFR fusion–positive cholangiocarcinomas and perhaps even place pemigatinib in the first line—or, if [the data are] in a gray zone or are negative, we’ll have to put it in context with gains in the second line and beyond.

Can dual checkpoint blockade improve upon single-agent anti–PD-1 plus chemotherapy as first-line treatment for HER2-negative advanced gastric and gastroesophageal (GEJ) cancer?

Featured presentation:

•Abstract 4006: Nivolumab plus ipilimumab combined with chemotherapy as first-line treatment for HER2-negative unresectable advanced or recurrent gastric/gastroesophageal junction cancer: a randomized Phase 3 trial (ATTRACTION-6)

Presentation time: Monday, June 1, 2026, 9:45 AM–12:45 PM CT | Oral Abstract Session

Lee: Coming from a background in thoracic cancer, I’m particularly interested to see the efficacy of dual checkpoint blockade in gastric/GEJ cancers. I’m definitely looking at subgroup analyses and seeing if there are specific disease features or co-mutations that have particular benefit over standard chemo-immunotherapy. The durability of benefit, toxicity profile, and the duration of CTLA-4 blockade needed will also be critical questions to answer moving forward if the trial is positive.

Will the data from SWOG S2107 validate the triplet of encorafenib, cetuximab, and nivolumab as a mechanistically driven approach for microsatellite-stable BRAF V600E–mutant metastatic CRC?

Featured presentation:

• Abstract 3504: Randomized Phase II encorafenib + cetuximab ± nivolumab for MSS BRAF V600E metastatic colorectal cancer (SWOG S2107)

Presentation time: Sunday, May 31st, 2026, 9:12–9:24 AM CT | Oral Abstract Session

Lee: The management of BRAF V600E–mutated CRC has evolved with the recent [phase 3] BREAKWATER trial [NCT04607421]. However, I’m still very excited for the data from this cooperative group trial. It is a randomized trial that builds off the non-randomized phase 1/2 [dataset (NCT04017650)] published in 2025, which showed that responders had a unique molecular profile characterized by MAPK signaling and immune activation that was not present in non-responders. I’m looking forward to this larger randomized phase 2 study and the additional mechanistic insights that it will provide.

What are some additional presentations of interest?

Marshall identified several additional high-impact abstracts that warrant close attention:

• Abstract 3507: Structured exercise program following adjuvant chemotherapy for colon cancer: A cost-utility analysis of the CHALLENGE trial

Presentation time: Sunday, May 31, 2026, 10:12–10:24 AM CT | Rapid Oral Abstract Session

• LBA4000: Efficacy and safety results from EMERALD-3: A phase 3, randomized study of tremelimumab plus durvalumab with or without lenvatinib combined with transarterial chemoembolization (TACE) in participants (pts) with unresectable embolization-eligible hepatocellular carcinoma (eeHCC)

Presentation time: Monday, June 1, 2026, 9:45–9:57 AM CT | Oral Abstract Session

• Abstract 4003: First-line treatment of QLS31905 plus chemotherapy in patients with pancreatic cancer and gastric cancer: Data from a phase 1b/2 study

Presentation time: Monday, June 1, 2026, 10:49–11:01 AM CT | Oral Abstract Session

Wainberg also singled out a phase 2 study evaluating savolitinib (Orpathys) in patients with MET-amplified gastric/GEJ adenocarcinomas. He noted that this MET inhibitor, which was developed in China, has shown promising anti-tumor activity in this specific patient population.

• Abstract 4011: A phase 2 pivotal study of savolitinib in patients with MET-amplified gastric cancer or gastroesophageal junction adenocarcinomas

Presentation time: Monday, June 1, 2026, 1:27–1:33 PM CT | Rapid Oral Abstract Session

References

1. Daraxonrasib demonstrates unprecedented overall survival benefit in pivotal phase 3 RASolute 302 clinical trial in patients with metastatic pancreatic cancer. News release. Revolution Medicines. April 13, 2026. Accessed May 13, 2026. https://ir.revmed.com/news-releases/news-release-details/daraxonrasib-demonstrates-unprecedented-overall-survival-benefit
2. FDA approves first targeted treatment for patients with cholangiocarcinoma, a cancer of bile ducts. FDA. April 17, 2020. Accessed May 13, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-treatment-patients-cholangiocarcinoma-cancer-bile-ducts
3. FDA grants accelerated approval to futibatinib for cholangiocarcinoma. FDA. September 30, 2022. Accessed May 13, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-futibatinib-cholangiocarcinoma