ASCO 2026 Ushers In a New Era for Pancreatic Cancer, Expands Targeted Therapy Options Across the GI Spectrum

During the 2026 ASCO Annual Meeting, OncLive® spoke with leading oncologists to capture their perspectives on potentially practice-changing presentations across gastrointestinal cancers and gastrointestinal stromal tumors that may soon translate into clinical practice. See their commentary below!

Pancreatic Cancer

Daraxonrasib vs Chemotherapy in Previously Treated Metastatic Pancreatic Adenocarcinoma: Primary and Final Analysis of the Phase 3 RASolute 302 Study (Abstract LBA5)

Arguably the biggest story at this year’s meeting came from the plenary session, where results of the phase 3 RASolute 302 trial (NCT06625320) showed that the oral, once-daily RAS(ON) multiselective inhibitor daraxonrasib (n = 248) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) and progression-free survival (PFS) compared with chemotherapy (n = 252) in patients with previously treated metastatic pancreatic ductal adenocarcinoma.

Vincent Picozzi, MD, Virginia Mason Medical Center:

“This presentation of the RASolute 302 trial is the most seminal thing that’s occurred in pancreatic cancer since the advent of chemotherapy… This really begins a new chapter of treatment for pancreatic cancer. I describe it as the ultimate do-over, in which we now have a new basis for treatment. All of our previous assessments and thoughts have to be challenged and potentially changed, and this is going to usher in a bright new era of treatment in which I think this class of drugs is going to impact virtually every patient with pancreatic cancer going forward.”

Benjamin Herzberg, MD, Columbia University Herbert Irving Comprehensive Cancer Center:

“The fact that [we saw] OS doubled in a disease that historically has had very few treatment options proves a few things. One, it proves that if we hit the right target, the drugs work. If we hit it well, we don’t need complex, exotic explanations for why certain things work and certain things don’t. No. 2, [it shows] that KRAS is targetable beyond G12C; it’s targetable with newer modalities like these molecular glue modalities. [This study] is proof of principle for a variety of new approaches to KRAS and to targeting cancers generally.”

In the RAS G12–mutant population, the median OS was 13.2 months (95% CI, 10.0-not estimable [NE]) with daraxonrasib (n = 228) vs 6.6 months (95% CI, 5.4-8.2) with chemotherapy (n = 231; HR, 0.40; 95% CI, 0.30-0.54; P < .0001); this translated to a 60% reduction in the risk of death. The 12-month OS rate was 53.3% with daraxonrasib vs 18.7% with chemotherapy. The median PFS was 7.3 months (95% CI, 6.3-8.1) vs 3.5 months (95% CI, 2.9-3.8; HR, 0.45; 95% CI, 0.34-0.59; P < .0001). Results were consistent in the intention-to-treat population, with a median OS of 13.2 months (95% CI, 10.0-NE) vs 6.7 months (95% CI, 5.8-8.0), respectively (HR, 0.40; 95% CI, 0.30-0.53; P < .0001). The median PFS was 7.2 months (95% CI, 5.7-7.5) with daraxonrasib vs 3.6 months (95% CI, 2.9-4.2) with chemotherapy (HR, 0.49; 95% CI, 0.38-0.64; P < 5.2×10⁻⁸).

Ferdinandos Skoulidis, MD, PhD, MRCP, The University of Texas MD Anderson Cancer Center:

“[RASolute 302] was undoubtedly the biggest, most impactful study presented at this year’s ASCO, and we saw this because it received a standing ovation during the plenary session. As a physician who started their training and scientific journey in pancreatic cancer and KRAS before moving to lung, I truly consider it a historic moment in time to have a targeted therapy that more than doubles the median OS for patients with pancreatic cancer.”

Kevin Kalinsky, MD, MS, Winship Cancer Institute of Emory University:

“RAS is a target that we’ve been hoping to impact for many years, and it was deemed an undruggable mutation. So just the fact that there’s now a drug that targets that mutation is remarkable. But even beyond that, pancreatic cancer has been a disease that has been so difficult to have advances in for so very long, and I think it was just so inspiring to see advances in that particular tumor type, because it also heralds where other drug development could go for that cancer, and also for others that harbor a RAS mutation.”

Daraxonrasib also delayed deterioration in patient-reported pain and global quality of life compared with chemotherapy. The safety profile was manageable with no new signals identified; 42% of patients in the daraxonrasib arm remained on treatment at the data cutoff vs 14% in the chemotherapy arm.

Daniel King, MD, Mayo Clinic:

“Although this might be a breakthrough, it’s hard to call it a miracle. These are not cures. We certainly now have a challenge to determine what are the reasons that patients are developing resistance to RAS treatments. How can we counteract that resistance, either by doubling down on RAS and adding more drugs against it, or by thinking about mechanisms of resistance and how we very cleverly design clinical trials that counteract those mechanisms? There’s a lot of work to do, but it is certainly a very exciting result.”

Robert Vonderheide, MD, DPhil, Abramson Cancer Center of the University of Pennsylvania:

“Although there’s great excitement about daraxonrasib, it’s on top of a backdrop of great progress in all sorts of areas for patients with pancreatic cancer. I think ultimately there will be not just one drug but multiple options that fit the right patient at the right time.”

Shubham Pant, MD, The University of Texas MD Anderson Cancer Center:

“[RASolute 302 shows that] this is…the year for pancreatic cancer. I don’t think there’s ever been a year for pancreatic cancer at ASCO in its history [until now].”

Colorectal Cancer

BREAKWATER: Progression-Free and Overall Survival Analyses of First-Line Encorafenib + Cetuximab + FOLFIRI in BRAF V600E–Mutant Metastatic Colorectal Cancer (Abstract LBA3503)

Final progression-free survival (PFS) and updated overall survival (OS) data from cohort 3 of the phase 3 BREAKWATER trial (NCT04607421) demonstrated that first-line encorafenib (Braftovi) plus cetuximab (Erbitux) and FOLFIRI (leucovorin calcium [folinic acid], fluorouracil, and irinotecan hydrochloride) nearly doubled PFS compared with FOLFIRI with or without bevacizumab (Avastin) in patients with previously untreated BRAF V600E—mutant metastatic colorectal cancer.

At a median PFS follow-up of 18.0 months in the experimental arm and 14.4 months in the control arm, the median PFS by blinded independent central review was nearly doubled at 15.2 months (95% CI, 13.6-NE) with encorafenib plus cetuximab and FOLFIRI vs 8.6 months (95% CI, 6.8-8.9) with FOLFIRI with or without bevacizumab (HR, 0.44; 95% CI, 0.28-0.72; P = .001). PFS benefit was consistent across all prespecified subgroups, including age, sex, ECOG performance status, number of organs involved, primary tumor sidedness, and presence of liver metastases. At a median follow-up of 20.6 months, the median OS had not been reached (95% CI, 21.0-not estimable [NE]) with encorafenib plus cetuximab and FOLFIRI. At a median follow-up of 20.7 months, the median OS with chemotherapy was 20.3 months (95% CI, 13.2-NE), resulting in an HR of 0.56 (95% CI, 0.34-0.94). The 18-month OS rates were 72.0% vs 54.9%, respectively.

The safety profile of encorafenib plus cetuximab and FOLFIRI was consistent with the known profiles of each regimen component, and no new safety signals were identified.

Paul Oberstein, MD, New York University Langone Perlmutter Cancer Center:

“One of the most impactful and biggest [studies] from ASCO this year was the BREAKWATER study, which looked at treatment of patients with BRAF-mutated colon cancer. This is another population that’s very difficult to treat, and this segment of the study, looking at a novel combination with FOLFIRI, showed significant benefit in that patient population. Combined with other studies presented at ASCO, it really expands the opportunities for targeted therapy for patients with BRAF-mutated colon cancer.”

Gastroesophageal Cancer

Zanidatamab + Chemotherapy ± Tislelizumab for First-Line HER2-Positive Locally Advanced or Metastatic Gastroesophageal Adenocarcinoma: PD-L1 Subgroup Analysis From HERIZON-GEA-01 (Abstract 4010)

A preplanned PD-L1 subgroup analysis from the phase 3 HERIZON-GEA-01 trial (NCT05152147) demonstrated that zanidatamab-hrii (Ziihera) plus tislelizumab (Tevimbra) and chemotherapy improved progression-free survival (PFS) and overall survival (OS) over trastuzumab (Herceptin) plus chemotherapy in patients with first-line HER2-positive locally advanced or metastatic gastroesophageal adenocarcinoma (GEA) regardless of PD-L1 expression status, including in patients with PD-L1—negative disease. In the intention-to-treat population, the previously published primary results showed that zanidatamab plus tislelizumab and chemotherapy (arm C; n = 302) produced a median PFS of 12.4 months (95% CI, 9.8-18.5) vs 8.1 months (95% CI, 7.0-8.9) with trastuzumab plus chemotherapy (arm A; n = 308; HR, 0.63; 95% CI, 0.51-0.78; P < .0001), a greater than 4-month improvement. The median OS was 26.4 months (95% CI, 21.5-30.3) vs 19.2 months (95% CI, 16.8-21.8; HR, 0.72; 95% CI, 0.57-0.90; P = .0043), a more than 7-month prolongation. The PD-L1 subgroup analysis presented at ASCO confirmed that PFS improvements were consistent regardless of PD-L1 status, whether assessed by tumor area positivity (TAP) score or combined positive score.

Notably, in patients with PD-L1–negative disease (TAP < 1%), the median OS in arm C was 29.7 months (95% CI, 24.7-not estimable) compared with 15.8 months (95% CI, 12.6-21.4) in arm A. Among patients with PD-L1–positive disease (TAP ≥ 1%), the median OS was 26.4 months (95% CI, 18.7-35.9) vs 21.2 months (95% CI, 17.7-25.2), respectively. The 24-month OS rates in PD-L1 TAP less than 1% and at least 1% subgroups were 63.7% and 53.5%, respectively, with the combination. The safety profile of zanidatamab-containing regimens was consistent with prior reports and manageable.

Geoffrey Y. Ku, MD, Memorial Sloan Kettering Cancer Center:

“These data reaffirm what was seen during the initial presentation and in the published data: that PD-L1–negative patients as well as PD-L1–positive patients both seem to benefit [from zanidatamab plus tislelizumab and chemotherapy]. What it doesn’t answer is the molecular basis underlying this very happy observation, but it’s something that hopefully we will be able to tease apart with additional correlative analyses in the months and years to come.”

Gastrointestinal Stromal Tumors

Primary Results of the Phase 3 PEAK Study of Bezuclastinib + Sunitinib vs Sunitinib Monotherapy in Advanced Gastrointestinal Stromal Tumors (Abstract 11500)

Primary results from the phase 3 PEAK trial (NCT05208047) demonstrated that bezuclastinib plus sunitinib (Sutent) cut the risk of progression or death in half and nearly doubled the objective response rate compared with sunitinib monotherapy in patients with imatinib-resistant or -intolerant advanced gastrointestinal stromal tumors (GIST), representing the first treatment ever to demonstrate a statistically significant advantage over an active comparator in this setting.

At the September 30, 2025, data cutoff, bezuclastinib plus sunitinib demonstrated a 50% reduction in the risk of disease progression or death compared with sunitinib alone (HR, 0.50; 95% CI, 0.39-0.65; P < .0001). The median progression-free survival (PFS) was 16.5 months (95% CI, 13.8-19.2) with bezuclastinib plus sunitinib vs 9.2 months (95% CI, 7.2-11.0) with sunitinib monotherapy. The mean duration of treatment was estimated at 21.4 months for patients receiving the combination. Of note, the PFS benefit with bezuclastinib plus sunitinib was consistent regardless of primary or secondary KIT mutation status, indicating broad activity across the heterogeneous mutation landscape that typically characterizes resistance in the second-line GIST setting. The combination was well tolerated, with no unique safety risks observed beyond the known profile of sunitinib.

Michael C. Heinrich, MD, Oregon Health & Science University Knight Cancer Institute:

“I definitely am excited about the results of the phase 3 PEAK study. It was a positive phase 3 study. The median PFS went from 9 months to 16 months, which is quite unprecedented in the second line, without a significant increase in toxicity reported with the combination. This will be the first public presentation in a scientific meeting.”

Andrew Wagner, MD, PhD, Dana-Farber Cancer Institute/Harvard Medical School:

“In the sarcoma field, there are actually quite a few big stories this year, [including the PEAK study]. The combination of bezuclastinib plus sunitinib has the potential to be practice-changing and replace sunitinib as second-line therapy for patients with GISTs.”