Advances in Pancreatic and Biliary Tract Cancers at ASCO GI 2026: Expert Insights

Anupriya Singhal, MD, PhD Memorial Sloan Kettering Cancer Center

Key Points

• Pancreatic ductal adenocarcinoma (PDAC) should be treated as a systemic disease early; many centers favor neoadjuvant therapy even for resectable disease, but the optimal sequence of surgery versus perioperative therapy remains unresolved.

• In metastatic PDAC, modified FOLFIRINOX and NALIRIFOX are both frontline options for ECOG 0–1 patients, with regimen selection and dose intensity increasingly guided by toxicity profiles and quality-of-life (QoL) considerations.

• PDAC is overwhelmingly KRAS-driven, and ASCO GI 2026 demonstrated that KRAS G12D targeting produces clinically meaningful signals.

• Homologous repair-deficient (HRD) PDAC is a distinct biologic subgroup with emerging signals supporting PARP inhibitor-based, chemotherapy-free strategies, including combinations with immunotherapy.

• HER2-positive biliary tract cancer (IHC 3+) represents a true oncogenic driver subgroup with meaningful benefit from HER2-directed therapy.

In an expert hepatobiliary and pancreatic cancer panel, Shubham Pant, MD, MBBS, of MD Anderson Cancer Center, and Wungki Park, MD, MS, of Memorial Sloan Kettering Cancer Center, joined moderators Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, to discuss practical decision-making in pancreatic and biliary tract cancers, emphasizing the growing impact of biomarker-directed therapy.

Is it Time for a Sequencing Shift in Resectable PDAC?

The panel, held at an event coinciding with the 2026 ASCO Gastrointestinal Cancers Symposium (ASCO GI 2026), opened with a key sequencing question in early-stage PDAC: whether to proceed directly with surgery or prioritize neoadjuvant systemic therapy.

Dr. Pant explained the systemic nature of PDAC and described a strong institutional bias toward neoadjuvant treatment even in technically resectable disease, particularly when Cancer Antigen (CA) 19-9 is markedly elevated (referenced a threshold of CA 19-9 >100)—identifying patients likely to declare early metastatic behavior and potentially sparing them morbid surgery without durable benefit. Dr. Park agreed with the systemic rationale but underscored the unresolved nature of sequencing, stressing the importance of not losing the opportunity for resection. He outlined a pragmatic strategy—enroll patients in clinical trials when possible, including recent personalized neoantigen vaccine studies which have demonstrated encouraging survival signals, and otherwise proceed with surgery followed by adjuvant therapy. Both highlighted ongoing cooperative group trials as key to resolving this question.

Frontline Metastatic PDAC: Weighing Toxicity Profiles 

Frontline treatment options for metastatic PDAC were explored with Dr. Pant, who compared modified FOLFIRINOX with NALIRIFOX. He discussed the limitations of cross-trial comparisons but highlighted the practical differentiator: toxicity. Neuropathy is the “not if, but when” adverse effect of oxaliplatin, Dr. Pant said, and pointed out that NALIRIFOX uses a lower oxaliplatin dose than FOLFIRINOX (60 mg/m² vs 85 mg/m²), which may be important for patients at higher neuropathy risk. He also cautioned that diarrhea may be more prominent with NALIRIFOX, requiring proactive counseling and early intervention.

Dr. Park described being liberal with dose modification as treatment evolves, noting that many patients can do well without “full throttle” dosing and that de-escalation is often necessary over time to preserve QoL. A practical pearl is that gemcitabine/nab-paclitaxel should not be reflexively labeled a gentler alternative. Weekly administration of the chemotherapy regimen can carry substantial hematologic toxicity. The panel discussed an off-protocol strategy used in collaboration with other centers: every-other-week dosing to improve tolerability. 

KRAS-Mutant PDAC: From “Undruggable” to Actionable

PDAC is overwhelmingly KRAS-driven (~90–95%), and ASCO GI 2026 demonstrated clinical efficacy signals from direct KRAS G12D targeting. Early-phase data for INCB161734, a selective KRAS G12D small-molecule inhibitor, demonstratedmeaningful single-agent activityin heavily pretreated PDAC, with reportedobjective response rates (ORRs) of approximately 37% and disease control rates of approximately 78%, alongside manageable on-target toxicities. Importantly, combination cohorts pairing INCB161734 with cytotoxic chemotherapy demonstrated early safety and efficacy, supporting continued development of KRAS inhibition at earlier stages of disease. Combining ASP3082 (setidegrasib), a KRAS G12D degrader, with mFOLFIRINOX producedhigh response rates (~58% in evaluable patients, with a confirmed ORR of ~40–45%), reinforcing the concept that direct KRAS suppression translates into clinically meaningful responses in PDAC. 

KRAS Wild-Type PDAC: Rare but Target-Rich

The panelists emphasized that KRAS wild-type PDAC is uncommon but represents a biologically distinct and often target-rich subgroup, enriched for actionable alterations, including kinase fusions and BRAF-class mutations. In this setting, fusion-focused RNA testing is essential, as DNA-only assays may miss relevant rearrangements.

HRD in PDAC and Chemo-Free Maintenance Concepts

At ASCO GI 2026, a single-arm phase 2 study evaluating durvalumab plus olaparib in metastatic PDAC with DNA damage repair alterations following platinum response reported an ORR of 32.5%, median progression-free survival of 6.7 months, and median overall survival of 15.4 months. In parallel, the POLAR trial at Memorial Sloan Kettering—testing maintenance pembrolizumab plus olaparib in HRD-selected metastatic PDAC—reflects the same biologic rationale. These data provide proof of concept that immune–PARP combinations may extend disease control in molecularly selected patients. 

Biliary Tract Cancer: HER2 as a True Driver

Shifting to biliary tract cancers, the panel stressed broad genomic profiling given the expanding list of actionable alterations and the risk of missing targets without comprehensive next-generation sequencing. A focal point was HER2–positive biliary tract cancer. Dr. Pant said that HER2 appears to function as a true oncogenic driver, particularly in IHC 3+ disease, where response rates to HER2-directed therapy can be substantial relative to historical chemotherapy options. He highlighted zanidatamab’s practical toxicity profile, focusing on diarrhea and infusion-related reactions, and emphasized proactive management (premedication and antidiarrheal readiness). The panel also underscored that HER2 prevalence differs by primary site, with gallbladder cancer described as having the highest rates, making HER2 testing especially important in that subgroup.

Future Clinical Outlook

ASCO GI 2026 reinforced that progress in pancreatic and biliary cancers increasingly depends on identifying actionable molecular subsets while simultaneously tailoring treatment intensity to patient priorities—balancing efficacy with toxicity, preserving QoL, and maintaining flexibility in dosing and sequencing.