Breaking the “Undruggable”: Key Pancreatic Cancer Signals from ASCO GI 2026
The ASCO GI 2026 abstracts reveal a dynamic and evolving landscape for pancreatic cancer drug development, characterized by a strategic shift away from monolithic chemotherapy towards targeted, immunomodulatory, and novel delivery-based combination therapies.
Here are the primary trends shaping the field:
- Targeting KRAS G12D: The presentation of first-in-human data for selective KRAS G12D inhibitors, such as INCB161734, marks a long-awaited breakthrough in directly targeting the most common mutation in pancreatic ductal adenocarcinoma (PDAC).
- Validating Novel Immune & Stromal Targets: Innovative agents are beginning to crack the tumor's defensive "shell." Candidates targeting CLDN18.2 (Spevatamig), CD40 (Mitazalimab), and GSK-3β (Elraglusib) are showing real potential in neutralizing the immunosuppressive environment that typically shields these tumors.
- Intensified Combination Regimens: The "quadruplet" approach is gaining momentum. Notably, the PAAG regimen—which integrates chemotherapy with PD-1 and anti-angiogenic inhibitors—has demonstrated a meaningful improvement in progression-free survival (PFS).
- Innovation in Delivery and Design: Efficiency is being reimagined through technology. This includes RenovoGem’s locoregional intra-arterial delivery systems and the use of AI-driven stratification for Glufosfamide, ensuring the right patients receive the most effective interventions.
ASCO GI 2026 Pancreatic Cancer Abstract: Pipeline Overview
The following table systematically captures and consolidates the structured data for all identified pancreatic cancer drug-treatment studies presented at ASCO GI 2026. Data is compiled from official abstracts, company press releases, and related clinical trial information.(Noah Medical-Conference)
| Drug Name (Generic + Code) | Abstract No. | Study Code / Trial ID | Phase | Study Design & Setting | Primary & Key Secondary Endpoints and Reported Results | Modality & Mechanism | Sponsor / Geography |
|---|---|---|---|---|---|---|---|
| Elraglusib (9-ING-41) | 653 (Oral), 761 (Poster) | NCT03678883 (Actuate-1801 Part 3B) | Randomized Phase II | Open-label, 2:1 randomization of Elraglusib + Gemcitabine/Nab-paclitaxel (GnP) vs. GnP alone in 1st-line metastatic PDAC. | Primary: mOS, 1-yr OS. Secondary: ORR, mPFS, Safety. Results: “Elraglusib + Gem/nab-paclitaxel cut risk of death by 38% vs chemo alone” 18. mOS: 10.1 vs 7.2 mo (HR 0.62; p=0.01); 1-yr OS: 44.1% vs 22.3%; mPFS: 5.6 vs 5.1 mo (NS); ORR: 28.4% vs 21.8%. Safety: Gr ≥3 neutropenia 52% (combo) vs 31% (control); Gr 1-2 transient visual impairment 66.5% in combo arm 1. | Small Molecule; selective GSK-3β inhibitor (chemosensitizer). Patent WO2024006750A1 describes oral dosage forms 21. | Actuate Therapeutics, Inc. / USA |
| INCB161734 | 654 | NCT06179160 | Phase I | First-in-human, dose-escalation/expansion of monotherapy ± mFOLFIRINOX or GnP in advanced/metastatic KRAS G12D-mutant PDAC. | Primary: Safety. Secondary: PK, preliminary efficacy (RECIST 1.1). Results (Monotherapy): Confirmed PRs of 23% (5/22 at 600mg) and 34% (10/29 at 1200mg). Disease control rates of 73% and 86%, respectively. Safety: Common TRAEs were nausea (58%), diarrhea (51%), vomiting (46%) 2. | Small Molecule; oral selective KRAS G12D inhibitor (covalent, binds inactive GDP state). Patent WO2024206858A1 lists as exemplar 22. | Incyte Corporation / USA |
| Penpulimab (AK105) + Anlotinib + GnP (“PAAG”) | 655 | NCT06051851 | Randomized Controlled Trial (likely Phase II) | Open-label, multi-center RCT of PAAG vs. Gemcitabine + Nab-paclitaxel (AG) in 1st-line metastatic PDAC. | Primary: PFS. Secondary: OS, ORR, DCR, Safety. Results: “mPFS 7.7 mo (PAAG) vs 4.5 mo (AG) (P < 0.001)”. ORR: 47.9% vs 28.6% (p=0.026); DCR: 92.6% vs 67.4% (p < 0.001). Safety: Gr ≥3 AEs 41.8% vs 38.5%, with leukocytopenia most common 3. | Quadruplet Combo: mAb (PD-1 inhibitor) + Small Molecule (multi-target TKI) + Chemotherapy. Anlotinib patent WO2020181214A1 covers chemo combos 24. | No external funding declared / China |
| Alternating Chemotherapy | 706 | NCT03703063 | Pilot Study | Single-arm study of alternating neoadjuvant GnP with Nal-irinotecan/5-FU/Folinic acid in resectable (R) and borderline-resectable (BR) PDAC. | Endpoints: Feasibility, toxicity, OS, surgical conversion. Results (R cohort): 93% resected; mOS 30.9 mo; 2-yr OS 64%. (BR cohort): 65% resected; mOS 26.4 mo. Safety: Gr ≥3 neutropenia 56%, diarrhea 28% 4. | Chemotherapy; novel sequencing strategy. | Ipsen / USA |
| Spevatamig (PT886) | 709 | NCT05482893 (TWINPEAK) | Phase I/II | Basket study with a cohort for Spevatamig + GnP in CLDN18.2-positive, 1st-line metastatic PDAC. | Primary: Safety/Tolerability. Secondary: ORR, DCR, DoR. Results: ORR 33%; DCR 93%; mPFS 7.3 mo Safety: No CRS has been observed. No grade ≥ 3 treatment-emergent anemia, neutropenia or thrombocytopenia have been observed in the monotherapy study 11. | Bispecific Antibody (targets CLDN18.2 and CD47). Patent WO2021003082A1 describes the bispecific construct 25. FDA Fast-Track & ODD granted. | Phanes Therapeutics / Multinational (USA, China) |
| Mitazalimab (ADC-1013) | 708 | NCT04888312 (OPTIMIZE-1) | Phase Ib/II | Open-label, single-arm dose-expansion of Mitazalimab + mFOLFIRINOX in 1st-line unresectable/metastatic PDAC. | Primary: ORR. Secondary: PFS, OS, Safety. Results: ORR 54.4% (42.1% confirmed); median DoR 12.6 mo, mPFS 7.7 mo; mOS 14.3 mo 16. Prior publication 9. | Agonistic mAb (fully human IgG1 CD40 agonist). Method patent WO2022266496A1 covers use with chemo in KRAS-mutant PDAC 26. | Alligator Bioscience / Europe (BE, FR, ES) |
| RenovoGem (Locoregional Gemcitabine) | 732 | TIGeR-PaC (Phase III) | Phase III | Randomized (1:1), open-label trial of intra-arterial (IA) gemcitabine via RenovoCath® vs. standard IV gemcitabine in locally advanced PDAC (LAPC). | Primary: OS. Secondary: Safety, PK/PD. Results: ASCO GI presentation to cover PK/PD sub-study data. An interim update was described as “promising new clinical data” 5, 13,14. | Drug-Device Combination; Trans-Arterial Micro-Perfusion (TAMP) of an antimetabolite. Device patent WO2018213760A1 describes the method 27. | RenovoRx, Inc. / USA |
| Glufosfamide | 755 | TH-CR-302 (Phase III) | Post-hoc analysis of Phase III | AI-enabled post-hoc analysis of a randomized Phase III trial to identify biomarker-selected subgroups. | Endpoint: Mean Survival. Results: Analysis showed a “~3-fold improvement in mean survival for biomarker-selected sub-groups” 19. | Alkylating Agent (chemotherapy pro-drug). | BullFrog AI (analysis) / Eleison Pharmaceuticals (drug) / USA |
Analysis of Future Trends in Pancreatic Cancer Drug R&D
The ASCO GI 2026 abstracts highlight a clear shift in pancreatic cancer R&D priorities: moving beyond the limits of conventional chemotherapy through integrated strategies targeting tumor biology, the immune microenvironment, and drug delivery innovation.
Pipeline Highlights from ASCO GI 2026
Distribution by Modality
The presented studies reflect strong diversification in therapeutic approaches. Antibody-based therapies lead the pipeline, including a PD-1 inhibitor (Penpulimab), a CD40 agonist (Mitazalimab), and a bispecific antibody (Spevatamig). Small molecule inhibitors account for 29%, targeting emerging pathways such as GSK-3β (Elraglusib) and KRAS G12D (INCB161734).
Distribution by Study Phase
Most programs are in early-to-mid clinical development. This reflects a focus on proof-of-concept validation before advancing into large-scale Phase III trials. Importantly, the pipeline spans the full development spectrum, including a first-in-human Phase I study (INCB161734) and a pivotal Phase III trial (TIGeR-PaC).
Key Mechanisms and Targets
The pipeline is increasingly shifting beyond traditional cytotoxic therapy toward novel, mechanism-driven approaches in pancreatic cancer. Key advances include:
- Targeting KRAS G12D (INCB161734)
- Deploying immune-priming strategies such as CD40 agonism (Mitazalimab) and CD47 blockade (Spevatamig)
- Overcoming resistance and stromal barriers through GSK-3β inhibition (Elraglusib)
- Anti-angiogenic treatment (anlotinib in the PAAG regimen).
Emerging Trends and Signals Pancreatic cancer R&D is entering a new phase of precision oncology, driven by biomarker-focused programs such as the KRAS G12D inhibitor INCB161734 and the CLDN18.2-targeted bispecific Spevatamig. In parallel, established first-line backbones like GnP and FOLFIRINOX are increasingly being used as combination platforms to improve outcomes. Innovation is also reshaping chemotherapy through optimized delivery and sequencing, including RenovoCath-enabled intra-arterial gemcitabine in TIGeR-PaC and an alternating GnP/NAL-IRI neoadjuvant approach.
Risk and Opportunity Assessment (12-36 Month Outlook)
From Early Signals to Pivotal Trials: What’s Ahead
Over the next 12–36 months, several near-term development opportunities could significantly advance these programs. For KRAS G12D inhibitors, early monotherapy activity with INCB161734 supports accelerating dose escalation and moving quickly into chemotherapy combinations, with the goal of defining the optimal regimen and dose for a larger, potentially registrational Phase II trial within 12–24 months.
In parallel, the immunotherapies Mitazalimab and Spevatamig are approaching Phase III readiness—if OPTIMIZE-1 confirms Mitazalimab’s strong overall response rate (ORR) signal, a pivotal trial with FOLFIRINOX could begin within 18 months, while positive Phase II results for Spevatamig would support Phase III testing in CLDN18.2-positive patients. Finally, RenovoGem remains anchored by the Phase III TIGeR-PaC trial in locally advanced pancreatic cancer, where a positive overall survival (OS) readout in 24–36 months could support approval of a first-in-class drug–device combination and potentially redefine the standard of care.
What Could Be Challenging: Key Risks to Monitor
As these programs intensify and move closer to late-stage development, several hurdles could limit success without careful execution.
Toxicity is a major concern, with elraglusib combinations showing higher neutropenia rates and a notable transient visual impairment signal (66.5% of patients), while the PAAG quadruplet also reported substantial severe adverse events—making proactive safety management critical for both approval and real-world adoption.
Another key risk is the need to validate early efficacy signals, since programs like INCB161734 and Mitazalimab are still supported largely by single-arm Phase I/II data, which may not hold up in randomized trials against current standards of care.
Finally, biomarker-driven approaches (such as KRAS G12D and CLDN18.2) depend on reliable, standardized diagnostic testing, and challenges like assay harmonization, defining clear positivity cutoffs, and ensuring access and affordability could become meaningful barriers to broad adoption and commercial scale.
Strategic Implications and Next Steps
Prioritize KRAS G12D Programs
First-in-human results from INCB161734 reinforce KRAS G12D as a viable target in PDAC. This supports high-priority investment, with emphasis on developing optimized combination regimens to improve depth and durability of response.
Strengthen CLDN18.2 Target Validation
CLDN18.2 is gaining momentum across multiple modalities, including bispecific antibodies and ADCs, positioning it as a leading emerging target in PDAC. The upcoming Phase II readout for Spevatamig will be a key inflection point—positive data should accelerate development and companion diagnostic planning.
Watch the Drug–Device Opportunity
RenovoGem in the TIGeR-PaC trial represents a potentially disruptive approach beyond standard systemic therapy in LAPC. Continued monitoring is warranted, as a positive outcome could reshape treatment expectations and clinical strategy in this setting.
Disclosure: All analysis is conducted by Noah. This content is for informational purposes only and does not constitute investment or medical advice.
Reference
[1] Results from the randomized phase 2 study (1801 Part 3B).
[2] Preliminary phase 1 results of INCB161734.
[3] A multi-centered, randomized controlled trial (RCT-PAAG).
[4] Alternating neoadjuvant gemcitabine-nab-paclitaxel (GnP).
[14] Clinical-Trial-Result-Analysis.
[15] Drug-Analysis.
[19] BullFrog AI Highlights Data-Driven Advances in Pancreatic Cancer Treatment at ASCO GI 2026.