June 2026 brought a wide range of important updates across pancreatic cancer and related GI oncology, from RAS-targeted therapy and chemotherapy sequencing to biomarker development, stromal biology, recurrence management, immunotherapy approaches, and resistance mechanisms.
This month’s selection includes updates on daraxonrasib, MEKiAUTO, PancreaSure, HSP47, OCLURANDOM, single-site recurrent PDAC, vopimetostat plus daraxonrasib, MoST-CIRCUIT, PRODIGE 61-FUNGEMAX, and adaptive resistance to KRASG12D blockade.
One of the most discussed moments around the month came from RASolute 302, presented as a late-breaking plenary on May 31 at ASCO 2026 by Brian M. Wolpin. The daraxonrasib data stood out as a memorable pancreatic cancer presentation and continued to shape conversations about RAS-targeted treatment in previously treated metastatic PDAC.
Together, these studies and reports reflect the continued movement of pancreatic cancer research toward more precise treatment strategies, better patient selection, deeper resistance biology, and new approaches to the tumour microenvironment.
RASolute 302: Daraxonrasib in Previously Treated mPDAC
RASolute 302 results were published in The New England Journal of Medicine on May 31, 2026. This phase 3, international, open-label, randomized trial evaluated daraxonrasib, an oral RAS(ON) multiselective inhibitor, versus investigator’s choice of chemotherapy in patients with previously treated metastatic pancreatic ductal adenocarcinoma.
A total of 500 patients were randomly assigned to daraxonrasib or chemotherapy. Of these, 91.8% had RAS G12 mutations, reflecting the central role of oncogenic RAS signaling in PDAC.
- In the RAS G12 population, median overall survival was 13.2 months with daraxonrasib versus 6.6 months with chemotherapy (HR 0.40; P<0.001).
- Median progression-free survival in the RAS G12 population was 7.3 months versus 3.5 months.
- Objective response rate in the RAS G12 population was 33.2% with daraxonrasib versus 11.8% with chemotherapy.
- Patient-reported time to deterioration in pain and global health status–quality of life was significantly longer with daraxonrasib.
Safety
Adverse events of grade 3 or higher, regardless of attribution, occurred in 61.8% of patients receiving daraxonrasib and 69.6% receiving chemotherapy. Treatment-related adverse events leading to discontinuation were less frequent with daraxonrasib (1.2%) than with chemotherapy (11.2%). One treatment-related death from pneumonitis occurred in the daraxonrasib group.
Takeaway: RASolute 302 showed significantly longer overall survival and progression-free survival with daraxonrasib compared with chemotherapy in previously treated metastatic PDAC. The data represent a major RAS-targeted treatment advance in a disease where meaningful drug development progress has historically been difficult.
MEKiAUTO: MEK and Autophagy Inhibition in PDAC
Published in JCO Precision Oncology on June 12, 2026, the MEKiAUTO study evaluated combined MEK inhibition and autophagy inhibition in pancreatic ductal adenocarcinoma, using both preclinical KPC mouse models and a phase I clinical trial in patients with metastatic KRAS-mutant PDAC.
The clinical trial tested this strategy with or without the anti-PD-L1 antibody atezolizumab. Tumour response and treatment sensitivity were further explored using multiplex immunofluorescence, reverse-phase protein array, and single-nucleus RNA sequencing of serial tumour specimens.
Key findings
- Combined MEK and autophagy inhibition suppressed tumour growth in KPC mouse models.
- In the phase I clinical trial, 14 patients were treated, and 4 experienced dose-limiting toxicity.
- Median progression-free survival was 7.7 weeks and median overall survival was 20.7 weeks.
- Paired tumour biopsies showed substantial malignant-cell heterogeneity in human PDAC.
Single-nucleus RNA sequencing identified an epithelial malignant-cell subtype enriched for autophagy and MAPK signaling that decreased after treatment. Higher baseline abundance of this subtype correlated with longer PFS, but this subtype was rare in TCGA PDAC tumours.
By contrast, KPC tumours and PDAC cell lines showed less heterogeneity and more uniform enrichment of this MAPK/autophagy-high state, consistent with their stronger preclinical responses.
Takeaway: MEKiAUTO showed that combined MEK and autophagy inhibition had stronger activity in preclinical PDAC models than in the clinical setting, where tolerability and efficacy were limited. The study highlights how tumour-cell-state heterogeneity may partly explain differences between preclinical and human PDAC responses, supporting the need for more representative models in PDAC drug development.
PancreaSure 5-Biomarker Panel Detects Advanced PDAC
Published in JCO Oncology Advances on June 9, 2026, this open-access study evaluated PancreaSure, a five-plex serum biomarker signature originally designed to detect stage I and II pancreatic ductal adenocarcinoma in high-risk surveillance populations.
PancreaSure measures circulating levels of TIMP1, ICAM1, CTSD, THBS1, and CA 19-9. In this retrospective blinded study, the assay was tested in 619 serum samples, including 224 patients with stage III or IV PDAC and 395 non–high-risk controls.
Key findings
- Sensitivity: 87.9% for stage III and IV PDAC
- Specificity: 97.7% in non–high-risk controls
- Stage comparison: sensitivity was higher in stage III and IV PDAC than in stage I and II PDAC (87.9% vs 77.3%; P = .002)
- Control comparison: specificity was higher in non–high-risk controls than in high-risk controls (97.7% vs 92.2%; P < .001)
- CA 19-9 comparison: PancreaSure had higher sensitivity than CA 19-9 alone (87.9% vs 77.2%; P < .001), with similar specificity
Takeaway: Although PancreaSure was developed to detect stage I and II PDAC in high-risk surveillance populations, this study showed that the panel also distinguished stage III and IV PDAC from non–high-risk controls with high sensitivity and specificity. Its intended role remains as an adjunct to imaging-based surveillance, not a replacement for imaging, biopsy, or diagnostic evaluation.
HSP47 as a Dual Target in PDAC
Published in Oncogene, a Nature Portfolio journal, on June 21, 2026, this translational study evaluated heat shock protein 47 (HSP47), a collagen chaperone involved in collagen folding, maturation, and secretion, as a potential therapeutic target and prognostic factor in pancreatic ductal adenocarcinoma.
Because collagen is a central component of PDAC fibrosis, the study examined whether HSP47 inhibition could affect both tumour cells and cancer-associated fibroblasts (CAFs), which contribute to the desmoplastic tumour microenvironment.
Key findings
- HSP47 knockdown reduced proliferation of both PDAC cells and CAFs in vitro.
- Therapeutic delivery of HSP47-siRNA reduced intratumoural fibrosis and increased open intratumoural blood vessels in orthotopic PDAC mouse models.
- Stable CAF-specific HSP47 knockdown additionally reduced PDAC tumour growth.
In human PDAC tissue microarrays, HSP47 was highly expressed in the stromal compartment of 84% of patients and in the tumour compartment of 21%. High HSP47 expression in the tumour compartment was independently associated with poorer overall survival (HR 1.571; p = 0.014), while stromal HSP47 expression alone was not prognostic.
Functional relevance was further explored in 3D human PDAC explants, where HSP47 knockdown reduced cytokeratin-positive tumour cells in 4 of 4 evaluable patients. These explant findings were exploratory because of the limited sample size.
Takeaway: This study supports HSP47 as a potential dual-cell target in PDAC, with effects on both tumour-cell survival and CAF-associated collagen deposition. The findings remain preclinical and translational, but they suggest that HSP47 inhibition may represent a strategy to interfere with tumour fibrosis and support further study of stromal remodelling in pancreatic cancer.
OCLURANDOM Trial Updates
Published in The Lancet Oncology in June 2026, the OCLURANDOM trial evaluated peptide receptor radionuclide therapy with [177Lu]Lu-dota-tate in patients with pretreated, progressive, somatostatin receptor-positive, metastatic pancreatic neuroendocrine tumours.
OCLURANDOM was a randomized, open-label, non-comparative, phase 2 trial conducted across 10 academic centers in France. Patients were randomly assigned to receive [177Lu]Lu-dota-tate every 8 weeks for up to four cycles or sunitinib 37.5 mg once daily. The primary endpoint was 12-month progression-free survival by central RECIST 1.1 review.
Key findings
- 12-month PFS: 80.5% with [177Lu]Lu-dota-tate versus 41.9% with sunitinib
- Median PFS: 20.7 months versus 11.0 months
- Best overall partial response: 63.4% versus 30.2%
- Median overall survival: 55.8 months versus 64.4 months, with no significant difference between groups
- Quality of life: Global Health Status score favored [177Lu]Lu-dota-tate by 10.3 points
Safety
Grade 3–4 adverse events occurred in 44% of patients receiving [177Lu]Lu-dota-tate versus 72% receiving sunitinib. Late adverse events were reported after [177Lu]Lu-dota-tate, including grade 2 or worse late events in 60% of evaluable patients. One treatment-related death due to acute leukemia occurred in the [177Lu]Lu-dota-tate group.
Takeaway: OCLURANDOM met its primary endpoint and supports clinically meaningful antitumor activity of [177Lu]Lu-dota-tate in pretreated, progressive, somatostatin receptor-positive metastatic pancreatic neuroendocrine tumours. Because the trial was designed as a non-comparative randomized phase 2 study, direct comparisons with sunitinib should be interpreted as post-hoc rather than confirmatory.
Single-Site Recurrent PDAC After Curative-Intent Surgery
Published in Annals of Surgical Oncology on June 16, 2026, this systematic review and meta-analysis evaluated treatment strategies for patients with single-site recurrent pancreatic ductal adenocarcinoma after curative-intent pancreatectomy.
The analysis focused on three recurrence patterns: liver-only, lung-only, and locoregional recurrence. The review included 22 observational studies, with 17 included in the quantitative synthesis. Because the available evidence was observational, the findings mainly reflect outcomes in highly selected patients.
Key findings
- In liver-only recurrence, local therapy was associated with longer overall survival than chemotherapy alone (HR 0.26; 95% CI 0.14–0.49), mainly driven by surgical resection (HR 0.18; 95% CI 0.11–0.31). Ablation did not reach statistical significance.
- In lung-only recurrence, surgical resection was associated with longer post-recurrence survival than conventional management (HR 0.35; 95% CI 0.26–0.48).
- In isolated locoregional recurrence, resection was associated with longer survival than conventional non-surgical management (HR 0.52; 95% CI 0.38–0.72).
SBRT data were limited to small non-comparative series and were summarized descriptively.
Takeaway: This meta-analysis suggests that selected patients with biologically limited and technically manageable single-site recurrent PDAC may have longer survival with local therapy. However, the evidence does not prove broad efficacy of local treatment, and prospective recurrence pattern-specific studies are needed to define optimal site-tailored strategies.
Vopimetostat Plus Daraxonrasib in MTAP-Deleted PDAC
On June 8, 2026, Tango Therapeutics announced initial data from an ongoing phase 1/2 study evaluating vopimetostat, an investigational oral PRMT5 inhibitor, in combination with Revolution Medicines’ RAS(ON) inhibitors in patients with MTAP-deleted and RAS-mutant metastatic pancreatic ductal adenocarcinoma.
As of the May 28, 2026 data cutoff, 59 patients with previously treated MTAP-deleted and RAS-mutant PDAC or NSCLC had received a vopimetostat-based combination with either daraxonrasib or zoldonrasib. In the daraxonrasib PDAC arm, patients received vopimetostat 200 mg or 250 mg once daily plus daraxonrasib 100 mg once daily.
Key findings
- Objective response rate: 92%
- Responses: 11 of 12 patients, with 9 confirmed responses
- Disease control rate: 100%
- 6-month PFS rate: 90%
- Median PFS: not reached at the time of reporting
- Safety: most treatment-related adverse events were grade 1 or 2, most commonly rash, stomatitis/mucositis, and diarrhea
- No related grade 4 or 5 adverse events and no discontinuations due to adverse events were reported
The company also reported data for vopimetostat plus zoldonrasib in MTAP-deleted, KRAS G12D-mutant PDAC. Among 27 response-evaluable patients with at least 14 weeks of follow-up, the ORR was 52%, the DCR was 96%, and the 6-month PFS rate was 74%.
Takeaway: These early phase 1/2 data suggest encouraging antitumor activity for vopimetostat-based combinations with RAS(ON) inhibitors in previously treated MTAP-deleted, RAS-mutant metastatic PDAC, especially the vopimetostat plus daraxonrasib arm. The results remain early and based on small response-evaluable cohorts, but Tango stated that the data support advancement of vopimetostat plus daraxonrasib toward phase 3 development in frontline MTAP-deleted pancreatic cancer.
MoST-CIRCUIT: Nivolumab Plus Ipilimumab in Advanced iCCA and GBC
Published in Clinical Cancer Research on June 4, 2026, the phase II MoST-CIRCUIT trial evaluated nivolumab plus ipilimumab in patients with advanced intrahepatic cholangiocarcinoma and gallbladder cancer.
The single-arm, nonrandomized study enrolled 60 patients, including 37 with iCCA and 23 with GBC. Most patients were previously treated, and 13 had received prior durvalumab.
Key findings
- Overall response rate was 12%, including 2% complete response and 10% partial response.
- ORR was 3% in iCCA and 26% in GBC.
- Six-month PFS was 27% overall, 19% in iCCA, and 39% in GBC.
- Median overall survival was 7 months.
- In immunotherapy-naïve patients, ORR was 19%, including 10% in iCCA and 38% in GBC.
Severe immune-related adverse events occurred in 20% of patients.
Takeaway: MoST-CIRCUIT showed limited overall efficacy for nivolumab plus ipilimumab in advanced biliary tract cancer, but activity appeared more encouraging in the gallbladder cancer subgroup.
PRODIGE 61-FUNGEMAX Trial Updates
Published in eClinicalMedicine in June 2026, the randomized phase II PRODIGE 61-FUNGEMAX trial evaluated whether a sequential first-line chemotherapy strategy could improve outcomes in patients with metastatic pancreatic ductal adenocarcinoma.
The open-label multicenter trial enrolled 288 chemotherapy-naive patients with histologically confirmed metastatic PDAC and ECOG performance status 0-1 across 31 centers in France. Patients were randomly assigned to one of three arms: sequential alternation of nal-IRI/5-FU and gemcitabine/nab-paclitaxel every 2 months, continuous nal-IRI/5-FU using the NAPOLI regimen, or continuous gemcitabine/nab-paclitaxel using the MPACT regimen.
Key findings
- 6-month PFS rate: 51.6% with sequential therapy, 32.3% with NAPOLI, and 45.3% with MPACT
- Median PFS: 6.2, 3.7, and 5.7 months, respectively, in the mITT/safety population
- Median OS: 11.6, 9.1, and 12.4 months, respectively, in the ITT population
- 12-month PFS rate: 20.3%, 12.7%, and 11.9%
- 24-month OS rate: 23.8%, 9.5%, and 12.5%
- Objective response rate: 42.7%, 20.8%, and 37.5%
- Disease control rate: 81.6%, 63.3%, and 77.3%
The primary endpoint was not met. Neither the sequential regimen nor the NAPOLI regimen significantly improved PFS compared with MPACT. Grade 3-4 adverse events occurred in 85.3% of patients in the sequential arm, 53.8% in the NAPOLI arm, and 69.5% in the MPACT arm. Quality of life was preserved in the sequential arm, with median time to definitive deterioration of 8.1 months, compared with 6.6 months for NAPOLI and 7.0 months for MPACT.
Takeaway: PRODIGE 61-FUNGEMAX showed that sequential alternation of nal-IRI/5-FU and gemcitabine/nab-paclitaxel is feasible in first-line metastatic PDAC and produced numerically higher long-term PFS and OS rates, but did not significantly improve median PFS or OS compared with standard MPACT. The findings remain hypothesis-generating and should not be interpreted as replacing current first-line standards, including triplet regimens in fit patients.
Adaptive Resistance to KRASG12D Blockade in PDAC
Published in Clinical Cancer Research on June 1, 2026, this translational study evaluated mechanisms of adaptive resistance to mutant-selective KRASG12D inhibition in pancreatic ductal adenocarcinoma. Because KRAS mutations are present in more than 90% of PDAC, and KRASG12D is the most common alteration, the study focused on how PDAC models react after KRASG12D blockade and whether vertical pathway inhibition could sustain RAS-MAPK suppression.
Key findings
- KRASG12D inhibition initially suppressed ERK signaling, but RAS-MAPK signaling reactivated over time in PDAC models.
- EGFR appeared to drive adaptive RAS-MAPK reactivation mainly in epithelial PDAC models.
- FGFR signaling appeared to drive adaptive reactivation mainly in mesenchymal PDAC models.
- A RAS(ON) multiselective inhibitor combined with mutant-selective KRAS inhibition suppressed RAS-MAPK reactivation across both epithelial and mesenchymal models.
In TCGA PDAC specimens, EGFR and ERBB3 expression correlated with epithelial markers, while FGFR1 correlated with mesenchymal markers, supporting the cell-state findings from the preclinical models.
In vivo, combined EGFR and KRAS inhibition improved antitumor activity mainly in epithelial PDAC models. By contrast, combined mutant-selective KRAS inhibition and RAS(ON) multiselective inhibition showed more consistent activity across both epithelial and mesenchymal models.
Takeaway: This study suggests that adaptive resistance to KRASG12D inhibition in PDAC can be driven by different receptor tyrosine kinases depending on tumour cell state. The findings support further clinical evaluation of mutant-selective KRAS inhibitors combined with RAS(ON) multiselective inhibitors as a broader strategy to overcome adaptive resistance in KRAS-mutant PDAC.
Read more about Top 10 Hepatobiliary Cancer Updates – May 2026 on OncoDaily.