The combination of vopimetostat, an investigational oral PRMT5 inhibitor, with the RAS(ON) inhibitor daraxonrasib (RMC-6236) produced a high objective response rate (ORR) in patients with MTAP-deleted, RAS-mutant metastatic pancreatic ductal adenocarcinoma (PDAC) in initial data from an ongoing phase 1/2 trial (NCT06922591).¹
Among 12 response-evaluable patients with PDAC in the vopimetostat-plus-daraxonrasib arm, the ORR was 92%, with 9 of 11 responses confirmed at the time of the data cutoff. The 6-month progression-free survival (PFS) rate was 90%, with median PFS that was not yet reached, and the disease control rate (DCR) was 100%.
In the vopimetostat-plus-zoldonrasib PDAC arm, which was restricted to patients harboring both MTAP deletion and a KRAS G12D mutation, 27 patients were response evaluable. The ORR was 52%; 10 of 14 responses were confirmed. The 6-month PFS rate was 74%, and the DCR was 96%.
“In the first reported data from the clinical combinations of our PRMT5 inhibitor vopimetostat and RAS(ON) inhibitors, we saw extremely encouraging early results, with 92% of patients with PDAC in the vopimetostat-plus-daraxonrasib arm achieving an [ORR], supporting the preclinical data showing synergistic activity of PRMT5 [targeting plus] RAS inhibition,” Malte Peters, MD, chief executive officer of Tango Therapeutics, stated in a news release. “Equally important, we are seeing encouraging signals of durability, with 90% of [patients with] PDAC still progression free at 6 months of follow-up. In addition, both combinations were generally well tolerated. Our primary focus is now to bring forward the PRMT5 [inhibitor]–plus-RAS-inhibitor combination approach in pancreatic cancer, [and] looking toward important upcoming data readouts for vopimetostat [as a] single agent in lung cancer and TNG456 in [glioblastoma multiforme], which we believe represent significant long-term opportunities for our company.”
PRMT5 Meets KRAS: A Precision Pairing in Pancreatic Cancer
- The combination of vopimetostat and daraxonrasib produced a 92% ORR among 12 response-evaluable patients with previously treated MTAP-deleted, RAS-mutant metastatic PDAC in an ongoing phase 1/2 trial, with a 100% DCR.
- Ninety percent of patients with PDAC treated with vopimetostat plus daraxonrasib remained progression free at 6 months, with a median PFS that was not yet reached at the May 28, 2026, data cutoff.
- Based on these results, the trial sponsor intends to advance vopimetostat plus daraxonrasib into a phase 3 randomized controlled trial in front-line MTAP-deleted pancreatic cancer, with trial design finalization targeted for the second half of 2026.
How was the phase 1/2 trial of vopimetostat plus daraxonrasib in PDAC designed?
This open-label, multicenter, dose-escalation and -expansion study was designed to determine the safety, tolerability, pharmacokinetics/ pharmacodynamics, and preliminary antineoplastic activity of oral vopimetostat in combination with daraxonrasib, zoldonrasib, mFOLFIRINOX (modified leucovorin, fluorouracil, irinotecan, and oxaliplatin), or gemcitabine plus nab-paclitaxel (Abraxane) in patients with pancreatic cancer with MTAP loss and pancreatic cancer or NSCLC with MTAP loss and RAS mutations.1,2
As of the data cutoff date of May 28, 2026, 59 patients had been treated across 2 combination arms: vopimetostat plus daraxonrasib (n = 20 patients with PDAC; n = 5 patients with NSCLC) and vopimetostat plus zoldonrasib (n = 34 patients with PDAC).1 All patients had advanced disease; 70% of patients in the daraxonrasib PDAC arm and 77% of those in the zoldonrasib arm had liver metastases. More than half of patients received their assigned combination as third-line therapy. In the vopimetostat-plus-daraxonrasib dose-escalation arm, patients received vopimetostat at 200 mg (dose level 1 )or 250 mg (dose level 2) once daily in combination with daraxonrasib at 100 mg once daily. Response evaluability required at least 14 weeks of follow-up.
What were the safety profiles of the vopimetostat-based regimens in PDAC?
Both combination regimens were reported as generally well tolerated across all dose levels, with no new safety signals observed as of the data cutoff. In the vopimetostat-plus-daraxonrasib arm, most treatment-related adverse effects (TRAEs) were grade 1 or 2 in severity. The most common TRAEs were rash, stomatitis/mucositis, and diarrhea. No related grade 4 or 5 AEs were reported, and no patients discontinued treatment due to AEs. Dose-limiting toxicities (DLTs) were absent at dose level 1; however, 3 DLTs were reported in 2 patients at dose level 2, including 1 case of grade 3 rash and one case of grade 3 stomatitis combined with fatigue. Two dose reductions occurred at dose level 1, and 1 occurred at dose level 2.
In the vopimetostat-plus-zoldonrasib arm, nausea and vomiting were the most common TRAEs, which were again predominantly grade 1 or 2. No related grade 4 or 5 AEs, no DLTs, 1 dose reduction, and no treatment discontinuations due to AEs were reported.
What’s next for investigating vopimetostat-based regimens in PDAC?
Based on the phase 1/2 data, the company announced plans to finalize the design of a phase 3 randomized controlled trial evaluating the vopimetostat-plus-daraxonrasib combination in the first-line MTAP-deleted PDAC setting in the second half of 2026, pending regulatory feedback. The company also indicated plans to evaluate the combination in the second-line setting for potential registration-directed development.
Additional anticipated milestones for the second half of 2026 include the disclosure of vopimetostat monotherapy data in lung cancer, the release of initial data for TNG456 in glioblastoma, the presentation of second- and third-line data with vopimetostat plus a RAS(ON) inhibitor in PDAC at a scientific conference, and the initiation of a phase 1/2 study evaluating vopimetostat in combination with ERAS-0015.
“Pancreatic cancer remains a largely intractable disease and an area where patients desperately need new therapies,” Brian Wolpin, MD, director of the Hale Family Center for Pancreatic Cancer Research at Dana-Farber Cancer Institute in Boston, Massachusetts, added in the news release. “In the frontline setting, chemotherapy has long been the standard of care, yet it presents significant tolerability challenges and overall limited efficacy against this aggressive disease. Building on the monotherapy activity already shown by these investigational PRMT5- and RAS(ON)- targeted therapies, these early combination data demonstrated the potential to meaningfully reshape how we treat this disease with a precision-guided, chemotherapy-free approach.”
References
- Tango Therapeutics, Inc. Tango Therapeutics announces combination of vopimetostat and daraxonrasib demonstrated 92% objective response rate in pancreatic cancer. Tango Therapeutics. June 8, 2026. Accessed June 8, 2026. https://www.globenewswire.com/news-release/2026/06/08/3307926/0/en/tango-therapeutics-announces-combination-of-vopimetostat-and-daraxonrasib-demonstrated-92-objective-response-rate-in-pancreatic-cancer.html
- Study to evaluate the safety, tolerability & efficacy of TNG462 in combination in PDAC & NSCLC patients. ClinicalTrials.gov. Updated May 14, 2026. Accessed June 8, 2026. https://clinicaltrials.gov/study/NCT06922591
