Daraxonrasib/Vopimetostat Yield Stunning Response Rate in MTAP-del Pancreatic Cancer

Combining the investigational PRMT5 inhibitor vopimetostat with daraxonrasib elicited an overall response rate (ORR) of 92% in patients with pancreatic ductal adenocarcinoma (PDAC).¹ These results were shared in a press release and subsequent conference call, which reported findings from a phase 1/2 trial (NCT06922591) evaluating vopimetostat in combination with either zoldonrasib or daraxonrasib in patients with MTAP-deleted and RAS-mutant metastatic PDAC.²

How effective was daraxonrasib plus vopimetostat in pancreatic cancer?

With the vopimetostat plus daraxonrasib combination in MTAP-deleted second and third-line PDAC, the 92% ORR was achieved with 11 out of 12 possible responses; 9 of the responses were confirmed partial responses (PRs) and 2 were unconfirmed PRs pending confirmation. The disease control rate was 100%, and the 6-month progression-free survival (PFS) rate was 90%.

Notably, patients with non–small cell lung cancer were also included in this trial arm, where they demonstrated an ORR of 100%, with 3 of 3 responses confirmed.

Reportedly, all patients who were not yet efficacy evaluable (n = 9) were ongoing on treatment with no disease progression as of the May 28, 2026, data cutoff.

“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 objective response, supporting the preclinical data showing synergistic activity of PRMT5 [plus] RAS inhibition,” stated Malte Peters, MD, chief executive officer of Tango Therapeutics, in the press release.¹

Patients were treated at one of 2 dose levels:

• Dose level 1 (PDAC, n = 16 and NSCLC, n = 5): vopimetostat at 200 mg and daraxonrasib at 100 mg
• Dose level 2 (PDAC, n = 4): vopimetostat at 250 mg and daraxonrasib at 100 mg.

Eligible patients had MTAP loss by next-generation sequencing or immunohistochemistry, 1 to 2 prior lines of therapy in the metastatic setting, and an ECOG performance status of 0 or 1. They were not permitted to have received prior PRMT5 or RAS inhibitors. In the daraxonrasib combination, patients with any RAS mutation were permitted.

Regarding safety, no new signals nor discontinuations due to adverse effects (AEs) were observed, with no grade 4 or 5 AEs or serious AEs. In dose level 1, 75% of patients with PDAC and 100% of patients with NSCLC experienced AEs. In the PDAC arm, the most common AEs were stomatitis/mucositis (56%), rash (44%), diarrhea (31%), and thrombocytopenia (13%). Grade 3 AEs were only observed in 25% of the PDAC arm, the most common being thrombocytopenia (13%). In dose level 2, 100% of patients experienced AEs, the most common being rash (100%), diarrhea (75%), and fatigue (75%). Grade 3 AEs were experienced by 75%, with 1 event of rash, stomatitis, and fatigue each.

The investigators also noted that daraxonrasib plus vopimetostat had a favorable RAS-associated safety profile with a median follow-up of 5.0 months. No grade 3 or higher RAS-associated treatment-related AEs were observed.

Based on these findings, the developers intended to advance the vopimetostat plus daraxonrasib combination into phase 3 development for patients with first-line, MTAP-deleted pancreatic cancer: “These compelling results reinforce our belief that a vopimetostat-based combination with RAS inhibitors may be a path to a chemotherapy-free option for patients with MTAP-deleted pancreatic cancer. Given these data, we intend to prioritize advancement of the vopimetostat plus daraxonrasib combination into phase 3 development in first-line, MTAP-deleted pancreatic cancer,” Peters added.

How effective was zoldonrasib plus vopimetostat in pancreatic cancer?

Combining vopimetostat with zoldonrasib led to a 52% ORR in patients with MTAP-deleted, KRAS G12D second or third-line PDAC. As of the data cutoff, 10 patients had confirmed PRs and 4 had unconfirmed PRs pending confirmation. The disease control rate was 96%, and the 6-month PFS rate was 74% (95% CI, 49%-88%).

The dose escalation range for this arm was vopimetostat once daily from 200 to 250 mg and zoldonrasib once daily from 600 to 1200 mg. There were 34 and 27 patients evaluable for safety and efficacy analysis, respectively.

Patients in the zoldonrasib arm had similar key inclusion criteria, though only patients with KRAS G12D were permitted in the zoldonrasib arm.

Regarding safety, no new signals nor discontinuations due to AEs were observed. Any grade AEs occurred in 92% of patients, the most common of which were nausea (35%), vomiting (35%), anemia (24%), and rash (all grade 1, 24%). Grade 3 AEs occurred in 26% of patients, and included anemia (18%) and diarrhea (3%). Three treatment-related serious AEs occurred, being anemia, thrombocytopenia, and blurred vision.

“Pancreatic cancer remains a largely intractable disease and an area where patients desperately need new therapies,” stated Brian Wolpin, MD, director of the Hale Family Center for Pancreatic Cancer Research, Dana-Farber Cancer Institute, in the release. “In the front-line 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.”

Wolpin was also the lead study author of the phase 3 RASolute 302 trial (NCT06625320), which broke headlines in April 2026, nearly doubling the overall survival (OS) of pretreated metastatic PDAC with single-agent daraxonrasib, and were shared at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.³ The FDA previously authorized the initiation of an expanded access program for daraxonrasib in patients with pretreated metastatic PDAC.⁴

References

1. Tango Therapeutics announces combination of vopimetostat and daraxonrasib demonstrated 92% objective response rate in pancreatic cancer. News release. Tango Therapeutics. June 8, 2026. Accessed June 9, 2026. https://tinyurl.com/yc2j8t9p
2. Vopimetostat and RAS(ON) combination data. Tango Therapeutics. June 8, 2026. Accessed June 9, 2026. https://tinyurl.com/bddyxw9x
3. Wolpin BM, Wainberg ZA, Hendifar AE, et al. Daraxonrasib, a RAS(ON) multi-selective inhibitor vs chemotherapy in previously treated metastatic pancreatic adenocarcinoma (mPDAC): primary and final analysis from the phase 3 RASolute 302 study. J Clin Oncol. 2026;44(suppl 17):LBA5. doi:10.1200/JCO.2026.44.17_suppl.LBA5
4. FDA permits expanded access for investigational pancreatic cancer drug. News release. FDA. May 1, 2026. Accessed June 9, 2026. https://tinyurl.com/4xbhx3pd