New data from an ongoing Phase 1/2 trial demonstrate remarkable efficacy for the combination of vopimetostat, an investigational PRMT5 inhibitor, and daraxonrasib, a RAS(ON) inhibitor, in patients with MTAP-deleted and KRAS-mutant metastatic pancreatic ductal adenocarcinoma (PDAC). The combination achieved a 92% objective response rate with encouraging durability signals, supporting advancement to Phase 3 development.

Clinical Takeaway

The combination of vopimetostat and daraxonrasib demonstrated exceptional efficacy in heavily pretreated patients with MTAP-deleted, KRAS-mutant pancreatic cancer, achieving a 92% objective response rate and 90% 6-month progression-free survival rate. These results support further investigation of a potential chemotherapy-free precision medicine approach in a patient population with historically poor outcomes.

Drug Profile & Mechanism

  • Vopimetostat: Investigational PRMT5 inhibitor with first- and best-in-class potential, targeting protein arginine methyltransferase 5
  • Daraxonrasib: RAS(ON) inhibitor developed by Revolution Medicines that targets active RAS proteins
  • Synergistic mechanism: Preclinical data showed enhanced activity when PRMT5 inhibition is combined with RAS inhibition in MTAP-deleted tumors

Target Population

  • Patients with MTAP-deleted and KRAS-mutant metastatic pancreatic ductal adenocarcinoma
  • Advanced disease: 70% of patients had liver metastases
  • Heavily pretreated: More than half of patients received combination as third-line treatment
  • Second and third-line setting for current data, with plans to advance to first-line treatment

Study Design

  • Trial type: Ongoing Phase 1/2 dose escalation study
  • Study population: 59 patients with previously treated MTAP-deleted and RAS-mutant PDAC or NSCLC
  • Dosing regimens:
    • Dose level 1: Vopimetostat 200 mg once daily + daraxonrasib 100 mg once daily
    • Dose level 2: Vopimetostat 250 mg once daily + daraxonrasib 100 mg once daily
  • Data cutoff: May 28, 2026

Efficacy Outcomes

  • PDAC Results (n=12 response evaluable):
    • Objective response rate: 92% (11/12 patients; 9 of 11 responses confirmed)
    • 6-month progression-free survival rate: 90%
    • Disease control rate: 100%
    • Median progression-free survival: Not yet reached
  • NSCLC Results (n=3 response evaluable):
    • Objective response rate: 100% (3 of 3 responses confirmed)

Safety Profile

  • Generally well tolerated across all dose levels with no new safety signals
  • Most common treatment-related adverse events: Rash, stomatitis/mucositis, and diarrhea
  • Severity: Most adverse events were Grade 1 or 2
  • Serious events: No related Grade 4 or 5 adverse events
  • Dose-limiting toxicities:
    • None at dose level 1 (200 mg/100 mg)
    • Three DLTs in two patients at dose level 2 (250 mg/100 mg): Grade 3 rash, Grade 3 stomatitis, and fatigue
  • Discontinuations: No discontinuations due to adverse events

Development Strategy

  • Phase 3 advancement: Tango plans to rapidly advance the combination into Phase 3 development for first-line MTAP-deleted pancreatic cancer
  • Regulatory engagement: Subject to feedback from regulatory authorities
  • Trial design: Phase 3 randomized-controlled trial in front-line pancreatic cancer
  • Second-line opportunities: Evaluation of registration-enabling pathways for second-line combination therapy

Key Clinical Implications

✔ Potential new targeted treatment approach: Results suggest possibility of chemotherapy-free precision medicine approach in MTAP-deleted pancreatic cancer

✔ Biomarker-driven therapy: MTAP deletion status may serve as a predictive biomarker for combination efficacy

✔ Durability signals: High 6-month PFS rate suggests sustained clinical benefit beyond initial response

✔ Manageable toxicity profile: Well-tolerated combination with no treatment discontinuations due to adverse events

✔ Rapid development pathway: Strong efficacy data support expedited advancement to registration-enabling Phase 3 trials

Bottom Line

The combination of vopimetostat plus daraxonrasib demonstrated exceptional efficacy in patients with MTAP-deleted, KRAS-mutant pancreatic cancer, achieving a 92% objective response rate with encouraging durability. These results provide encouraging early evidence of activity in a biomarker-selected population with historically poor outcomes and support further clinical development of the combination. The favorable safety profile and potential for a chemotherapy-free approach make this combination particularly promising for improving patient outcomes in this challenging malignancy.

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