Vopimetostat Plus Daraxonrasib Yields 82% ORR in MTAP-Deleted PDAC

The oral, chemotherapy-free combination of the investigational PRMT5 inhibitor vopimetostat (TNG462) and the RAS(ON) inhibitor daraxonrasib (Rasonque) produced responses in most patients with largely pretreated MTAP-deleted, RAS-mutant metastatic pancreatic ductal adenocarcinoma (PDAC), according to updated phase 1/2 data presented in a poster at the European Society for Medical Oncology (ESMO) 2026 Congress.¹

Among 22 efficacy-evaluable patients with PDAC in the ongoing TNG462-C102 study (NCT06922591), the objective response rate (ORR) was 82% (n = 18/22), all partial responses, and the disease control rate was 100% as of an August 20, 2026, data cutoff. Seven of the responses were confirmed after the cutoff, according to a news release from Tango Therapeutics. Median progression-free survival (PFS) had not been reached, and the 6- and 9-month PFS rates were both 88.4% (95% CI, 60.3%-97.1%), at a median follow-up of 7.1 months.^1,2

"In this updated analysis, the large majority of patients remained progression-free at [9] months despite being heavily pretreated, with more than half receiving the combination as third-line therapy," Alexander Spira, MD, codirector of the Virginia Cancer Specialists Research Institute, NEXT Oncology, a principal investigator of the study and first author of the poster, stated in the news release.²

Study Design and Patients

The open-label dose escalation and expansion study enrolled patients with metastatic MTAP-deleted, RAS-mutant PDAC or non–small cell lung cancer (NSCLC). Patients with any RAS mutation received vopimetostat plus daraxonrasib, and those with KRAS G12D–mutant disease received vopimetostat plus zoldonrasib, a G12D-selective RAS(ON) inhibitor. Patients with PDAC could have received up to 2 prior systemic therapies.¹

Vopimetostat selectively inhibits PRMT5 in tumor cells with MTAP loss, which occurs in an estimated 30% to 40% of PDAC cases, according to the poster.

In the daraxonrasib arm, 29 patients with PDAC and 5 with NSCLC were treated. Efficacy-evaluable patients with PDAC received daraxonrasib 100 mg with vopimetostat 200 mg (dose level 1 [DL1]; n = 19) or 250 mg (DL2; n = 3). Among all 29 patients with PDAC, the median age was 66.0 years (range, 44-74), 72.4% had liver metastases, and 58.6% had received 2 prior therapies. KRAS G12V was the most common variant (51.7%), followed by G12R (20.7%).

Efficacy by Line of Therapy

The efficacy-evaluable population included 7 patients treated in the second line, 13 in the third line, and 2 in the first line, for whom standard of care was not considered appropriate. The ORR was 85.7% in the second line and 84.6% in the third line. The 9-month PFS rate was 100% among second-line patients and 80.8% (95% CI, 41.0%-95.0%) among third-line patients.

Based on pharmacokinetic analysis, at DL1, daraxonrasib 100 mg given with vopimetostat led to increased exposure comparable to that of daraxonrasib 300 mg alone, and vopimetostat exposure was unaffected.

Safety Findings

At DL1, 76.0% of 25 patients with PDAC had treatment-related adverse events (TRAEs), and 40.0% had grade 3 TRAEs. No grade 4 or grade 5 TRAEs occurred, and there were no dose-limiting toxicities (DLTs) or withdrawals because of TRAEs. TRAEs led to dose interruption in 40.0% of patients and dose reduction in 20.0%. The most common TRAEs were stomatitis or mucositis (48.0%), rash (44.0%), and diarrhea (28.0%), all grade 1 or 2. The most frequent grade 3 TRAEs were anemia (12.0%) and thrombocytopenia (8.0%).

DL2 was considered not tolerable, with 2 of 4 patients experiencing DLTs: grade 3 acneiform rash in 1 patient, and grade 3 stomatitis and fatigue in another. Investigators selected DL1 as the candidate phase 3 dose.

In the 5 patients with NSCLC treated at DL1, the ORR was 80%, with all responses confirmed, and 1 patient had a grade 3 TRAE.

Zoldonrasib Combination

Among 35 efficacy-evaluable patients with KRAS G12D–mutant PDAC treated across 4 dose levels, the confirmed ORR was 54.3%, including 1 complete response, and the disease control rate was 97.1%. ORRs were 73.3% in the second line (n = 15) and 40.0% in the third line (n = 20). The 9-month PFS rate was 60.5% (95% CI, 39.1%-76.4%) overall, 74.3% in the second line, and 53.8% in the third line.

Among 39 safety-evaluable patients, 28.2% had grade 3 TRAEs and 1 patient (2.6%) had a grade 4 aspartate aminotransferase increase. No grade 5 TRAEs, DLTs, or treatment withdrawals were reported, and 15.4% of patients required dose reductions. Nausea and vomiting (38.5% each) were the most common TRAEs, and grade 3 anemia occurred in 17.9%. The investigators selected vopimetostat 200 mg plus zoldonrasib 1200 mg for continued evaluation.

Phase 3 Plans

The poster compared the outcomes indirectly to those of the phase 3 RASolute 302 trial (NCT06625320), in which daraxonrasib monotherapy produced an ORR of 31.6% and a median PFS of 7.2 months in second-line PDAC.

After discussions with the FDA, Tango plans to begin a global, randomized registrational trial in the first half of 2027 comparing vopimetostat 200 mg plus daraxonrasib 100 mg with standard-of-care chemotherapy in previously untreated MTAP-deleted PDAC, with ORR and PFS as dual primary end points and overall survival as a key secondary end point. The company also plans to discuss a potential second-line pathway with regulators.

Malte Peters, MD, CEO and president of Tango, stated in the release that the combination's response rate and durability surpass any published PDAC dataset. The results come from a small, nonrandomized study with limited follow-up and have not been compared directly with other regimens.

"The depth and durability of responses reported with the vopimetostat and daraxonrasib combination are encouraging, particularly for patients who had already received multiple lines of treatment," said Anna Berkenblit, MD, MMSc, chief scientific and medical officer of the Pancreatic Cancer Action Network, in the news release.²

REFERENCES

1. Spira A, Henry J, O'Reilly EM, et al. A phase 1/2 study of vopimetostat in combination with daraxonrasib or zoldonrasib in patients with MTAP deleted RAS mutant (MTAPdel/RASmut) metastatic PDAC and NSCLC. Presented at: European Society for Medical Oncology Congress 2026; October 23-27, 2026; Madrid, Spain. Poster 3149P.

2. Tango Presents Promising Results from Phase 1/2 Study of Vopimetostat and Daraxonrasib in Pancreatic Cancer and Provides Updates to Development Strategy. News release. Tango Therapeutics. October 23, 2026. Accessed October 23, 2026. https://tinyurl.com/ymertbda