Tango Therapeutics has reported encouraging Phase 1/2 results for vopimetostat combined with Revolution Medicines’ daraxonrasib, achieving an 82% objective response rate among patients with previously treated metastatic pancreatic cancer carrying MTAP deletions and RAS mutations. The investigational combination also produced an estimated nine-month progression-free survival rate of 88%, with median progression-free survival not yet reached. Presented at the European Society for Medical Oncology Congress 2026, the findings support plans for a randomized Phase 3 trial in first-line pancreatic cancer during the first half of 2027.
The results offer promising evidence for a biomarker-directed treatment strategy in pancreatic ductal adenocarcinoma, a highly aggressive cancer with limited therapeutic options. However, the findings come from a small, nonrandomized study, and the combination’s survival benefits, comparative effectiveness and long-term safety remain unproven.
How did vopimetostat and daraxonrasib achieve an 82% response rate in pancreatic cancer?
Tango Therapeutics evaluated vopimetostat, an investigational PRMT5 inhibitor, alongside daraxonrasib, a RAS(ON) inhibitor developed by Revolution Medicines, in an ongoing Phase 1/2 study involving patients with MTAP-deleted, RAS-mutant advanced cancers.
As of the August 20 data cutoff, 34 patients had received the combination, including 29 with metastatic pancreatic ductal adenocarcinoma and five with non-small cell lung cancer. Of the pancreatic cancer participants, 22 were considered efficacy-evaluable because they had started treatment at least 14 weeks before the cutoff.
Among these 22 patients, 18 experienced an objective response, producing a response rate of 82%. Eleven responses were confirmed partial responses at the data cutoff, while seven were initially unconfirmed but subsequently confirmed during follow-up.
The study also reported a 100% disease control rate, indicating that all efficacy-evaluable pancreatic cancer patients achieved either a treatment response or disease stabilization under the study’s assessment criteria.
Median progression-free survival had not been reached after a median follow-up of 7.1 months, while the estimated nine-month progression-free survival rate was 88%. Follow-up ranged from 3.3 to 12.5 months, reflecting the relatively early maturity of the dataset.
These findings are notable because most evaluable participants had received substantial previous treatment. Thirteen of the 22 pancreatic cancer patients were receiving the combination as third-line therapy, a setting where treatment options can become increasingly limited.
Nevertheless, objective response rate measures tumor shrinkage rather than demonstrating improved survival. The study’s small population and absence of a randomized comparator mean that the results cannot establish superiority over available chemotherapy or other targeted treatments.
Why could dual PRMT5 and RAS inhibition offer a new strategy for MTAP-deleted pancreatic cancer?
The proposed therapeutic benefit of the combination involves targeting two biological vulnerabilities associated with cancer-cell survival and proliferation. Vopimetostat inhibits PRMT5, an enzyme involved in regulating protein function, gene expression and cellular processes essential for cancer growth. The approach is particularly relevant in tumors with deletion of the MTAP gene, which can create increased sensitivity to selective PRMT5 inhibition.
MTAP loss disrupts normal methionine salvage metabolism and contributes to the accumulation of methylthioadenosine, a molecule that influences PRMT5 activity. This altered metabolic environment creates an opportunity to selectively target cancer cells with MTAP deletion while potentially reducing effects on normal tissues.
Daraxonrasib targets active RAS signaling, a pathway frequently altered in pancreatic cancer. RAS mutations contribute to uncontrolled cellular growth and can make tumors resistant to conventional treatment approaches.
Combining PRMT5 inhibition with RAS pathway blockade could potentially produce stronger antitumor effects than targeting either mechanism independently. The strategy is based on disrupting complementary processes that support malignant cell survival.
Tango Therapeutics considers the updated response data supportive of this biological rationale, particularly because the combination demonstrated activity in patients who had already received chemotherapy.
However, the trial was not designed to determine the individual contribution of each medicine to the observed responses. Randomized studies and additional translational research will be needed to clarify whether the combination produces additive or synergistic effects and whether its benefits justify the associated toxicity.
What did the Phase 1/2 study reveal about treatment durability and safety?
The estimated nine-month progression-free survival rate of 88% provides an encouraging preliminary indication that some patients may experience sustained disease control. However, median progression-free survival remains immature, and longer follow-up is required to determine the duration of benefit across the study population.
Safety findings also provide important context for the planned Phase 3 regimen. At the lower combination dose level, 25 pancreatic cancer patients were safety-evaluable after receiving vopimetostat 200 mg once daily and daraxonrasib 100 mg once daily.
No dose-limiting toxicities or treatment discontinuations caused by treatment-related adverse events were reported in this group. There were also no Grade 4 or Grade 5 treatment-related adverse events, although Grade 3 events occurred in 40% of participants.
The most frequently reported treatment-related adverse events included stomatitis in 48%, rash in 44% and diarrhea in 28% of patients. All reported events within these three categories were Grade 1 or 2.
Dose reductions were necessary in 20% of patients, indicating that treatment modifications may be required even at the proposed Phase 3 dose. The higher dose level, involving vopimetostat 250 mg daily alongside daraxonrasib, was less tolerable. Three dose-limiting toxicities occurred in two of four safety-evaluable patients, supporting the decision to proceed with the lower vopimetostat dose.
These observations are encouraging for a combination of two targeted agents, but the occurrence of Grade 3 toxicities remains clinically important. Larger studies must establish whether the treatment’s potential benefits outweigh its adverse effects, particularly when administered to previously untreated patients.
Did vopimetostat combinations show activity in lung cancer and other pancreatic cancer subgroups?
Tango Therapeutics also reported early findings involving the combination of vopimetostat and daraxonrasib in five patients with MTAP-deleted, RAS-mutant non-small cell lung cancer. Four of these patients achieved confirmed partial responses, producing an objective response rate of 80%, while the disease control rate reached 100%. The findings suggest potential activity beyond pancreatic cancer, although the five-patient cohort is too small to establish reliable response expectations.
The company separately evaluated vopimetostat in combination with zoldonrasib, another RAS(ON) inhibitor developed by Revolution Medicines, among patients with MTAP-deleted pancreatic cancer carrying the KRAS G12D mutation. In this cohort, 35 patients were efficacy-evaluable, with an objective response rate of 54%. The responses included 18 confirmed partial responses and one confirmed complete response, while the nine-month progression-free survival rate was estimated at 61%.
Disease control was reported in 97% of evaluable patients. These results provide additional preliminary evidence supporting the investigation of PRMT5 inhibition alongside RAS-directed treatment. Among 39 safety-evaluable patients receiving the vopimetostat-zoldonrasib combination, Grade 3 treatment-related adverse events occurred in 28%, while one Grade 4 event was reported. No treatment-related deaths or withdrawals due to treatment-related adverse events were reported.
Although the daraxonrasib combination produced a higher numerical response rate than the zoldonrasib combination, the results cannot establish comparative superiority because the cohorts involved different mutation profiles, treatment regimens and patient characteristics.
How will Tango Therapeutics’ planned Phase 3 trial test the combination against chemotherapy?
Following discussions with the U.S. Food and Drug Administration, Tango Therapeutics intends to initiate a global randomized registrational Phase 3 study during the first half of 2027.
The study will enroll previously untreated patients with MTAP-deleted pancreatic ductal adenocarcinoma, representing an earlier treatment setting than the population evaluated in the current Phase 1/2 results. Participants will be randomized equally to receive either vopimetostat 200 mg once daily plus daraxonrasib 100 mg once daily or standard-of-care chemotherapy.
The planned dual primary endpoints are objective response rate and progression-free survival, while overall survival will serve as a key secondary endpoint. This design will allow investigators to determine whether the targeted combination provides meaningful benefits compared with established first-line treatment, rather than relying on historical comparisons or uncontrolled response rates.
Importantly, the transition from previously treated disease to first-line therapy introduces uncertainty. Patients receiving their initial treatment may have different disease characteristics, expected outcomes and tolerance for treatment-related adverse effects. The company also intends to discuss the possibility of pursuing regulatory approval for the combination in second-line pancreatic cancer, potentially creating another development pathway if regulators consider the existing and forthcoming evidence sufficient.
Malte Peters, chief executive officer of Tango Therapeutics, indicated that the updated results reinforced the company’s confidence in the combination and supported its strategy of advancing PRMT5 inhibition alongside RAS-targeted therapies. Anna Berkenblit, chief scientific and medical officer of the Pancreatic Cancer Action Network, similarly emphasized the importance of evaluating the encouraging findings through a larger randomized study capable of establishing meaningful benefits for patients.
What comes next for targeted pancreatic cancer treatment after the latest Tango Therapeutics findings?
The most important next milestone will be initiation of the planned Phase 3 study and confirmation of its final clinical protocol, including eligibility criteria, statistical assumptions and treatment comparison. Further maturation of the Phase 1/2 results will also help clarify progression-free survival, response durability and longer-term tolerability. These findings may inform expectations for the larger study but cannot replace prospective randomized evidence.
The combination’s biomarker-directed strategy could eventually support more personalized treatment for patients with MTAP-deleted, RAS-mutant pancreatic cancer. However, its potential applicability to patients without MTAP deletion remains investigational, and the current findings should not be generalized to all pancreatic cancers.
Tango Therapeutics has also expressed interest in evaluating PRMT5 inhibitor combinations across additional tumor types and mutation profiles. The early lung cancer findings provide a rationale for exploration, but each indication will require appropriate clinical validation.
For patients with metastatic pancreatic cancer, the reported 82% response rate represents a promising early signal in a disease where durable treatment responses remain difficult to achieve. Nevertheless, the small sample size, limited follow-up and absence of a control group prevent definitive conclusions about survival or superiority. The planned Phase 3 trial will determine whether combining vopimetostat with daraxonrasib can translate these preliminary results into reproducible clinical benefits sufficient to support a future regulatory application.
