FDA Grants Breakthrough Therapy Designation to Daraxonrasib Plus Chemotherapy in First-Line Metastatic Pancreatic Cancer
核心洞察
The FDA granted Breakthrough Therapy Designation to daraxonrasib combined with gemcitabine and nab-paclitaxel for treatment-naive metastatic pancreatic adenocarcinoma (搜索), announced September 14, 2026.
The designation was supported by the Phase 1/2 RMC-GI-102 trial, where 40 previously untreated patients achieved a confirmed objective response rate of 58%, including one complete response.
At the December 1, 2025 data cutoff, median progression-free and overall survival had not been reached, with estimated 6-month rates of 84% and 90%, respectively.
The U.S. Food and Drug Administration (搜索) has granted Breakthrough Therapy Designation to RASONQUE (搜索) (daraxonrasib) in combination with gemcitabine and nab-paclitaxel (GnP) for the treatment of treatment-naive metastatic pancreatic adenocarcinoma (搜索) (PDAC), Revolution Medicines announced on September 14, 2026. The designation applies to patients with previously untreated disease and represents an effort to move RAS (搜索)-targeted therapy into the first-line setting.
The combination remains investigational for this indication, with safety and efficacy not yet established. RASONQUE (搜索) was recently approved by the FDA for the treatment of adult patients with metastatic PDAC who have received at least one prior systemic therapy or who are not candidates for multiagent systemic therapy.
RMC-GI-102 Data Underpin the Designation
The Breakthrough Therapy Designation is based on data from patients with treatment-naive RAS (搜索) mutant metastatic PDAC who received RASONQUE (搜索) in combination with GnP in the open-label, multicenter Phase 1/2 RMC-GI-102 trial (NCT06445062), which evaluates RAS(ON) inhibitor combinations in gastrointestinal malignancies.
In the relevant cohort, patients received daraxonrasib at 200 mg orally once daily in 28-day cycles combined with GnP administered on a day 1 and day 15 schedule. As of a December 1, 2025 data cutoff, 40 patients with previously untreated RAS (搜索) mutant metastatic PDAC had been treated.
In previously reported results from these 40 patients, the combination produced a confirmed objective response rate of 58%, including one complete response. Median progression-free survival and overall survival had not yet been reached at the data cutoff. The estimated 6-month progression-free survival rate was 84%, and the estimated 6-month overall survival rate was 90%.
The safety profile was described as manageable and generally consistent with the known profiles previously observed for both daraxonrasib and GnP individually. The most common Grade 3 or higher treatment-related adverse events included anemia, decreased neutrophil count, and fatigue.
"This Breakthrough Therapy Designation underscores the significant unmet need among patients with previously untreated metastatic pancreatic adenocarcinoma (搜索) and recognizes the importance of advancing new treatment options earlier in their treatment journey," said Alan Sandler, M.D., chief development officer of Revolution Medicines. "RASONQUE (搜索) monotherapy demonstrated compelling clinical benefit in the RASolute 302 trial, leading to FDA approval for patients with previously treated metastatic pancreatic adenocarcinoma or those who are not candidates for multiagent systemic therapy. Data from the RMC-GI-102 study have now shown the therapeutic potential of RASONQUE in combination with GnP, a commonly used multiagent systemic therapy, in treatment-naive patients."
Phase 3 RASolute 303 Underway
The RMC-GI-102 data informed the design of RASolute 303 (NCT07491445), the ongoing global Phase 3 trial evaluating RASONQUE (搜索) as monotherapy and in combination with GnP versus GnP alone in patients with previously untreated metastatic PDAC, independent of tumor RAS (搜索) genotype.
The randomized, open-label study began treating patients in April 2026 and is designed to enroll approximately 900 patients, randomly assigned 1:1:1 to daraxonrasib once daily as monotherapy, daraxonrasib once daily plus GnP, or GnP alone. Eligible patients must have confirmed metastatic PDAC with no prior systemic treatment in the metastatic setting, an ECOG performance status of 0 or 1, and documented tumor RAS (搜索) mutational status, whether mutant or wild type.
The dual primary endpoints are overall survival and progression-free survival. Key secondary endpoints include objective response rate, duration of response, safety and tolerability, pharmacokinetics, and quality of life.
Prior Approval and Regulatory History
Daraxonrasib monotherapy was approved by the FDA on August 26, 2026, for patients with metastatic PDAC who have received at least one prior systemic therapy or who are not candidates for multiagent systemic therapy, based on findings from the Phase 3 RASolute 302 trial (NCT06625320). In the overall study population, median overall survival was 13.2 months with daraxonrasib versus 6.7 months with standard-of-care chemotherapy, corresponding to a hazard ratio of 0.40. Median progression-free survival was 7.2 versus 3.6 months, and objective response rates were 30% and 11%, respectively. Daraxonrasib became the first FDA-approved therapy of its class for metastatic pancreatic adenocarcinoma (搜索).
That approval was reviewed under the FDA Commissioner's National Priority Voucher pilot program and granted 6.5 months ahead of the standard user fee deadline. Prior to full approval, the FDA permitted an expanded access program for daraxonrasib in previously treated metastatic PDAC in May 2026. In July 2026, the European Medicines Agency (搜索)'s Committee for Medicinal Products for Human Use began a phased review of daraxonrasib, an accelerated assessment pathway for medicines addressing unmet medical needs. The following month, the European Society for Medical Oncology (搜索) issued a Clinical Practice Guideline Express Update recommending daraxonrasib monotherapy after chemotherapy progression in patients with RAS (搜索) G12-mutated metastatic PDAC and an ECOG performance status of 0 or 1.
According to Revolution Medicines, this is the third Breakthrough Therapy Designation for daraxonrasib and the fifth across the company's portfolio of RAS (搜索)(ON) inhibitors.
Mechanism and Safety Profile
Daraxonrasib is an oral, RAS (搜索)(ON) multi-selective, noncovalent, tri-complex inhibitor (TCI). It suppresses RAS signaling by blocking the interaction between wild-type and mutant RAS(ON) proteins and their downstream effectors, binding intracellular cyclophilin A (搜索) to engage GTP-bound RAS mutations, including G12, G13, and Q61 variants, as well as RAS wild-type. The agent is being investigated through a global Phase 3 registrational program in patients with PDAC and metastatic RAS mutant non-small cell lung cancer (搜索) (NSCLC). Outside the U.S., RASONQUE (搜索) is an investigational agent that has not been approved by any regulatory authority.
For the approved indication, RASONQUE (搜索) carries Warnings and Precautions for dermatologic and soft tissue toxicity, stomatitis and oral disorders, diarrhea, gastrointestinal perforation, interstitial lung disease (ILD)/pneumonitis, and embryo-fetal toxicity. In clinical trials of patients with pancreatic adenocarcinoma (搜索), dermatologic toxicity occurred in 86% of patients treated with RASONQUE, of which 10% were Grade 3; stomatitis occurred in 57%, of which 9% were Grade 3; and diarrhea occurred in 63%, of which 6% were Grade 3. Gastrointestinal perforation occurred in 0.9% of patients, of which 0.5% were Grade 3, with one Grade 4 event and one fatal event. ILD/pneumonitis occurred in 2.4% of patients, of which 0.9% were Grade 3, with one fatal event.
Serious adverse reactions occurred in 30% of patients treated with RASONQUE (搜索), with those occurring in at least 2% of patients including diarrhea (3.7%), pyrexia (3.3%), sepsis (2.9%), fatigue (2.1%), and hemorrhage (2.1%). Adverse reactions leading to permanent discontinuation occurred in 2.9% of patients, including two patients who discontinued due to rash (0.8%). The most common adverse reactions (at least 20%) were rash, diarrhea, stomatitis, nausea, fatigue, vomiting, abdominal pain, edema, decreased appetite, and hemorrhage.
Prophylactic measures recommended when initiating RASONQUE (搜索) include a topical corticosteroid applied to the face and chest plus emollient creams, limiting sun exposure with broad-spectrum sunscreen of SPF 30 or higher, and consideration of prophylactic oral antibiotics such as doxycycline or minocycline.
Disease Burden
PDAC is the most common form of pancreatic cancer and among the most challenging malignancies. Approximately 55,000 people are diagnosed with PDAC in the U.S. each year, and more than 50,000 die from the disease with current standard of care. Because early-stage pancreatic cancer often causes few or no symptoms, approximately 80% of patients are diagnosed after the disease has spread, when treatment options are more limited. For patients with metastatic PDAC, the five-year relative survival rate is approximately 3% in the U.S.
Breakthrough Therapy Designation is intended to expedite the development and review of potential new medicines designed to treat serious conditions and address significant unmet medical needs. Pursuant to FDA guidelines, the medicine needs to have shown preliminary clinical evidence demonstrating substantial improvement on a clinically significant endpoint over available medicines.