Daraxonrasib
Pharmaceutical compound
From Wikipedia, the free encyclopedia
Daraxonrasib is an investigational new drug being developed by Revolution Medicines and evaluated for the treatment of solid tumours. It is an orally administered small molecule pan-RAS inhibitor.[1]
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| Pronunciation | /dəˌræksɒnˈræsɪb/ də-RAK-son-RAS-ib |
| Other names | RMC-6236 |
| Drug class | Antineoplastic |
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| Formula | C44H58N8O5S |
| Molar mass | 811.06 g·mol−1 |
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The drug inhibits all three key members of the Ras superfamily: KRAS, HRAS, and NRAS. The three RAS proteins are GTPases that become active when bound to GTP but normally convert this GTP to GDP and thereby become inactive. RAS proteins that are bound to GDP and GTP are termed respectively RAS(OFF) and RAS(ON).[2] Daraxonrasib targets RAS in the ON state, but not in the OFF state.[1][3]
It is undergoing clinical studies in RAS-driven cancers, including pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC).[3] The drug received breakthrough therapy designation from the US Food and Drug Administration (FDA) in 2025.[4] It is undergoing regulatory review by both the European Medical Association (EMA) and the FDA.[5] In July 2026, the FDA accepted for review the company's New Drug Application (NDA) under the Commissioner's National Priority Voucher (CNPV) Program.[6][7]
Pharmacology
Mechanism of action
Daraxonrasib is a small molecule which inhibits proteins of the RAS superfamily. It is a molecular glue which noncovalently binds RAS proteins in the ON state.[8] To inhibit RAS, daraxonrasib first binds a chaperone molecule (cyclophilin A), which results in a complementary surface. This surface is able to bind RAS superfamily proteins, forming a tri-complex and thereby blocking RAS signaling and limiting RAS-driven cancer growth.[1][8]
Safety and tolerability
In clinical study and through expanded access case studies, the safety profile of daraxonrasib appears to be relatively manageable.[9][10][11] The most predominant side effects observed to date include rash, diarrhea, fatigue, nausea, split fingertips,[10] mucositis and stomatitis.[12]
RAS proteins
The RAS proteins are expressed on the inner surface of a cell's plasma membrane and to lesser extents the cell's intracellular Golgi apparatus, endoplasmic reticulum, and endosome membranes.[13][14] RAS proteins can develop mutations that cause them to bind GTP continuously, keeping them constantly in the ON state, causing uncontrolled growth, and thereby promoting various malignancies.[13] Patients with a cancer harboring a RAS-activating mutation generally have poorer prognoses and shorter survival time than patients with the same cancer but without a RAS mutation.[14]
Daraxonrasib reverses continuous activation of RAS by forming a tri-complex consisting of one of the three RAS proteins bound to GTP and cyclophilin A, and thus inhibiting RAS. Consequently, daraxonrasib has proven effective in suppressing the cancers promoted by any one of RAS superfamily proteins.[15][16][17][18][19]
A mutationally active RAS protein occurs in one out of every 5 human cancers,[13] promotes up to 30% of human cancers,[20] and in the U.S. appears responsible for 200,000 new cancer cases each year.[20][21] One of the three RAS proteins is mutated in about 90% of pancreatic ductal adenocarcinomas; 40% of colorectal adenocarcinomas; 30% of skin cutaneous melanomas; ~30% of cases of non-small cell lung cancer; and a smaller proportion of most other solid tumor types.[13][21]
Clinical trials of daraxonrasib are underway to evaluate its safety, tolerability, pharmacokinetics, and preliminary clinical activity in treating patients with a wide range of advanced solid tumors which harbor a RAS mutation.[22][23]
Clinical trials
Pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent type of pancreatic cancer.[24] Mutations in a RAS protein occur in, and appear responsible for, more than 90% of PDAC cases.[13][21] These mutations lead to excessive RAS signaling and uncontrolled growth of their target cells, and make these cases good candidates for treatment with daraxonrasib.[20][25] Early-phase clinical studies found that daraxonrasib was effective and safe in treating metastatic PDAC, and lead to the candidate receiving breakthrough therapy designation from the U.S. FDA.[25]
Daraxonrasib is currently being studied in three late-phase clinical studies in PDAC, each in a different treatment setting.[3]
Rasolute 302
A phase III study (RASolute 302) assessed the efficacy of daraxonrasib in second line (previously treated) metastatic PDAC compared to standard treatments which use chemotherapy.[26] The trial, while still ongoing as of July 2026, met all primary and key secondary endpoints, including progression-free survival (PFS). The study randomly assigned 248 patients to receive daraxonrasib and 252 patients to receive chemotherapy. The median overall survival in the overall population was 13.2 months for daraxonrasib-treated and 6.7 months for daraxonrasib-untreated patients. The hazard ratio for death was 0.40 (a 60% reduction in risk of death; p < 0.0001). Daraxonrasib was generally well tolerated with a manageable safety profile.[9][27][28] Its side effects included rash, diarrhea, fatigue, nausea and raw, split fingertips.[10] Subsequent to this study, the U.S. FDA issued a "safe to proceed" letter to Revolution Medicines, allowing the sponsor to initiate an expanded access treatment protocol for daraxonrasib in patients with previously treated metastatic PDAC.
Rasolute 303
Daraxonrasib is, as of July 2026, being evaluated in a phase III study (RASolute 303) in first line (not yet treated) metastatic PDAC.[29] The trial is evaluating two novel treatment regimens in comparison to standard of care chemotherapy: daraxonrasib alone (monotherapy) and daraxonrasib in combination with gemcitabine and nab-paclitaxel.[29]
Rasolute 304
Daraxonrasib is being evaluated in a phase III study (RASolute 304) in resectable PDAC in combination with surgery in the adjuvant setting. Patients whose cancer was resected and received adjuvant or neoadjuvant chemotherapy are eligible for participation in the study. The trial is investigating daraxonrasib adjuvant to surgery versus the standard of care of patient observation via blood testing and screening. This trial positions daraxonrasib as a maintenance therapy for resectable PDAC.[30][31]
A trial examined daraxonrasib treatment in 35 previously untreated patients with metastatic PDAC. The study reported that the patients had grade 1 to 3 but no grades 4 or 5 adverse events due to the treatment (see Common Terminology Criteria for Adverse Events). Of the 35 patents, 34 patients exhibited a control of their disease. Daraxonrasib was generally well tolerated. The safety profile is manageable with no new safety signals.[9] Although the trial was randomized, it was open-label (i.e., not blinded), and both the patient and outcome assessors knew if a patient was administered daraxonrasib.[32]
Non-small-cell lung cancer
Non-small-cell lung cancer (NSCLC) represents about 85% of all lung cancers. Mutations in RAS proteins are present in ~30% of NSCLC cases.[33] In a phase 1 study, 73 patients with NSCLC were treated with daraxonrasib. Safety and efficacy in this group supported further development.[34][35][36] Currently, as of July 2026, the drug is being evaluated in NSCLC in one ongoing phase 3 clinical study, RASolve 301 and other earlier-stage studies.[3][34]
Rasolve 301
Daraxonrasib is being studied in a phase 3 clinical study (RASolve 301) in second line (previously treated) NSCLC.[3] The trial is evaluating daraxonrasib in comparison to standard of care chemotherapy (docetaxel) in this treatment setting.[37] Revolution Medicines is also planning a phase 3 clinical study in first line (not yet treated) NSCLC, building on early data in this indication.[3]
Combination studies in NSCLC and PDAC remain ongoing, including in combination with TNG462 (a PRMT5 inhibitor for MTAP deleted cancers).[38]
Melanoma
Melanoma is the sixth most common cancer diagnosed in the US and the deadliest form of skin cancer.[18] At least five patients with RAS-driven metastatic melanomas have been treated with daraxonrasib through early-stage clinical studies. These included: a 77-year-old female with mutated NRAS-driven metastatic melanoma who saw rapid clinical and symptomatic improvement with mild toxicity;[11][39] a 76-year female with mutated NRAS-driven melanoma metastatic to the brain and lymph nodes who achieved a complete response but after 245 days relapsed;[11] an 82-year-old male with mutated NRAS-driven melanoma who achieved a partial response to daraxonrasib;[18] a 43-year-old with metastatic NRAS-driven melanoma and achieved stable disease, which progressed again after 140 days of treatment;[18] a 55-year-old male with acral lentiginous melanoma, who achieved stable disease for 10 months of daraxonrasib treatment.[40] All patients were heavily pretreated prior to treatment.[11][18][40]
Daraxonrasib is also being studied in combination with BMS-986504 (a PRMT5 inhibitor for MTAP deleted cancers) in melanoma in a phase 2 study, as of July 2026.[41]
Other solid tumors
Daraxonrasib is being studied in other types of solid tumors as well, including in gastrointestinal tract and biliary tract cancers in combination with anvumetostat in MTAP deleted cancers.[42] Earlier-phase studies of daraxonrasib include patients with colorectal cancer.[43][44]
Research
Combination treatments for PDAC
Mice made to express genetically engineered PDAC-like mouse tumors or patient-derived human PDAC tumors were treated with a combination of three cancer-inhibiting agents, daraxonrasib, afatinib, and SD36. Mice treated with this combination therapy had far more complete and durable repressions of their PDAC tumors than mice treated with only daraxonrasib. These results suggest that treating patients with PDAC (and perhaps other cancers) with daraxonrasib in combinations with other anticancer agents prove superior to treatment with daraxonrasib alone.[45] Subsequent studies in mice with PDAC indicated that adding cancer immunotherapy to daraxonrasib increased the effectiveness of treatment.[46][47] Other combinations in PDAC models in vitro and in vivo have shown that combinations of daraxonrasib with KRAS inhibitors improve treatment efficacy as compared to daraxonrasib alone.[48] This early combination treatment research may inform future clinical work and/or treatment.
Melanoma
Researchers have studied daraxonrasib in NRAS-mutant melanoma mouse models and found the drug to be effective at controlling disease in this preclinical setting.[11] Though few melanoma patients have been treated with daraxonrasib to date, many cases of melanoma are driven by an NRAS mutation, and thus could potentially benefit from treatment with the drug based on preclinical work, according to researchers studying the drug in this context.[11][21]
Glioblastoma
Cell lines of glioblastoma were treated with daraxonrasib, then exposed to radiation, as KRAS signaling is known to be an important mediator of radioresistance for this cancer type. Based on results from these cell lines, reported in a preprint, researchers concluded that daraxonrasib treatment may present a promising radiosensitizing strategy for glioblastoma.[49]
Osteosarcoma
A small subset of osteosarcoma patients exhibit a KRAS mutation and thus may be candidates for treatment with daraxonrasib.[21][50] In an in vitro cell model of KRAS-mutant osteosarcoma, researchers found that daraxonrasib selectively inhibited the proliferation and invasiveness of this model cell line.[50] Similar results were found in a KRAS-wild type osteosarcoma cell line, but to a lesser extent.[50]
Hematologic malignancies
Work in acute myeloid leukemia suggests that resistance to commonly-used drugs, including FLT3 inhibitors (such as gilteritinib) and Bcl-2 inhibitors (such as venetoclax) is driven by RAS. Researchers tested acute myeloid leukemia cell lines by treating them with daraxonrasib in combination with either a FLT3 inhibitor or Bcl-2 inhibitor. The study found that treatment with daraxonrasib overcomes RAS-mediated resistance to both drug types in vitro, and researchers suggest this could be a basis for clinical study in this indication.[51]
