Daraxonrasib

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]}

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]

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]

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]}

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]

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]}

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.

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]}

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]

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]

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]