daraxonrasib (RMC-6236)

P1, N=604, Recruiting, Revolution Medicines, Inc. | Trial primary completion date: Apr 2026 --> Dec 2026

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Likewise, a combination of selective inhibitors of KRAS (RMC-6236/daraxonrasib), EGFR family (afatinib), and STAT3 (SD36) induced the complete regression of orthotopic PDAC tumors with no evidence of tumor resistance for over 200 d posttreatment. Of importance, this combination therapy was well tolerated. In sum, these results should guide the development of new clinical trials that may benefit PDAC patients.

P1, N=120, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting | N=350 --> 120 | Trial completion date: Feb 2029 --> Nov 2026 | Trial primary completion date: Feb 2027 --> Oct 2026

P3, N=590, Recruiting, Revolution Medicines, Inc. | N=420 --> 590

Successful generation of a BrM-derived organoid line enabled high-throughput drug screening, which recapitulated the patient's clinical resistance to standard therapies [gemcitabine/nab-paclitaxel, 5-fluorouracil (5-FU)], and showed sensitivity to afatinib, everolimus and RMC-6236...Physicians should also be aware that KRAS wild-type pancreatic cancer with atypical amplifications is likely to exhibit unique metastatic tropisms. Finally, we suggest that patient-derived organoids pharmacotyping can mirror clinical drug responses and help evaluate therapeutic avenues for patient treatment.

Recently, RAS(ON) multi-selective inhibitors like RMC-7977, and the investigational agent daraxonrasib, were described that inhibit RAS[GTP] signaling in partnership with cyclophilin A (CYPA). Moreover, two clinical case studies in patients with NRAS-mutated melanoma treated with daraxonrasib demonstrated clear anti-tumor activity in one patient, but progressive disease in another with co-occurring NRAS and MAP2K1 mutations at baseline. These findings support the potential for daraxonrasib in treatment of patients with NRAS-mutated melanoma, and reveal candidate mechanisms of monotherapy resistance, underscoring the need for combination therapies to improve outcomes.

Abcb1a/1b-mediated transport of daraxonrasib across the BBB was validated by oral co-administration of the ABCB1/ABCG2 inhibitor elacridar, resulting in 20-fold increased brain penetration in wild-type mice (P < 0.01). ABCB1 function could limit brain penetration and possibly efficacy of daraxonrasib against brain metastases. Collectively, these preclinical findings may help in optimizing the application of daraxonrasib in clinical settings.

P=N/A, N=0, Available, Revolution Medicines, Inc.

In contrast, macrophage-conditioned medium had little effect on regorafenib and increased sensitivity to dabrafenib, suggesting that resistance depends on the inhibitory profile of each drug. The multi-kinase inhibitor masitinib-which targets several kinases along this resistance network-strongly restored sensitivity to trametinib and RMC-6236. Together, these data define a macrophage-driven resistance network in KRAS-mutant colorectal cancer organoids and support combined inhibition of RAS-pathway and tyrosine kinase signalling.

Here, we analyzed paired baseline and end-of-treatment samples from 40 patients treated with the RAS inhibitor daraxonrasib and identified recurrent alterations in 18 cases...We then identified a TCI that targets RAS Y64 mutants and combination therapies to target resistance driven by kinase-dead BRAF. These findings uncover convergent resistance mechanisms that undermine the molecular glue function and offer a mechanistic blueprint for enhancing therapeutic efficacy in RAS-driven malignancies.

Daraxonrasib was associated with treatment-related adverse events of grade 3 or higher in one third of patients with previously treated RAS-mutated PDAC; antitumor activity was also reported. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.).