{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T09:04:14Z","timestamp":1790327054525,"version":"4.1.0"},"reference-count":32,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Introduction: Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis, and RAS gene mutations are present in more than 90% of cases. For this reason, direct RAS inhibition is a promising, but thus far difficult to achieve, therapeutic strategy. Daraxonrasib (RMC-6236) is a first-in-class, oral, non-covalent, multiselective inhibitor of the active form of RAS. It forms an intracellular trimeric complex with cyclophilin A, blocking both mutant and wild-type variants of the KRAS, NRAS, and HRAS genes. The aim of this systematic review was to evaluate the efficacy and safety of daraxonrasib in previously treated patients with RAS-mutated PDAC. Methods: This review was conducted in accordance with the PRISMA 2020 guidelines. A systematic search was conducted in PubMed, Web of Science, and ClinicalTrials.gov for studies published between January 2020 and July 2026. Two studies met the inclusion criteria and were analyzed: the Phase 1\u20132 RMC-6236-001 (n = 168) and the Phase 3 RASolute 302 trial (n = 500), involving a total of 668 patients. The risk of bias was assessed using the Cochrane RoB 2.0 tool for the randomized trial and the Methodological Index for Non-Randomized Studies (MINORS) tool. Results: In the RASolute 302 trial, daraxonrasib out performed investigator-selected chemotherapy in a population of patients with the RAS G12 mutation, improving median overall survival (13.2 vs. 6.6 months; HR 0.40), progression-free survival (7.3 vs. 3.5 months; HR 0.45), and objective response rate (33.2% vs. 11.8%; all p &lt; 0.001), and also delayed the onset of pain and deterioration in quality of life. These results were consistent with the earlier RMC-6236-001 study (objective response rate [ORR] 35%, median overall survival [OS] 13.1 months in patients with RAS G12 mutation treated in the second-line setting). Daraxonrasib exhibited a predictable toxicity profile, consisting mainly of Grade 1\u20132 dermatologic and gastrointestinal symptoms, with lower rates of hematologic toxicity and treatment discontinuation than with chemotherapy. Conclusions: Daraxonrasib demonstrates clinically relevant and statistically significant efficacy with an acceptable safety profile in previously treated patients with metastatic RAS G12-mutated PDAC, the population for which the strongest randomized evidence is currently available. These findings support its potential as a promising new treatment option in this setting. Further studies are needed regarding rare RAS gene variants and forms of the disease with wild-type RAS.<\/jats:p>","DOI":"10.3390\/cancers18193112","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T08:09:02Z","timestamp":1790323742000},"page":"3112","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Efficacy and Safety of Daraxonrasib (RMC-6236) in Previously Treated Metastatic RAS-Mutated Pancreatic Ductal Adenocarcinoma: A Systematic Review"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-8136-9997","authenticated-orcid":false,"given":"Natalia","family":"Gierulska","sequence":"first","affiliation":[{"name":"Student Scientific Society, Department of Clinical Oncology and Chemotherapy, Medical University of Lublin, 20-059 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Jankowska","sequence":"additional","affiliation":[{"name":"Student Scientific Society, Department of Clinical Oncology and Chemotherapy, Medical University of Lublin, 20-059 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6632-4938","authenticated-orcid":false,"given":"Zuzanna","family":"D\u0105browska","sequence":"additional","affiliation":[{"name":"Student Scientific Society, Department of Clinical Oncology and Chemotherapy, Medical University of Lublin, 20-059 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2211-1413","authenticated-orcid":false,"given":"Julia","family":"Piekarz","sequence":"additional","affiliation":[{"name":"Student Scientific Society, Department of Clinical Oncology and Chemotherapy, Medical University of Lublin, 20-059 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Sk\u00f3rzewska","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology and Chemotherapy, Medical University of Lublin, 20-059 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"113471","DOI":"10.1016\/j.ejca.2023.113471","article-title":"Risk factors for early-onset pancreatic ductal adenocarcinoma: A systematic literature review","volume":"198","author":"Chandana","year":"2023","journal-title":"Eur. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s13402-022-00732-2","article-title":"Research advances and treatment perspectives of pancreatic adenosquamous carcinoma","volume":"46","author":"Zhang","year":"2022","journal-title":"Cell. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Bi, Y., Li, D., Pang, R., Du, C., Li, D., Zhao, X., and Lv, H. (2025). Diagnosis methods for pancreatic cancer with the technique of deep learning: A review and a meta-analysis. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1597969"},{"key":"ref_5","first-page":"900","article-title":"Lewis antigen negative pancreatic cancer: An aggressive subgroup","volume":"56","author":"Liu","year":"2020","journal-title":"Int. J. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/j.annonc.2023.08.009","article-title":"Pancreatic cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","volume":"34","author":"Conroy","year":"2023","journal-title":"Ann. Oncol."},{"key":"ref_7","unstructured":"National Comprehensive Cancer Network (2026). NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma (Version 2.2026), National Comprehensive Cancer Network."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"znae220","DOI":"10.1093\/bjs\/znae220","article-title":"Effects of limb lengths in gastric bypass surgery","volume":"111","author":"Poljo","year":"2024","journal-title":"Br. J. Surg."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e2350756","DOI":"10.1001\/jamanetworkopen.2023.50756","article-title":"NALIRIFOX, FOLFIRINOX, and Gemcitabine With Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Cancer","volume":"7","author":"Nichetti","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e27679","DOI":"10.1016\/j.heliyon.2024.e27679","article-title":"Efficacy and safety of first-line chemotherapies for patients with advanced pancreatic ductal adenocarcinoma: A systematic review and network meta-analysis","volume":"10","author":"Kang","year":"2024","journal-title":"Heliyon"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1002\/jso.27832","article-title":"Focused ultrasound and concurrent chemotherapy for the treatment of advanced pancreatic cancer: A systematic review","volume":"130","author":"Bennett","year":"2024","journal-title":"J. Surg. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s12964-021-00789-w","article-title":"Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: Limitations and prospects: A systematic review","volume":"19","author":"Li","year":"2021","journal-title":"Cell Commun. Signal."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"956","DOI":"10.5152\/tjg.2021.211106","article-title":"Prognostic Value of COX-2, NF-\u03baB, and Sp1 Tissue Expressions in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-analysis","volume":"32","author":"Renaldi","year":"2021","journal-title":"Turk. J. Gastroenterol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"799","DOI":"10.32604\/or.2024.045356","article-title":"Targeting KRAS in pancreatic cancer","volume":"32","author":"Stickler","year":"2024","journal-title":"Oncol. Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Jung, O., Soto, A., Wolfe, A.L., and Mahajan, S.S. (2025). Daraxonrasib, a pan-RAS inhibitor, selectively inhibits osteosarcomas with activated KRAS by halting AKT signaling and matrix metalloprotease activity. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0329946"},{"key":"ref_16","unstructured":"U.S. Food and Drug Administration (2026). FDA Approves Daraxonrasib for RAS-Active (RAS-ON) Solid Tumors, U.S. Food and Drug Administration. FDA Press Release."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1158\/2326-6066.CIR-25-0744","article-title":"RAS(ON) Multiselective Inhibition Drives Antitumor Immunity in Preclinical Models of NRAS-Mutant Melanoma","volume":"14","author":"Carvalho","year":"2025","journal-title":"Cancer Immunol. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1056\/NEJMoa2605555","article-title":"Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer","volume":"395","author":"Wainberg","year":"2026","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1056\/NEJMoa2505783","article-title":"Daraxonrasib in Previously Treated Advanced RAS-Mutated Pancreatic Cancer","volume":"394","author":"Wolpin","year":"2026","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/JCO.19.02105","article-title":"Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability\/Mismatch Repair\u2013Deficient Cancer: Results From the Phase II KEYNOTE-158 Study","volume":"38","author":"Marabelle","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1158\/1078-0432.CCR-17-3099","article-title":"Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations","volume":"24","author":"Hu","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/s43018-024-00894-y","article-title":"Pembrolizumab in microsatellite-instability-high and mismatch-repair-deficient advanced solid tumors: Updated results of the KEYNOTE-158 trial","volume":"6","author":"Marabelle","year":"2025","journal-title":"Nat. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e2200706","DOI":"10.1200\/PO.22.00706","article-title":"Efficacy of Immune Checkpoint Inhibition and Cytotoxic Chemotherapy in Mismatch Repair-Deficient and Microsatellite Instability-High Pancreatic Cancer: Mayo Clinic Experience","volume":"7","author":"Coston","year":"2023","journal-title":"JCO Precis. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1038\/s41591-026-04299-5","article-title":"Pembrolizumab and olaparib in homologous-recombination-deficient metastatic pancreatic cancer: The phase 2 POLAR trial","volume":"32","author":"Park","year":"2026","journal-title":"Nat. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1056\/NEJMoa1903387","article-title":"Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer","volume":"381","author":"Golan","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3929","DOI":"10.1200\/JCO.21.01604","article-title":"Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer","volume":"40","author":"Kindler","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.annonc.2020.11.005","article-title":"Prevention and management of dermatological toxicities related to anticancer agents: ESMO Clinical Practice Guidelines","volume":"32","author":"Lacouture","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kadasah, S.F. (2025). Targeting the MAPK Pathway in Cancer. Int. J. Mol. Sci., 27.","DOI":"10.20944\/preprints202512.0686.v1"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1053\/j.gastro.2020.08.063","article-title":"AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor Colitis and Hepatitis: Expert Review","volume":"160","author":"Dougan","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4073","DOI":"10.1200\/JCO.21.01440","article-title":"Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update","volume":"39","author":"Schneider","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wang, J., Ma, Y., Lin, H., Wang, J., and Cao, B. (2024). Predictive biomarkers for immune-related adverse events in cancer patients treated with immune-checkpoint inhibitors. BMC Immunol., 25.","DOI":"10.1186\/s12865-024-00599-y"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3112\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T08:20:30Z","timestamp":1790324430000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3112"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":32,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["cancers18193112"],"URL":"https:\/\/doi.org\/10.3390\/cancers18193112","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,25]]}}}