Divarasib

{{Short description|Experimental cancer drug}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Use dmy dates|date=July 2025}}

{{Infobox drug | image = Divarasib.svg | image_class = skin-invert-image | width = 300px

| legal_status =

| IUPAC_name = <nowiki>1-{(3</nowiki>''S''<nowiki>)-4-[(7</nowiki>''M''<nowiki>)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoro-2-{[(2</nowiki>''S''<nowiki>)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-3-methylpiperazin-1-yl}prop-2-en-1-one</nowiki> | C = 29 | H = 32 | Cl = 1 | F = 4 | N = 7 | O = 2 | SMILES = C[C@H]1CN(CCN1C2=NC(=NC3=C(C(=C(C=C32)Cl)C4=C(C(=CC(=N4)N)C)C(F)(F)F)F)OC[C@@H]5CCCN5C)C(=O)C=C | StdInChI = 1S/C29H32ClF4N7O2/c1-5-21(42)40-9-10-41(16(3)13-40)27-18-12-19(30)22(26-23(29(32,33)34)15(2)11-20(35)36-26)24(31)25(18)37-28(38-27)43-14-17-7-6-8-39(17)4/h5,11-12,16-17H,1,6-10,13-14H2,2-4H3,(H2,35,36)/t16-,17-/m0/s1 | StdInChIKey = ZRBPIAWWRPFDPY-IRXDYDNUSA-N }}

'''Divarasib''' ('''GDC-6036''') is an experimental anticancer drug which acts as an inhibitor of the G12C mutant form of Kirsten rat sarcoma virus (KRAS), an oncogene commonly present in several forms of cancer. It is in early stage clinical trials against various types of cancer, including colorectal cancer, lung cancer and advanced solid tumors.<ref>{{cite journal | vauthors = Ros J, Vaghi C, Baraibar I, Saoudi González N, Rodríguez-Castells M, García A, Alcaraz A, Salva F, Tabernero J, Elez E | title = Targeting ''KRAS'' G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver | journal = International Journal of Molecular Sciences | volume = 25 | issue = 6 | page = 3304 | date = March 2024 | pmid = 38542278 | pmc = 10970443 | doi = 10.3390/ijms25063304 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Brazel D, Nagasaka M | title = Divarasib in the Evolving Landscape of KRAS G12C Inhibitors for NSCLC | journal = Targeted Oncology | volume = 19 | issue = 3 | pages = 297–301 | date = May 2024 | pmid = 38739329 | pmc = 11111488 | doi = 10.1007/s11523-024-01055-y }}</ref><ref>{{cite journal | vauthors = Tenekeci AK, Unal AA, Ceylan F, Nahit Sendur MA | title = An updated overview of K-RAS G12C inhibitors in advanced stage non-small cell lung cancer | journal = Future Oncology | location = London, England | volume = 20 | issue = 37 | pages = 3019–3038 | date = 2024 | pmid = 39360933 | pmc = 11572139 | doi = 10.1080/14796694.2024.2407280 }}</ref><ref name="Sacher_2023">{{cite journal | vauthors = Sacher A, LoRusso P, Patel MR, Miller WH, Garralda E, Forster MD, Santoro A, Falcon A, Kim TW, Paz-Ares L, Bowyer S, de Miguel M, Han SW, Krebs MG, Lee JS, Cheng M, Arbour K, Massarelli E, Choi Y, Shi Z, Ma J, Shu C, Cui N, Musib L, Choudhury A, Mishra R, Nishino M, Gadgeel SM | title = Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation | journal = The New England Journal of Medicine | volume = 389 | issue = 8 | pages = 710–721 | date = 2023 | pmid = 37611121 | doi = 10.1056/NEJMoa2303810 | hdl = 2268/311523 | hdl-access = free }}</ref> The compound is currently being developed by Roche and Genentech as a targeted therapy for patients with solid tumors harboring the KRAS G12C mutation.<ref name="Kotani_2023">{{cite journal | vauthors = Kotani D, Fakih M, Strickler JH, Falchook G, Durm G, Govindan R, Ngang J, Eng C, Bando H, Cercek A, Argilés G, Segal NH, Goel A, Overman MJ, Garralda E, Prenen H, Kuboki Y, Yoshino T, Choudhury A, Nishino M, Gadgeel SM | title = Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial | journal = Nature Medicine | volume = 30 | issue = 1 | pages = 271–278 | date = 2023 | pmid = 38052910 | pmc = 10803265 | doi = 10.1038/s41591-023-02696-8 }}</ref>

==Mechanism of action== Divarasib is a covalent inhibitor that specifically targets the KRAS G12C mutant protein, which is found in approximately 13% of non-small cell lung cancer (NSCLC) cases and 1-3% of colorectal cancer cases.<ref name="Sacher_2023" /> The drug binds irreversibly to the cysteine residue at position 12 of the KRAS protein, locking it in its inactive GDP-bound state and thereby preventing the downstream oncogenic signaling that drives tumor growth.<ref name="Sacher_2023" />

The compound demonstrates significantly higher potency compared to other KRAS G12C inhibitors, with in vitro studies showing it to be 5 to 20 times more potent than sotorasib (Lumakras) and adagrasib, the first two KRAS G12C inhibitors to receive FDA approval.<ref name="OncoLive2023">{{cite web | title = Divarasib Displays Early-Phase Activity in KRAS G12C–Mutant Solid Tumors | date = 2023-09-05 | url = https://www.onclive.com/view/divarasib-displays-early-phase-activity-in-kras-g12c-mutant-solid-tumors | website = OncLive | access-date = 2025-07-18 }}</ref> This enhanced potency is attributed to its optimized binding to the switch II pocket of the KRAS G12C protein.<ref name="Diehl_2024">{{cite journal | vauthors = Diehl JA, Sacher A, LoRusso P, Patel MR, Miller WH, Garralda E, Forster MD, Santoro A, Falcon A, Kim TW, Paz-Ares L, Bowyer S, de Miguel M, Han SW, Krebs MG, Lee JS, Cheng M, Arbour K, Massarelli E, Choi Y, Shi Z, Ma J, Shu C, Cui N, Musib L, Choudhury A, Mishra R, Nishino M, Gadgeel SM | title = Circulating Tumor DNA Dynamics Reveal KRAS G12C Mutation Heterogeneity and Response to Treatment with the KRAS G12C Inhibitor Divarasib in Solid Tumors | journal = Clinical Cancer Research | volume = 30 | issue = 17 | pages = 3788–3798 | date = 2024 | doi = 10.1158/1078-0432.CCR-24-0255 | pmid = 38995268 | pmc = 11369623 }}</ref>

==Clinical development== ===Phase I studies=== The safety and efficacy of divarasib were first evaluated in a phase I dose-escalation study (NCT04449874) in patients with advanced or metastatic solid tumors harboring KRAS G12C mutations.<ref name="Sacher_2023" /> The study enrolled patients across multiple tumor types, including NSCLC, colorectal cancer, and pancreatic cancer, with doses ranging from 50 mg to 400 mg administered orally once daily.<ref name="Sacher_2023" /> The study established the recommended phase II dose at 400 mg once daily, based on both safety and pharmacokinetic considerations.<ref name="Sacher_2023" /> The most common treatment-related adverse events were gastrointestinal, including nausea, diarrhea, and vomiting, with most events being grade 1 or 2 in severity.<ref name="Sacher_2023" />

===Combination therapy studies=== Divarasib is being evaluated in combination with various anticancer agents to potentially enhance efficacy and overcome resistance mechanisms. A notable phase Ib study evaluated divarasib in combination with cetuximab, an EGFR inhibitor, in patients with KRAS G12C-positive colorectal cancer.<ref name="Kotani_2023" /> This combination demonstrated promising activity with an objective response rate of 62% in the colorectal cancer cohort.<ref name="Brazel_2024">{{Cite journal | vauthors = Brazel D, Nagasaka M | title = Divarasib in the Evolving Landscape of KRAS G12C Inhibitors for NSCLC | journal = Targeted Oncology | volume = 19 | issue = 3 | pages = 297–301 | date = 2024-05-01 | pmid = 38739329 | pmc = 11111488 | doi = 10.1007/s11523-024-01055-y | language = en | issn = 1776-260X }}</ref>

Additional combination studies are ongoing, including trials with pembrolizumab, an PD-1 inhibitor, for the treatment of NSCLC (NCT05789082), and with experimental SHP2 inhibitors to address potential resistance mechanisms. <ref name="Brazel_2024" /><ref>{{Cite report | title = A Phase Ib/II, Open-Label, Multicenter Study Evaluating the Safety, Activity, and Pharmacokinetics of Divarasib in Combination With Other Anti-Cancer Therapies in Patients With Previously Untreated Advanced Or Metastatic Non-Small Cell Lung Cancer With a KRAS G12C Mutation | issue = NCT05789082 | date = 2025-06-19 | url = https://clinicaltrials.gov/study/NCT05789082 | last = Hoffmann-La Roche | publisher = clinicaltrials.gov }}</ref>

===Phase II and III studies=== Divarasib is currently being evaluated in phase II and phase III clinical trials as both monotherapy and in combination with other agents for various tumor types.<ref name="Gadgeel_2024">{{cite journal | vauthors = Gadgeel SM, Sacher A, LoRusso P, Patel MR, Miller WH, Garralda E, Forster MD, Santoro A, Falcon A, Kim TW | title = Krascendo-170 Lung: A phase Ib/II study of divarasib + pembrolizumab ± platinum-based chemotherapy and pemetrexed in untreated KRAS G12C+advanced non-small cell lung cancer (NSCLC) | journal = Journal of Clinical Oncology | volume = 42 | issue = 16_suppl | article-number = TPS8651 | date = 2024 | doi = 10.1200/JCO.2024.42.16_suppl.TPS8651 }}</ref> The Krascendo-170 Lung study is evaluating divarasib in combination with pembrolizumab and platinum-based chemotherapy in treatment-naïve patients with advanced NSCLC.<ref name="Gadgeel_2024" />

==Efficacy== In the phase I study, divarasib demonstrated notable antitumor activity across multiple solid tumor types.<ref name="Sacher_2023" /> Among patients with NSCLC, the objective response rate was 53.4% (95% CI, 42.5-64.2), with a disease control rate of 88.8%.<ref name="Sacher_2023" /> The median duration of response was 11.0 months, indicating durable responses in a significant proportion of patients.<ref name="Sacher_2023" /> For colorectal cancer patients, the single-agent activity was more modest, with an objective response rate of 26.5% (95% CI, 15.0-40.2).<ref name="Sacher_2023" /> However, when combined with cetuximab, the response rate improved significantly to 62%, demonstrating the potential benefit of combination approaches in this indication.<ref name="Kotani_2023" /> Long-term follow-up data from the phase I study showed sustained responses, with many patients remaining on treatment for extended periods without disease progression.<ref name="Sacher_2024">{{cite journal | vauthors = Sacher A, LoRusso P, Patel MR, Miller WH, Garralda E, Forster MD, Santoro A, Falcon A, Kim TW, Paz-Ares L | title = Long-term follow-up of single-agent divarasib in patients with KRAS G12C-positive solid tumors | journal = Annals of Oncology | volume = 35 | issue = suppl_2 | pages = S616MO | date = 2024 | doi = 10.1016/j.annonc.2024.08.1092 }}</ref>

==Adverse effects== Divarasib has demonstrated a manageable safety profile in clinical trials. The most frequently reported treatment-related adverse events include gastrointestinal toxicities such as nausea (45% of patients), diarrhea (42%), and vomiting (25%).<ref name="Sacher_2023" /> Other common adverse events include fatigue, decreased appetite, and skin-related toxicities.<ref name="Sacher_2023" /> Grade 3 or higher treatment-related adverse events occurred in approximately 38% of patients, with the most common being gastrointestinal disorders and laboratory abnormalities.<ref name="Brazel_2024" /> Treatment discontinuation due to adverse events was relatively uncommon, occurring in less than 10% of patients in most studies.<ref name="Sacher_2023" />

==Regulatory status== As of 2024, divarasib remains an investigational agent and has not yet received regulatory approval from the FDA or other major regulatory agencies.<ref name="CancerNetwork2023">{{cite web | title = Divarasib Yields Sustained Responses in Advanced KRAS G12C+ Solid Tumors | date = 2023-08-29 | url = https://www.cancernetwork.com/view/divarasib-yields-sustained-responses-in-advanced-kras-g12c-solid-tumors | website = Cancer Network | access-date = 2025-07-18 }}</ref> The drug is currently being developed through multiple phase II and phase III clinical trials across various tumor types and treatment settings.<ref name="Gadgeel_2024" />

== See also == * ACBI3 * Adagrasib * MRTX1133 * Olomorasib * RMC-9805 * Sotorasib

== References == {{reflist}}

==External links== *[https://clinicaltrials.gov/study/NCT04449874 GO42144 Clinical Trial on ClinicalTrials.gov] *[https://www.cancer.gov/publications/dictionaries/cancer-drug/def/divarasib National Cancer Institute Drug Dictionary Entry]

Category:Experimental cancer drugs Category:Amines Category:Trifluoromethyl compounds Category:Pyridines Category:Chloroarenes Category:Fluoroarenes Category:Ureas Category:Pyrrolidines Category:Quinazolines Category:Piperazines Category:Acrylamides