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Divarasib
Experimental cancer drug From Wikipedia, the free encyclopedia
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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.[1][2][3][4] The compound is currently being developed by Roche and Genentech as a targeted therapy for patients with solid tumors harboring the KRAS G12C mutation.[5]
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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.[4] 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.[4]
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.[6] This enhanced potency is attributed to its optimized binding to the switch II pocket of the KRAS G12C protein.[7]
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Clinical development
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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.[4] 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.[4] The study established the recommended phase II dose at 400 mg once daily, based on both safety and pharmacokinetic considerations.[4] The most common treatment-related adverse events were gastrointestinal, including nausea, diarrhea, and vomiting, with most events being grade 1 or 2 in severity.[4]
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.[5] This combination demonstrated promising activity with an objective response rate of 62% in the colorectal cancer cohort.[8]
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. [8][9]
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.[10] The Krascendo-170 Lung study is evaluating divarasib in combination with pembrolizumab and platinum-based chemotherapy in treatment-naïve patients with advanced NSCLC.[10]
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Efficacy
In the phase I study, divarasib demonstrated notable antitumor activity across multiple solid tumor types.[4] 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%.[4] The median duration of response was 11.0 months, indicating durable responses in a significant proportion of patients.[4] 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).[4] However, when combined with cetuximab, the response rate improved significantly to 62%, demonstrating the potential benefit of combination approaches in this indication.[5] 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.[11]
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%).[4] Other common adverse events include fatigue, decreased appetite, and skin-related toxicities.[4] Grade 3 or higher treatment-related adverse events occurred in approximately 38% of patients, with the most common being gastrointestinal disorders and laboratory abnormalities.[8] Treatment discontinuation due to adverse events was relatively uncommon, occurring in less than 10% of patients in most studies.[4]
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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.[12] The drug is currently being developed through multiple phase II and phase III clinical trials across various tumor types and treatment settings.[10]
See also
References
External links
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