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Divarasib (RG6330, GDC-6036)

Modality: Kirsten rat sarcoma virus gene (KRAS) G12C inhibitor

Disease State: Non-small cell lung cancer (NSCLC)

Summary

Divarasib (GDC-6036, RG6330) is a selective, oral, investigational molecule designed to target KRAS G12C, a driver mutation in cancer.^1,2 KRAS is one of the most prevalent oncogenes in human cancers, with the highest mutation rate among all cancers.^3-5 By locking the mutant KRAS G12C into its inactive GDP-bound state, divarasib turns off oncogenic signaling in preclinical models.²

Clinical Trials

Divarasib

NCT ID	Study Phase	Enrollment Status	Study Title
NCT05789082		Recruiting	A Study Evaluating the Safety, Activity, and Pharmacokinetics of Divarasib as a Single Agent or in Combination With Other Anti-Cancer Therapies in Participants With Previously Untreated Advanced or Metastatic Non-Small Cell Lung Cancer With a KRAS G12C Mutation	View details
NCT06793215	Phase III	Recruiting	A Study Evaluating the Efficacy and Safety of Divarasib and Pembrolizumab Versus Pembrolizumab and Pemetrexed and Carboplatin or Cisplatin in Participants With Previously Untreated, KRAS G12C-Mutated, Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer	View details
NCT06497556	Phase III	Active, not recruiting	A Study Evaluating the Efficacy and Safety of Divarasib Versus Sotorasib or Adagrasib in Participants With Previously Treated KRAS G12C-positive Advanced or Metastatic Non-Small Cell Lung Cancer	View details
NCT04302025	Phase II	Recruiting	A Study of Multiple Therapies in Biomarker-selected Participants With Resectable Stages IB-III Non-small Cell Lung Cancer (NSCLC)	View details
NCT03178552	Phase II	Active, not recruiting	A Study to Evaluate the Efficacy and Safety of Multiple Targeted Therapies as Treatments for Participants With Non-Small Cell Lung Cancer (NSCLC)	View details

Proposed Mechanism of Action

The KRAS protein is a signaling GTPase that cycles between active GTP-bound and inactive GDP-bound states to regulate intracellular signaling in response to extracellular growth factors^3,6-7
GTP-bound KRAS activates multiple downstream signaling pathways involved in cell proliferation, migration, and survival, including the MAPK and PI3K pathways^6-8
Oncogenic mutations in the KRAS protein interfere with the transition from GTP-bound to GDP-bound states.^4-6,8 Locking KRAS G12C in its constantly active state increases downstream oncogenic signaling
Divarasib (GDC-6036, RG6330) is designed as an orally available small molecule, and in preclinical studies showed potent and selective inhibition of the KRAS G12C protein^1,2
Selectively binds the switch II pocket of the KRAS G12C protein through a specific interaction with the cysteine residue at position 12 and irreversibly locks it in the inactive GDP-bound state^2,3,9
By locking the mutant KRAS G12C into its inactive GDP-bound state, divarasib turns off oncogenic signaling in preclinical models²

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GDP
guanosine diphosphate
GTP
guanosine triphosphate
KRAS
Kirsten rat sarcoma virus gene
NSCLC
non-small cell lung cancer