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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

NSCLC
Phase	Enrollment Status	Title
Phase II	Recruiting	Multicenter, Phase II, Neoadjuvant and Adjuvant Study of Multiple Therapies in Biomarker-Selected Patients with Resectable Stages IB-III Non-Small Cell Lung Cancer (NAUTIKA1)	View Details
Phase III	Recruiting	A Phase III, Randomized, Open-Label, Multicenter Study Evaluating the Efficacy and Safety of Divarasib Versus Sotorasib or Adagrasib in Patients With Previously Treated KRAS G12C-Positive Advanced or Metastatic Non-Small Cell Lung Cancer (Krascendo 1)	View Details
Phase II/III	Active, not recruiting	A Phase II/III Multicenter Study Evaluating the Efficacy and Safety of Multiple Targeted Therapies as Treatments for Patients With Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) Harboring Actionable Somatic Mutations Detected in Blood (B-FAST: Blood-First Assay Screening Trial) (B-FAST)	View Details
Phase III	Recruiting	A Phase III, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Divarasib and Pembrolizumab Versus Pembrolizumab and Pemetrexed and Carboplatin or Cisplatin in Patients With Previously Untreated, KRAS G12C-Mutated, Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer(Krascendo 2)	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