A Randomized Phase 3 Study of MRTX849 versus Docetaxel in Patients with Previously Treated Non-Small Cell Lung Cancer with KRAS G12C Mutation

RAS proteins are part of the family of small GTPases and are activated in
response to growth factor stimulation and various other extracellular stimuli
to regulate intracellular signaling pathways responsible for growth, migration,
survival and differentiation of cells. The activation of RAS proteins at the
cell membrane by growth factors results in the binding of key effector
molecules, formation of signaling complexes, and the initiation of a cascade of
intracellular signaling pathways within the cell including the RAF and PI3
kinase pathways. RAS proteins normally alternate between GTP- and GDP-bound
conformations, where the GTP-bound conformation represents the *On* and
GDP-bound the *Off* state. Dependence of RAS and other GTPases on guanine
nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) to
switch them on and off allows both processes to be highly regulated and
responsive to multiple signal inputs. In contrast, oncogenic mutants of RAS
generally function by preventing hydrolysis of GTP, thereby generating
constitutively active GTP-bound RAS molecules with severe consequences for the
cell including uncontrolled cellular growth and malignant transformation.
KRAS is the most frequently mutated gene of the RAS family, and KRAS mutations
occur in approximately 30% of lung adenocarcinomas, 50% of colorectal cancers,
and 90% of pancreatic ductal adenocarcinomas. Mutation of the glycine at
residue 12 produces a steric block that prevents GAP proteins from accessing
KRAS, thereby inhibiting GTP hydrolysis resulting in a highly activated
GTP-bound form of RAS. Mutation of that amino acid residue to cysteine, noted
as KRAS G12C (also known as KRAS (p.G12C), comprises approximately 14% of lung
adenocarcinoma and defines a unique segment of lung cancer without a current
targeted therapy option. Large genomics studies characterizing lung cancers
have indicated that KRAS mutations, including G12C, are mutually exclusive with
other known oncogenic driver mutations in non-small cell lung cancer (NSCLC)
including EGFR, ALK, ROS1, RET, and BRAF indicating that KRAS mutations define
a unique segment of lung cancer without a current targeted therapy option.
Functional genomics studies have demonstrated that NSCLC cancer cells
exhibiting KRAS mutations are highly dependent on KRAS function for cell growth
and survival.

MRTX849 (also known as adagrasib) is a potent and orally available small
molecule inhibitor of KRAS G12C. MRTX849 demonstrated potent inhibition of
KRAS-dependent signal transduction and cancer cell viability with selectivity
for KRAS G12C of over 1000-fold compared to KRAS wild-type. MRTX849
demonstrated broad-spectrum antitumor activity across several KRAS
G12C-positive patient- or cell-derived tumor models implanted in mice,
including complete tumor responses in a subset of models. Collectively, these
results support the evaluation of MRTX849 in patients with malignancies having
KRAS G12C mutations. Initial clinical trial observations with MRTX849 include
demonstration of confirmed objective responses in NSCLC and colorectal cancer.

This study has been transitioned to CTIS with ID 2023-507263-19-00 check the CTIS register for the current data.

To compare the efficacy of MRTX849 versus docetaxel in patients with NSCLC with
KRAS G12C mutation and who have received prior treatment with a platinum-based
regimen and immune checkpoint inhibitor therapy.

This Phase 3 study compares the efficacy of MRTX849 versus docetaxel in
patients with metastatic NSCLC with KRAS G12C mutation who have previously
received treatment with a platinum-based chemotherapy regimen and an immune
checkpoint inhibitor.

Eligible patients will be randomized 2:1 to MRTX849 or docetaxel
Study treatment will be administered in 3-week cycles. Patients randomized to
the investigational arm will receive MRTX849 administered orally (PO) at a
starting dose of 600 mg twice daily (BID). Patients randomized to the
comparator arm will receive treatment with docetaxel. Docetaxel will be
administered by intravenous infusion at 75 mg/m2 over 1 hour or according to
institutional practices every 3 weeks. Premedication with dexamethasone (or
institutional equivalent) will be required in accordance with local standards.

Please check the protocol (English, V7.2 dated 21Apr2023) - Table 2 Schedule of
assessments. Risks associated
with the study are described in the informed consent form, section 6