A Phase 2 Trial of Adagrasib Monotherapy and in Combination with Pembrolizumab and a Phase 3 Trial of Adagrasib in Combination with Pembrolizumab versus Pembrolizumab plus Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer with KRAS G12C Mutation

RAS proteins are part of the family of small GTPases that 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 leading to 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. The 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, comprise approximately 14% of lung adenocarcinoma and defines a
unique segment of lung cancer without a current targeted therapy option.

Adagrasib is a potent and orally available small molecule inhibitor of KRAS
G12C. Adagrasib demonstrates 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. Adagrasib demonstrated broad-spectrum
antitumor activity across several KRAS G12C-positive patient- or cell-derived
tumor models implanted in mice at well-tolerated dose levels, including
complete tumor responses in a subset of models. Collectively, these results
support the evaluation of Adagrasib in patients with malignancies having KRAS
G12C mutations.


Pembrolizumab is a monoclonal antibody (mAb) directed against programmed cell
death 1 (PD-1) and blocks the interaction between PD-1 and its ligands, thereby
releasing PD-1-mediated inhibition of T-cell proliferation (including cytotoxic
CD8+ T-cells) and cytokine production.

The rationale for the combination of adagrasib with pembrolizumab stems from
various lines of work. First, large-scale functional genomics studies have
demonstrated that NSCLC cells exhibiting KRAS mutations are highly dependent on
KRAS function for cell growth and survival, supporting the potential role of
adagrasib in KRAS G12C mutated NSCLC. Second, clinical observations of
patients with KRAS mutant NSCLC suggest that these tumors have higher tumor
mutational burden, which putatively results in an increase in tumor neoantigens
and increased responsiveness to PD 1/PD-L1-directed immunotherapy. Studies in
mutant KRAS G12C tumor models show that adagrasib enhances the potential for
tumor cells to present antigens and reconditions the tumor microenvironment
through changes in the proportions of key cell populations, both of which are
predicted to augment susceptibility to immune checkpoint inhibition. Thus, not
only has activity been observed with each agent individually, but these
observations also suggest potential synergistic activity of the combination of
adagrasib with pembrolizumab to translate into significant antitumor activity.


The Phase 2 portion of the study evaluates the efficacy and safety of adagrasib
monotherapy and in combination with pembrolizumab in cohorts of patients with
advanced NSCLC with KRAS G12C mutation and any PD-L1 TPS and who are candidates
for first-line treatment.

This study has been transitioned to CTIS with ID 2023-508922-83-00 check the CTIS register for the current data.

Primary Objective:

To evaluate the efficacy of adagrasib monotherapy and in combination with
pembrolizumab administered in the first-line treatment setting to patients
having NSCLC with KRAS G12C mutation.

Secondary Objectives:

• To characterize the safety and tolerability of the monotherapy and the
combination regimen in the selected population.
• To evaluate secondary efficacy endpoints using monotherapy and the
combination regimen in the selected population.
• To evaluate the pharmacokinetics (PK) of adagrasib administered as
monotherapy and in combination with pembrolizumab.

Study 849-007 is an open-label clinical trial evaluating the efficacy of
MRTX849 administered as monotherapy and in combination with pembrolizumab in
the first-line treatment setting to patients with NSCLC with KRAS G12C
mutation. Secondary and exploratory objectives include evaluation of safety,
adagrasib PK, pharmacodynamic for the combination regimen in the study
population.

Arms:
PD-L1 TPS < 1% - 1:1 randimized:
o Cohort 1a, adagrasib 400mg twice daily (BID) in combination with
pembrolizumab or
O Cohort 1b, adagrasib 600mg twice daily monotherapy

PD-L1 TPS >= 1% - assign to:
o Cohort 2, adagrasib 400mg twice daily in combination with
pembrolizumab

Genetic eligibility may be established using tumor tissue samples or ctDNA.
Submission of tumor tissue samples for all enrolled patients is required for
central laboratory testing for retrospective confirmation of KRAS mutation
status, PD-L1 TPS status and identification of concurrent gene alterations.
Samples for the central laboratory must be submitted in a timely manner (e.g.,
within 90 days after initiation of study treatment).

The presence of tumor KRAS G12C mutation for the purpose of patient eligibility
and the PD-L1 TPS status used to stratify patients in cohorts must be
established using Sponsor pre-approved methods and laboratories.

Study treatment will be expressed in 3-week cycles.
Adagrasib is to be administered orally on a continuous basis until disease
progression, or protocol defined reason for discontinuation.
Pembrolizumab will be administered by intravenous (IV) infusion, 200 mg over
approximately 30 minutes every 3 weeks (Q3W).

Patients will receive study treatment until disease progression, unacceptable
adverse events, receipt of maximal number of cycles per local standard-of-care,
investigator decision, patient refusal or death. Patients experiencing
clinical benefit in the judgment of the Investigator may continue study
treatment beyond disease progression as defined by RECIST 1.1. In the event a
patient discontinues study treatment for a reason other than objective disease
progression, disease assessments post-treatment should continue until objective
disease progression is documented by the Investigator or start of subsequent
anti-cancer therapy, whichever is sooner.

Adagrasib Monotherapy and in combination with pembrolizumab

Please check the protocol - Schedule of assessments in the Section "Study
Summary".

Risks associated with the study are described in the informed consent form,
section 6.