A Randomized Phase 3 Study of Adagrasib in Combination with Cetuximab Versus Chemotherapy in Patients with Advanced Colorectal Cancer with KRAS G12C Mutation with Disease Progression On or After Standard First-Line Therapy

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 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)), comprise approximately 3% of
colorectal cancer (CRC) and defines a unique segment of CRC without a current
targeted therapy option.
Adagrasib is a potent and orally available small molecule inhibitor of KRAS
G12C. Adagrasib 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. Adagrasib 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 Adagrasib in
patients with malignancies having KRAS G12C mutations. Initial clinical trial
observations with Adagrasib include demonstration of confirmed objective
responses in NSCLC and colorectal cancer.
The epidermal growth factor receptor (EGFR) is constitutively expressed in many
normal epithelial tissues and is also detected in many human cancers including
those of the colon and rectum. Cetuximab is a human/mouse chimeric monoclonal
antibody (mAb) that binds the extracellular domain of epidermal growth factor
receptor (EGFR) and blocks the interaction between EGFR and its ligand,
epidermal growth factor (EGF). Cetuximab binds specifically to the EGFR on both
normal and tumor cells, and competitively inhibits the binding of epidermal
growth factor (EGF) and other ligands, such as transforming growth factor-
alpha. Nonclinical studies have shown that binding of cetuximab to the EGFR
blocks phosphorylation and activation of receptor-associated kinases, resulting
in inhibition of cell growth, induction of apoptosis, and decreased matrix
metalloproteinase and vascular endothelial growth factor production.
Cetuximab is indicated as monotherapy or in combination with chemotherapy for
the treatment of KRAS wildtype metastatic CRC. Signal transduction through EGFR
results in activation of wild-type KRAS protein. However, in cells with
activating KRAS somatic mutations, the mutant KRAS protein is continuously
active and appears independent of EGFR regulation. Retrospective subset
analyses of KRAS mutant and wildtype populations across several randomized
clinical trials have indicated that cetuximab in patients with KRAS mutations
results in no clinical benefit.
The rationale for combining Adagrasib with cetuximab in KRAS G12C mutant CRC
stems from various lines of work. Efforts to target the RAS-RAF-MEK pathway in
CRC have been hindered by adaptive feedback reactivation of pathway signaling
as a mode of therapeutic resistance. For example, BRAF inhibition in BRAF V600
mutant CRC leads to loss of negative feedback signals regulated by the MAPK
pathway, leading to receptor tyrosine kinase (RTK)-mediated reactivation of
MAPK signaling through wildtype RAS and RAF. Similarly, in KRAS mutant cancers,
MEK inhibitor treatment leads to adaptive feedback activation of RAS signaling,
often through EGFR or other RTKs, limiting efficacy. Indeed, early preclinical
studies with KRAS G12C inhibitors, such as ARS-1620 and AMG510, have suggested
a potential role for adaptive feedback as a mechanism of resistance to KRAS
G12C inhibition alone.
Therefore, interrupting the adaptive feedback loop following KRAS G12C
inhibition may overcome adaptive resistance and improve clinical efficacy in a
manner similar to BRAF V600E mutant colorectal cancer, where targeting EGFR*a
primary driver of feedback reactivation in CRC*in combination with BRAF
inhibition led to an improvement in clinical efficacy. In line with this
hypothesis, the addition of an EGFR inhibitor to a KRAS G12C inhibitor resulted
in significant improvement in antitumor activity compared to either single
agent alone in nonclinical KRAS G12C mutant xenograft models. The combination
of Adagrasib and the small molecule EGFR inhibitor afatinib demonstrated
significantly greater antitumor efficacy compared with either single agent in
all five KRAS G12C mutant xenograft models evaluated, including multiple models
exhibiting complete or near-complete responses to the combination. In multiple
nonclinical KRAS G12C human xenograft colorectal cancer mouse models,
anti-tumor activity was significantly enhanced with the combination of
Adagrasib and cetuximab, whereas Adagrasib or cetuximab alone exhibited little
to no effect on tumor growth inhibition. These observations suggest the
combination may address mechanisms responsible for a limited response to
Adagrasib single agent treatment. In summary, these data support the rationale
for combining Adagrasib with cetuximab for the treatment of KRAS G12C-mutant
CRC.
This Phase 3 study compares the efficacy of Adagrasib in combination with
cetuximab against chemotherapy in patients with CRC with KRAS G12C mutation who
have previously experienced radiographic disease progression on or after
standard first-line chemotherapy

This study has been transitioned to CTIS with ID 2023-506241-30-00 check the CTIS register for the current data.

Primary objectives:
To compare the efficacy of Adagrasib in combination with cetuximab versus
chemotherapy (FOLFIRI or mFOLFOX6) administered in the second-line treatment
setting to patients with CRC with KRAS G12C mutation.

Secondary objectives:
• To evaluate secondary efficacy endpoints in the study population.
• To evaluate the safety and tolerability in the study population.
• To evaluate the pharmacokinetics (PK) of Adagrasib administered in
combination with cetuximab.
• To evaluate health-related quality of life (HRQOL) and cancer-related
symptoms in the study population.

Exploratory objectives:
• To explore correlations between tumor biomarkers, gene alterations and
efficacy.
• To evaluate the Progression-Free Survival in the next-line of therapy (PFS2)
in the study population.

Study 849-010 is an open-label, randomized Phase 3 clinical trial comparing the efficacy of Adagrasib administered in combination with cetuximab versus chemotherapy (FOLFIRI or mFOLFOX6) in the second-line treatment setting in patients with CRC with KRAS G12C mutation. Patients will have previously experienced radiographic disease progression on or after treatment with a standard first-line fluoropyrimidine-based chemotherapy regimen containing either oxaliplatin or irinotecan. Secondary objectives include evaluation of safety and tolerability, secondary efficacy endpoints, PROs, and Adagrasib PK in the study population. The presence of KRAS G12C mutation in tumor tissue for the purpose of patient eligibility must be established using Sponsor pre-approved methods and laboratories. Presence of tumor KRAS G12C mutation may be established using a Sponsor-approved local test or the Sponsor-provided central laboratory test. Sponsor-approval process includes review of analytical performance and validation of tests to ensure locked-down assay cutoffs (ie, criteria to determine whether subjects are biomarker-positive or negative) before use of the test(s) in the study for patient enrollment. Patient eligibility for study enrollment based on objective disease progression on or after a standard first-line fluoropyrimidine-based chemotherapy regimen (containing either oxaliplatin or irinotecan) will be evaluated by the Investigator. Data entered into the case report form (CRF) are to include all prior systemic treatment regimens received for colorectal cancer, the date of at least one radiographic evaluation prior to the occurrence of disease progression on first-line treatment, and the date the radiographic evaluation demonstrated disease progression, as well as specifics about organ systems (e.g., lung, liver, lymph node, bone and/or brain) having tumors that increase in size or are new. Eligible patients will be randomized 1:1 to the experimental arm (Adagrasib with cetuximab) or the control arm (FOLFIRI or mFOLFOX6 chemotherapy). Randomization will be stratified by: 1. Region (USA/Canada vs. other), 2. Time to disease progression after beginning first-line treatment (<6 months vs. >=6 months). The requirements for tumor KRAS G12C for determining eligibility are presented in Table 1 and Figure 1. The Schedule of Assessments is presented in Table 2. Study treatment will be expressed in 4-week (28 day) cycles. Patients randomized to the experimental arm will receive Adagrasib 600 mg BID and cetuximab 500 mg/m2 by intravenous (IV) infusion every 2 weeks, i.e., Days 1 and 15 of each treatment cycle. Patients randomized to the chemotherapy control arm will receive FOLFIRI or mFOLFOX6 depending on their first-line treatment regimen. Patients who received prior irinotecan will receive mFOLFOX6; patients who received prior oxaliplatin will receive FOLFIRI. In the chemotherapy control arm, patients will receive appropriate pre-medications followed by either: • FOLFIRI administered on days 1 and 15 of each cycle: - irinotecan 180 mg/m² IV, - folinic acid 400 mg/m² IV, and - fluorouracil 400 mg/m² given as an IV bolus, then 2400 mg/m² given as a continuous infusion over 46-48 hours. OR • mFOLFOX6 administered on days 1 and 15 of each cycle: - oxaliplatin 85 mg/m² IV, - folinic acid 400 mg/m2 IV, and - fluorouracil 400 mg/m2 given as an IV bolus, then 2400 mg/m² given as a continuous infusion over 46-48 hours. AND, OPTIONALLY • A VEGF/VEGFR inhibitor (bevacizumab or locally approved bevacizumab biosimilar, ramucirumab, or ziv-aflibercept, at the discretion of the Investigator) used as local standard-of-care may be given as a concomitant therapy with control arm chemotherapy in accordance to package labeling at the discretion of the Investigator. For an individual patient, the dose of study drug(s) may be reduced or interrupted as appropriate based on protocol-defined treatment modification criteria (Section 5). Disease response and progression will be evaluated in accordance with Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Disease progression as documented by the Investigator in the CRF will be the basis for patient management and supportive statistical analyses of radiology-based study endpoints. Blinded central radiology review for disease response and progression will be performed for the purpose of primary statistical analyses of these study endpoints. Disease assessments must be performed as scheduled according to the calendar to prevent the introduction of bias in the assessment of efficacy based on toxicity. Timely and complete disease assessments and transfer of radiographic documentation to the Central Radiology Laboratory is critical to the integrity of this clinical trial. Patients will receive study treatment as assigned at randomization until disease progression, unacceptable adverse events, investigator decision, patient refusal or death, whichever comes earlier. Patients experiencing clinical benefit in the judgment of the Investigator may continue study treatment beyond disease progression as defined by RECIST 1.1 if specified criteria are met (see Section 3). 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. No crossover to the alternative treatment assignment is provided in this study.

The trial will compare the effectiveness of Adagrasib in combination with
cetuximab (investigational arm) versus standard of care second-line treatment
consisting of either FOLFIRI or mFOLFOX6 chemotherapy (comparator arm).
Patients will have a 50% chance of receiving the investigational arm (Adagrasib
with cetuximab) and a 50% chance of receiving the comparator arm (FOLFIRI or
mFOLFOX6 chemotherapy). This means 1 out of 2 people will get Adagrasib with
cetuximab. Patients will receive Adagrasib by mouth and cetuximab as an
intravenous infusion.

Please see protocol section 7.0 for the study procedure and assessments.
Please see section 6.0 in the ICF for possible side effects and complications.