A PHASE 2, RANDOMIZED, OPEN-LABEL STUDY OF ENCORAFENIB AND CETUXIMAB PLUS
PEMBROLIZUMAB VERSUS PEMBROLIZUMAB ALONE IN PARTICIPANTS WITH PREVIOUSLY UNTREATED BRAF V600E-MUTANT, MSI-H/DMMR METASTATIC COLORECTAL CANCER

Approximately 20-25% of metastatic colorectal cancer (mCRC) tumors with BRAF
V600E mutation are also MSI-H/dMMR (Venderbosch et al, 2014; André et al,
2020). The combined presence of a BRAF mutation and MSI-H/dMMR is associated
with a poorer prognosis which is believed to be primarily driven by the BRAF
mutation (Venderbosch et al, 2014). The encorafenib + cetuximab regimen was
approved in the US and EU in patients with previously treated mCRC with BRAF
V600E mutation based on data from the Phase 3 study BEACON in which patients
treated with encorafenib + cetuximab showed statistically significant
improvements compared to standard chemotherapy (Kopetz et al, 2019). The PD-1
inhibitor pembrolizumab has been approved for the treatment of patients with
treatment-naïve mCRC who were MSI-H/dMMR based on the results of the Phase 3
study KEYNOTE-177 (NCT02563002) in which patients were randomized to receive
pembrolizumab as monotherapy or standard first-line mCRC chemotherapy.

The rationale for combining encorafenib and cetuximab with pembrolizumab lies
in the hypothesis that tumor progression in these patients is driven by both
genomic instability, reflected by an MSI-H/dMMR status, mediating
susceptibility to checkpoint inhibition, as well as MAPK signaling, which is
driven by mutation in BRAF, which in turn functions as a dominant driver for
oncogene and EGFR signaling. Combining pembrolizumab with encorafenib and
cetuximab is thus believed to demonstrate greater antitumor activity in
patients with mCRC that is both MSI-H/dMMR and BRAF mutated than pembrolizumab
or encorafenib+cetuximab alone.

This study has been transitioned to CTIS with ID 2024-512119-34-00 check the CTIS register for the current data.

Comparing the efficacy of encorafenib and cetuximab plus pembrolizumab (triplet
group [group A]) vs. pembrolizumab (control group [group B]).
Assessing the overall safety and tolerability of group A vs. group B.
Assessing the efficacy of group A vs. group B.
Confirming BRAF and MSI status in tumor tissue.
Assessing the effect on PROs of group A vs. group B.
Understanding the relationship between the studied therapeutic intervention(s)
and the biology of the participant's disease.
Understanding the surgical conversion rate of group A vs. group B.

This is an open-label, randomized Phase 2 study investigating encorafenib and
cetuximab plus pembrolizumab (triplet group [group A]) versus pembrolizumab
alone (control group [group B]) as first-line treatment in participants with
metastatic colorectal cancer (mCRC) testing positive for MSI-H/dMMR and BRAF
V600E mutation.
Approximately 104 participants in approximately 90 study centers in
approximately 16 countries will be randomized 1:1 to encorafenib and cetuximab
plus pembrolizumab (group A) or pembrolizumab (group B) (approximately 52
participants per group).
Participants will receive up to 18 administrations (approximately 2 years) of
pembrolizumab; however, Arm A treatment group can continue to receive
encorafenib and cetuximab after this period if indicated by treating physician.
Each cycle of treatment will last 42 days.

Participants will receive either encorafenib (300 mg orally once daily) +
cetuximab (500 mg/m2 Q2W IV) once every 2 weeks + pembrolizumab (400 mg Q6W IV)
once every 6 weeks or just pembrolizumab (400 mg Q6W IV). Study treatment will
be administered until disease progression according to RECIST v1.1 data or
until one of the other protocol-defined criteria for study treatment
discontinuation is met. In certain circumstances, continuation of treatment
after disease progression may be allowed. In both treatment groups, the
duration of treatment with pembrolizumab will not exceed 18 administrations
(approximately 24 months).

Physical exam including measurement of height, weight, blood pressure,
respiratory rate, heart rate, temperature, eye exam and a skin exam.
Performance status assessment.
Blood samples for routine testing, tumor markers, thyroid function, testing for
hepatitis and HIV (if needed), and biomarker tests. cycle 1 blood volume =
approximately 55ml and future cycles = approximately 25ml (excluding biomarker
samples).
Pregnancy test for women.
ECG measurements.
CT, PET-CT or MRI scan of the chest, abdomen, and pelvis and, if necessary, and
MRI scan of the brain.
Possibility for new tumor sample if no archive biopsy available or insufficient
during pre-screening.
Questionnaires regarding quality of life on an electronic tablet (EORTC
QLQ-C30, EQ-5D-5L, PGIS, PGIC).
Completion of encorafenib dose diary (group A only).

Drug risk (Most common)
Encorafenib:

•Constipation
• Decreased appetite
• Diarrhea
• Sleep problems
• Dry skin
• Tired feeling
• Fever
• Hair loss
• Headache
• Itch
• Muscle or joint pain
• Nausea
• Pain, such as pain in arms, legs and back
• Redness, swelling, numbness and peeling of the skin on the palms of the hands
and soles of the feet (hand-foot skin reaction)
• Skin rashes including redness, itching, hives and swollen patches of skin
•Skin redness
•Skin tags, new moles on the skin or changes in existing moles
•Small, rough bumps on the skin
• Thickening of external part of the skin
• Tingling, numbness or abnormal sensitivity to pain or touch and nerve pain
• Vomit
• Weakness

Cetuximab:

• Skin reactions, mainly acne-like rashes (inflamed hair follicles, acne and
rash) and/or less commonly as itchy, dry skin,
scaling of the skin, excessive hair growth, or nail disorders, manifesting
as pain, tenderness, and tearing of fingernails and toenails
• During or shortly after the cetuximab infusion, you may experience mild to
moderate infusion-related reactions such as fever and chills, dizziness,
respiratory distress
• Inflammation of the gut wall, mouth and nose (in some cases severe), which
can lead to nosebleeds in some patients
• Decrease in the concentration of magnesium in the blood
• Increase in blood levels of certain liver enzymes

Pembrolizumab:

• itchy skin
• loose or watery stools
• cough