A PHASE 3 TRIAL OF FIANLIMAB (REGN3767, ANTI-LAG-3) + CEMIPLIMAB VERSUS PEMBROLIZUMAB IN PATIENTS WITH PREVIOUSLY UNTREATED UNRESECTABLE LOCALLY ADVANCED OR METASTATIC MELANOMA

From protocol amendment 1 16Feb2022, section 1. Introduction

1.2. Phase 3 Study, R3767-ONC-2011
Despite the recent advances in the treatment of unresectable or metastatic
melanoma, a significant portion of patients do not respond to or progress
within 12 months of treatment with current immune checkpoint inhibitors or
combination blockade. In addition, combination blockade of CTLA-4 + PD-1
carries significant potential for toxicity, demonstrating the need for
additional therapies with comparable efficacy but with a more favorable safety
profile. In view of the results of study CheckMate-067, there is a rationale
for exploring new combination of
immune-checkpoint inhibitors that build upon the activity of anti-PD-1 agents
but with a more favorable toxicity profile than the ipilimumab-nivolumab
combination.

Preliminary studies with fianlimab + cemiplimab in anti-PD-(L)1 naïve advanced
melanoma patients suggest that this combination in the first line treatment may
prove more efficacious than anti-PD-1 treatment alone, and with a better
tolerability than CTLA-4 + PD-1 inhibition.

Additional background information on the study drug and development program can
be found in the Investigator*s Brochure for fianlimab.

Thus, this phase 3 study of the combination of fianlimab and cemiplimab versus
pembrolizumab in patients with previously untreated unresectable locally
advanced or metastatic melanoma is planned.

This study has been transitioned to CTIS with ID 2023-505772-30-00 check the CTIS register for the current data.

From protocol amendment 3 27JUn2022, Clinical Study Protocol Synopsis, page 1

Primary Objective
• To demonstrate superiority of fianlimab 1600 mg + cemiplimab and/or fianlimab
400 mg+ cemiplimab compared to pembrolizumab, as measured by progression-free
survival (PFS).

Secondary Objectives
• To demonstrate superiority of fianlimab 1600 mg + cemiplimab and/or fianlimab
400 mg + cemiplimab compared to pembrolizumab, as measured by overall survival
(OS).
• To demonstrate superiority in ORR of fianlimab 1600 mg + cemiplimab and/or
fianlimab 400 mg + cemiplimab compared to pembrolizumab.
• To characterize the ORR, PFS, and OS with fianlimab 1600 mg + cemiplimab
and/or fianlimab 400 mg + cemiplimab compared to cemiplimab to inform the
contribution of each components.
• To assess immunogenicity of fianlimab 1600 mg + cemiplimab and/or fianlimab
400 mg and cemiplimab.
• To assess impact of fianlimab 1600 mg + cemiplimab and/or fianlimab 400 mg +
cemiplimab on physical functioning and role functioning and global health
status/quality of life, as compared to pembrolizumab in adults.
• To characterize safety and tolerability of treatment in patients 12 to <18
years of age.
• To characterize ORR, PFS, and OS with treatment in patients 12 to <18 years
of age.
• To assess the safety and tolerability of fianlimab + cemiplimab compared to
pembrolizumab and to cemiplimab.
• To characterize pharmacokinetics (PK) of treatment using sparse PK sampling
in patients aged >=12 years.

From protocol amendment 3 27Jun2022, Clinical Study Protocol Synopsis, page 2

This is a phase 3 study in patients aged >=12 years with unrespectable locally
advanced or metastatic melanoma who have not received a previous systemic
treatment for advanced disease.
For adult and adolescent patients there are 4 main arms to the study, which
will be conducted in a randomized, double-blind fashion:
• Arm A: fianlimab (1600 mg every 3 weeks [Q3W], intravenously, [IV]) +
cemiplimab (350 mg Q3W IV)
• Arm A1: fianlimab (400 mg every 3 weeks [Q3W], intravenously, [IV]) +
cemiplimab (350 mg Q3W IV)
• Arm B: pembrolizumab (200 mg Q3W IV) + saline/dextrose placebo (placebo)
• Arm C: cemiplimab (350 mg Q3W IV) + saline/dextrose placebo (placebo)

The study will enroll a total of approximately 1,590 patients.

• Approcimately1230 patients will be randomized in the first portion of the
study. The first 180 randomized patients will be used for a futility analysis
conducted by sponsor. These 180 patients include approximately 40 patients
enrolled in a 2:1:1 randomization ratio (20 for Arm A and 10 each for Arms B
and C) under Protocol Amendment #1, and approximately 140 patients (40 each for
Arms A, A1, and B and 20 for Arm C) in 2:2:2:1 randomization ratio under
Protocol Amendment 03. The next up to 1,050 patients will be randomized in a
2:2:2:1 randomization ratio (300 patients each for Arms A, A1, and B and 150
patients for Arm C). These patients (the PFS population) will be used for
primary analysis of primary endpoint of PFS between Arms A and/or A1 versus Arm
B. The PFS population will also be used for final analysis of a secondary
endpoint of ORR and for the assessment of contribution of components to the
combination of cemiplimab and fianlimab in Arms A and/or A1 versus Arm C.
• The next additional approximately 360 patients will be randomized in a 1:1:1
randomization ratio (120 patients) each for Arms A, A1, and B . These patients
together with the PFS population will result in a total of 1410 patients 420
each for Arms A, A1, and B and 150 for arm C) for OS for analysis. The
analysis of PFS discussed above will not be conducted until the study is fully
enrolled with these additional patients

All patients enrolled in the study will be stratified based on clinical
prognostic indicators: by their baseline lactate dehydrogenase (LDH) level
(normal vs elevated), M stage (stage III vs M1a-b vs M1c vs M1d, according to
eighth Edition of American Joint Committee on Cancer melanoma classification),
and previous exposure to anti-Programmed Death 1 (PD 1)/Programmed Death Ligand
1 (PD-L1) therapy in the adjuvant or neo-adjuvant setting (yes vs no).

Blinding
For all parameters, the study will be blinded, except for an unblinded
pharmacist at each site.

Unblinding
Unblinding will occur upon request to Regeneron Medical Monitor by the
Investigator after confirmation of disease progression by the Blinded
Independent Central Review (BICR).
Emergency unblinding by the Investigator will be permitted in case of a true
medical emergency
Patients who have confirmed disease progression will receive standard of care
treatment as per their local guidance and investigator*s decision.

From protocol amendment 3 27Jun2022, Clinical Study Protocol Synopsis, page 6-7

Dose/Route/Schedule: The combination of cemiplimab plus fianlimab, the
combination of pembrolizumab plus placebo and the combination of cemiplimab
plus placebo will be prepared by an unblinded pharmacist at the investigative
site and will be administered in a blinded fashion for all patients.
All infusions for adults and adolescents will be administered as a 30 minute
(±10 minutes) IV infusion in an outpatient setting, every 3 weeks.

Cemiplimab
Cemiplimab 350 mg Q3W IV is the approved regimen (LIBTAYO®, cemiplimab) for
treatment of cutaneous squamous cell carcinoma (CSCC), basal cell carcinoma
(BCC), and non-small cell lung carcinoma (NSCLC).
Cemiplimab will be supplied as a liquid in sterile, single-use vials.
Instructions on dose preparation are provided in the pharmacy manual.

Fianlimab and Cemiplimab (for combination / co-infusion administration)
Based on efficacy and safety data from an ongoing phase 1 study,
R3767-ONC-1613, the fianlimab 1600 mg Q3W IV dose with cemiplimab 350 mg Q3W IV
was recommended to advance to phase 3. The efficacy of fianlimab 400 mg Q3W IV
with cemiplimab 350 mg Q3W IV has not been studied but is being added as it is
in line with the expectation to consider lower doses in oncology setting and
also consistent with the doses used for other anti-LAG-3 antibodies that are
being utilized in phase 2 and 3 clinical trials in melanoma and in other solid
tumors.
Fianlimab 1600 mg and400 mg Q3W IV will be supplied as a liquid in sterile,
single-use vials. Instructions on dose preparation are provided in the pharmacy
manual.
Fianlimab and cemiplimab will be administered simultaneously as a mixed
co-infusion.

Pembrolizumab
Pembrolizumab 200 mg Q3W IV is an approved dose for the treatment of advanced
and metastatic melanoma.
For adolescent patients randomized to Arm B, pembrolizumab will be dosed based
on body weight at 2.0 mg/kg Q3W IV (max. 200 mg).
Pembrolizumab will be prepared for co-infusion (with saline placebo) at the
investigative sites as a liquid in sterile. Instructions on dose preparation
are provided in the pharmacy manual.

Safety: The first 6 adolescent patients (12 to <18 years old) will be allocated
to treatment Arm A and included in a safety run-in to confirm the safety and
tolerability of the 1600 mg dose of fianlimab (Q3W) in combination with
cemiplimab (350mg Q3W) in adolescent patients with melanoma. Subsequent
adolescent patients will be randomized to all study arms.
The dose limiting toxicity (DLT) evaluation period for pediatrics is 28 days
with the intent to monitor the safety and tolerability of the first 2 doses of
study drug(s). The dose will be considered acceptable for randomization of
additional adolescent patients if there is no more than 1 DLT in the first 6
evaluable patients. In the event of >1 DLT in the first 6 evaluable patients,
see Section 6.1.2.

From protocol amendment 1 16Feb2022, section 3 Hypothesis and Rationale:
3.3. Risk-Benefit
A patient being screened for R3767-ONC-2011 who has documented or suspected
ongoing SARS CoV-2 infection should not be enrolled in the study.
A patient being screened for R3767-ONC-2011 who had either documented or
suspected SARS CoV-2 may be enrolled per the investigator*s medical judgment if
the patient has:
• Recovered from COVID-19 (all COVID-19-related symptoms and major clinical
findings which can potentially affect the safety of the patient have resolved)
and:
* It is recommended at least one COVID-19 PCR test be conducted to confirm that
the patient is negative for SARS-CoV-2.
* If COVID-19 PCR testing is not feasible, it is advised that at least three
months have transpired since the initial diagnosis.

3.3.1. Risk Benefit for Fianlimab + Cemiplimab
The primary objective of the Study 2011 is to demonstrate the superiority for
the proposed combination of fianlimab+cemiplimab (Arm A) compared to the
pembrolizumab, an approved therapy (Arm B) in patients with previously
untreated unresectable locally advanced or metastatic melanoma.
Cutaneous melanoma is one of the most aggressive forms of skin cancer and its
incidence in both males and females has continued to rise over the past 40
years (Section 1.1).
Antibodies to the inhibitory receptor lymphocyte-activation gene 3 (LAG-3),
such as fianlimab, represent an appealing potential treatment strategy to
invigorate the immune response to cancer, especially in combination with
antibodies that block PD-1, such as cemiplimab. See Section 3.2.1.5. for
rationale of selection of cemiplimab.
Early clinical data indicate that melanoma patients who received previous
anti-PD-1 therapy but progressed can respond to concurrent blockade of LAG-3
and PD 1 (Ascierto, 2017). Ex vivo analyses, in studies in patients with
metastatic melanoma, provide impetus to study the hypothesis that therapeutic
blockade of both LAG-3 and PD-1 may lead to enhanced T-cell function and
clinically meaningful responses compared to PD-1 monotherapy (Section 1.1.4).
The ongoing FIH study, R3767-ONC-1613, included a cohort of patients with
advanced melanoma who were naïve to PD-(L)1 inhibition therapy. In these
patients, the response rate to combination cemiplimab and fianlimab therapy is
approximately 66% (22/33 patients; (Hamid, 2021), comparing favorably to
landmark PD-1 inhibition response rates of approximately 26-45% (with caveats
of small patient numbers in study 1613, follow-up time differences,
investigator assessed vs central review, etc) (Topalian, 2014) (Robert, 2015a)
(Robert, 2015b), (Carlino, 2018) (Larkin, 2019).
The safety of the fianlimab (1600mg) in combination with cemiplimab (350mg) has
been shown in FIH study 1613 and the current version of the Investigator*s
Brochure. The overall safety profile of the fianlimab + cemiplimab combination
is generally similar to that observed with cemiplimab monotherapy and other
anti-PD-1 antibodies. Adrenal insufficiency was reported at a higher rate in
patients treated with the finalimab+cemiplimab combination than those treated
with cemiplimab monotherapy, these events were mostly low grade and all
manageable with corticosteroids. The rate of adrenal insufficiency that has
been observed is similar to that reported with anti-CTLA-4 + anti-PD-1
treatment (8.9% fianlimab + cemiplimab vs 8% ipilimumab + nivolumab, vs 0.5%
cemiplimab monotherapy) (see fianlimab IBv5, nivolumab USPI, and cemiplimab
IBv7 respectively), and within the same range as reported for relatlimab +
nivolumab 4.2%-13% [reported rates vary depending on the study: 4.2% (a
randomized phase 3 study of the combination relatlimab + nivolumab vs
nivolumab, (Lipson, 2021)) and 13% (a single arm neo-adjuvant/adjuvant study of
the combination, (Amaria, 2021))]. Other endocrinopathies and immune-related
adverse events have been observed to occur at similar rates compared to
anti-PD-1 monotherapy. As summarized in the current Investigator Brochure, the
important identified risks of the fianlimab combination with cemiplimab include
IRR and irAEs, and these risks were well managed with the risk minimization
strategy implemented in the study.
While no adolescent patients were enrolled in phase 1 study R3767-ONC-1613, the
safety profile in the adolescent patient population is anticipated to be
comparable to that seen in adults (Section 6.1.1). In addition, to further
minimize the potential for unexpected safety risks of fianlimab in combination
with cemiplimab in adolescent patients, a 6-patient safety lead-in is included
in this phase 3 study (Section 6.1, Adolescents). Subsequent adolescent
patients will be randomized to Arms A, B, or C. Despite the small numbers of
adolescent patients affected with melanoma, these patients are often diagnosed
with melanoma which display a genomic profile similar to that seen in adults,
indicating that therapies for adult patients could also be efficacious in the
adolescent patient population. Including adolescent patients in the phase 3
study will provide clinical evidence on the safety, PK and efficacy to assess
the benefit-risk of the combination of fianlimab + cemiplimab in adolescents
with melanoma.
Thus, taking into account the risk minimization measures outlined in this phase
3 protocol to minimize important risks to patients, the potential for
therapeutic benefit and medical need for new combination therapy, the
risk-benefit profile is anticipated to be positive for coadministration of
fianlimab, anti-LAG-3 antibody, with cemiplimab, anti-PD-1, in the phase 3
study, in the population of patients with previously untreated, unresectable
locally advanced or metastatic melanoma.

3.3.2. Risk Benefit for Cemiplimab Monotherapy
Cemiplimab monotherapy serves as a comparator (Arm C) in this study to assess
the contribution of cemiplimab to the proposed combination. See Section
3.2.1.5. for rationale of selection of cemiplimab.
LIBTAYO® has been approved by Health Authorities for the treatment of patients
with locally advanced/metastatic CSCC, BCC and NSCLC in TPS PD-L1 >=50%. The
similar weight-based Q2W dose (3 mg/kg) has shown preliminary clinical evidence
of monotherapy cemiplimab on efficacy with similar safety profile in patients
with melanoma enrolled in Study R2810-ONC-1606.
In this study, cemiplimab will be administered at the approved dose (350 mg
Q3W) in patients with previously untreated, unresectable locally advanced or
metastatic melanoma, and the risk-benefit is considered to be favorable given
the risk minimization outlined in the study protocol to manage the important
risks known for cemiplimab.

3.3.3. Risk Benefit for the Active Comparator, Pembrolizumab
Pembrolizumab serves as the active comparator (Arm B) for this study.
Pembrolizumab is approved, using the dose regimen, in the US and EU for the
treatment of adult patients with unresectable or metastatic melanoma (Keytruda
[Summary of Product Characteristics], 2021) (Pembrolizumab [Package Insert],
2021). See Section 3.2.1.5 for information on the rationale for inclusion of
pembrolizumab.