A Phase 2 Randomized Study of Relatlimab plus Nivolumab in
Combination with Chemotherapy vs. Nivolumab in Combination with Chemotherapy as First Line Treatment for Participants with Stage IV or Recurrent Non-small Cell Lung Cancer (NSCLC)

NSCLC remains the leading cause of cancer-related mortality worldwide,
accounting for approximately 18% of all cancer deaths.Until recently, the
treatment of participants with advanced NSCLC whose tumors did not have a
targetable genetic alteration was cytotoxic chemotherapy alone. In spite of
treatment, participants with metastatic NSCLC treated with PDCT had a median
survival of approximately 10 months and a 5-year survival rate of less than 5%.

Nivolumab, relatlimab, and platinum doublet chemotherapy (PDCT) each have
non-overlapping
anti-cancer mechanisms and may have synergistic and/or additive activity as
combination therapy, with few overlapping toxicities. Lymphocyte-activation
gene 3 (LAG-3) is often expressed on chronically exhausted T-cells and is
frequently co-expressed with programmed death-ligand 1
(PD-L1) on tolerized tumor-infiltrating lymphocytes (TILs) across tumor types.
The rationale for combining a LAG-3 inhibitor and an anti-programmed cell death
protein 1 (PD-1)/PD-L1 agent originates from evidence suggesting that LAG-3 has
a potential role in T-regulatory cells
suppression and anti-PD-1 resistance. The current standard of care,
anti-PD-(L)1 (± anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]
antibody) in combination with PDCT has demonstrated significant improvement in
overall survival (OS) as well as progression-free survival
(PFS) in participants with previously untreated metastatic non-small cell lung
cancer (NSCLC).
There are several candidate biomarkers which may select participants who will
benefit from the addition of relatlimab to nivolumab plus chemotherapy.
Multiple clinical trials have established the correlation between PD-L1
expression and increased response to PD-1 and PD-L1 immune
checkpoint inhibition. Data from CA224020 demonstrated preliminary evidence
that participants with LAG-3 expression are more likely to respond to treatment
with relatlimab in combination with nivolumab. Recently, fibrinogen-like
protein 1 (FGL-1) was identified as a new ligand for
LAG-3 that is responsible for its T-cell inhibitory function and potentially a
new mechanism for immuno-evasion. Therefore, FGL-1 may be a novel biomarker to
predict outcomes of anti-PD-1 and anti-LAG-3 tumor therapies.
The benefit of the relatlimab plus nivolumab combination continues to be
explored in several types of metastatic malignancies. The combination therapy
of relatlimab plus nivolumab has had an acceptable safety profile at all dose
levels tested up to 1440 mg of relatlimab plus 480 mg of
nivolumab given every 4 weeks with no maximum tolerated dose reached. The
combination of nivolumab 360 mg every 3 weeks (Q3W) plus relatlimab 720 mg or
360 mg Q3W and 4 cycles of PDCT is expected to have a synergistic effect in the
first line (1L) NSCLC population based on
the clinical activity shown by the 2 individual combinations (nivolumab plus
relatlimab and nivolumab plus PDCT) and their distinct but complementary
mechanisms of action.


The aim of this randomized Phase 2 study is to confirm the safety profile of
nivolumab plus relatlimab in combination with PDCT and to determine if
nivolumab plus relatlimab in combination with PDCT improves ORR when compared
to nivolumab plus PDCT in participants with previously untreated Stage IV or
recurrent NSCLC.

This study has been transitioned to CTIS with ID 2023-508372-10-00 check the CTIS register for the current data.

Part 1: dose safety confirmation

Primary:
To evaluate the proportion of participants with TRAEs leading to
discontinuation within 12 weeks after the first dose of nivolumab plus
2 different dose levels of relatlimab (360 mg and 720 mg) in combination with
PDCT in dose safety evaluable participants with histologically confirmed 1L
Stage IV or recurrent NSCLC

Secondary:
To evaluate the safety and tolerability of nivolumab plus 2 different doses of
relatlimab (360 mg and 720 mg) in combination with PDCT in all participants
with histologically confirmed 1L Stage IV or recurrent NSCLC that were treated
during the dose safety confirmation period

Part 2:

Primary:
To evaluate ORR nivolumab plus relatlimab in combination with PDCT relative to
nivolumab in combination with PDCT in participants with histologically
confirmed 1L Stage IV or recurrent NSCLC

Secondary:
- To evaluate the PFS of nivolumab plus relatlimab in combination with PDCT
relative to nivolumab in combination with PDCT in participants with
histologically confirmed 1L Stage IV or recurrent NSCLC.
- To evaluate the duration of response (DoR) of nivolumab plusrelatlimab in
combination with PDCT relative to nivolumab in combination with PDCT in
participants with histologically confirmed 1L Stage IV or recurrent NSCLC
-To evaluate ORR and PFS of nivolumab plus relatlimab in combination with PDCT
relative to nivolumab in
combination with PDCT in participants with histologically confirmed 1L Stage IV
or recurrent NSCLC, in subgroups defined by PD-L1 expression, LAG-3 expression,
FG-L1 expression
- To evaluate the safety and tolerability of nivolumab plus relatlimab in
combination with PDCT in histologically confirmed 1L Stage IV or recurrent
NSCLC.

This multi-center, randomized trial will evaluate the efficacy and safety of
the combination of nivolumab plus relatlimab and PDCT vs nivolumab and PDCT in
adults with untreated Stage IV or recurrent NSCLC. The study will be carried
out in 2 parts: Part 1, a site-and-subject blind dose
safety confirmation and Part 2, a open-label randomized, controlled trial.

Part 1 - Dose safety confirmation (n * up to 120): Site-and-subject blinded,
randomized dose safety confirmation. Eligible participants will be randomized
1:1 to Arms A or B to evaluate the safety and tolerability of the combination
of nivolumab plus relatlimab 720 mg and PDCT and confirm the safety profile.
The relatlimab 360 mg Q3W dose in Arm B will be evaluated to generate
additional safety data at this dose level. The randomization will be stratified
by histology (SQ vs NSQ). After all treated participants have been followed-up
for a minimum of 12 weeks, an analysis will take place to determine whether
the established threshold for the dose-safety evaluable population has been met
and to evaluate the totality of the Part 1 safety data. In addition, the
proportion of treatment-related adverse events (TRAEs) leading to
discontinuation within
12 weeks of the first dose will be monitored for each arm separately using
Bayesian continuous monitoring plan.

Part 2 (n = 300): Randomized,open-label controlled trial that will further
evaluate the efficacy and safety of the nivolumab, relatlimab plus chemotherapy
combination vs nivolumab plus chemotherapy. Only after the safety of nivolumab
plus relatlimab and PDCT has been evaluated
in Part 1 of the study can enrollment begin in Part 2 of the study, with the
selected Phase 2 dose of relatlimab in combination with nivolumab + PDCT. At
this time, participants that are in screening and found to be eligible will be
randomized 1:1 into experimental Arm C or control Arm D of Part 2 of the trial.
Enrollment will end when approximately 300 participants have been randomized.
The primary analysis for ORR is planned to occur approximately 5 months after
the last patient is randomized. The final analysis for PFS will occur when
approximately 235 events have occurred.The stratification factors for
randomization in Part 2 are histology (SQ vs NSQ), and ECOG performance status
(0 vs 1) and PD-L1 level (>= 1% [including NQ] vs < 1%).

The Part 1 dose safety confirmation period is 12 weeks after the first dose. Up
to approximately 120 eligible participants to enroll in the study will be
randomized 1:1 to experimental Arms A or B. Nivolumab plus relatlimab, the
immune checkpoint inhibitors hereon referred to as
immunotherapy, will be administered in a site-and-subject blinded manner,
whereas chemotherapy will be administered as open label.

Arm A: Nivolumab 360 mg Q3W + relatlimab 720 mg Q3W + 4 cycles of
histology-based PDCT
Arm B: Nivolumab 360 mg Q3W + relatlimab 360 mg Q3W + 4 cycles of
histology-based PDCT

During the treatment phase of Part 2 of the study, participants will receive
the following treatments. Immunotherapy will be administered in a
double-blinded manner whereas chemotherapy will be administered as open label:

Arm C: Nivolumab 360 mg Q3W + relatlimab 720 mg (or 360 mg(a)) Q3W + 4 cycles
of histology based PDCT(b) or

Arm D: Nivolumab 360 mg Q3W + placebo Q3W + 4 cycles of histology-based PDCT

(a) The relatlimab dose to be included in Arm C will be determined by the
outcome of the dose safety confirmation that will take place in Part 1 of the
study.
(b) Histology-based PDCT will be as follows:
- NSQ: Carboplatin area under the concentration-time curve (AUC) 5 or 6 or
cisplatin 75 mg/m2 + pemetrexed 500 mg/m2 (maintenance permitted)
- SQ: Carboplatin AUC 6 + paclitaxel 200 mg/m2 or nab-paclitaxel 100 mg/m2

Dose reductions are not permitted for immunotherapy.
All participants will be treated until progression, presence of intolerable
toxicities, withdrawal of consent, or study end, whichever comes first.
Continuous safety evaluations and tumor assessments will guide the decision to
treat a participant with additional cycles of study therapy if
the participant has confirmed clinical benefit.

Participants will be allowed to continue study treatment until the first
occurrence of any of the
following situations:
* Progressive disease defined by RECIST v1.1 unless participants meet criteria
for treatment
beyond progression.
* Clinical deterioration suggesting that no further benefit from treatment is
likely.
* Intolerability to therapy.
* Participant meets criteria for discontinuation of study treatment.

For full details, see the study schedules on pages 17-24 of the study protocol.

* Participation in this study will last approximately 33 months and include
approximately 16 visits to the study site ( based on 12 cycles of treatment)

The study visits will take approximately 2-6 hours on average each

* During the screening, the patient is presented with an informed consent form.
This is reviewed and if the patient wishes to take part it is
signed by the patient. Medical history of the patient is reviewed with the
patient.
* In the study participants will get physical examinations including
temperature, blood pressure, heart rate, respiratory rate and oxygen in blood
and measurement of height and body weight.
* Blood and urine tests will be performed. Drawing blood may be painful or
cause some bruising.
* Subjects will be tested for hepatitis and HIV
* ECGs will be done and CT/ MRI scans and echocardiogram
* Women of childbearing potential will have a pregnancy test done.
* A sample of a previously taken tumor biopsy will be obtained if possible at
screening or an optional fresh biopsy may be taken.Also optinal tumor biopsies
during treatment can be done. Risks of tumor biopsy include pain, small chance
of bruising. The biopsy procedure is usually performed while under local
anesthesia.
* The patient will be questioned during visits regarding (adverse events) side
effects and the medication use.
* participants will be asked to complete questionnaires
* participants will receive an unregistered drugs and additional chemo that
will have potential side effects

Possible side effects of the study drug that are already known are described in
the Patient Information and Investigator's Brochure.