A Randomized, Double-Blind, Multicenter, Phase 2 Study of Retifanlimab in Combination With INCAGN02385 (Anti-LAG-3) and INCAGN02390 (Anti-TIM-3) as First-Line Treatment in Participants With PD-L1-Positive (CPS >= 1) Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck

According to GLOBOCAN epidemiological estimates of incidence and mortality of
cancer worldwide, in 2018, there were approximately 835,000 new cases of cancer
arising from the lips, oral cavity, oropharynx, hypopharynx, and larynx, the
primary tumor sites that generally comprise SCCHN, with the number of deaths in
the same year being approximately 431,000. A large percentage of patients with
SCCHN primarily present with locally advanced, stage III/IV disease that is
initially treated with multimodal therapy including systemic treatment,
radiation, and/or surgery. Patients who progress after initial definitive
therapy require subsequent treatment for R/M disease; patients who initially
present with metastatic disease generally receive the same therapy as those
with recurrent disease after definitive treatment.
For patients with recurrent unresectable or metastatic SCCHN, platinum-based
chemotherapy has been the standard first-line treatment for the last decade,
conferring a median OS of around 10 months. In 2016, the PD-1 inhibitors
nivolumab and pembrolizumab were approved by the FDA as second-line treatment
for patients who had progressed after platinum-based therapy following positive
data demonstrating improved OS of nivolumab/pembrolizumab over investigator's
choice systemic therapy in this population. In 2019, based on the results of
the KEYNOTE-048 study, the approval of pembrolizumab as first-line therapy has
changed the treatment paradigm for patients with R/M SCCHN. Pembrolizumab as
monotherapy in patients with PD-L1-positive (CPS-1) tumors, or in combination
with chemotherapy irrespective of PD-L1 status, demonstrated superior OS over
the EXTREME regimen.
For patients with R/M SCCHN who have progressed on anti-PD-1 therapy, there are
limited therapeutic options. Those who progressed on or after PD-1 plus
chemotherapy may be treated with single-agent chemotherapy, cetixumab, or other
experimental therapies. Those whose disease progresses on PD-1 monotherapy may
be eligible for treatment with platinum-based chemotherapy regimens or
single-agent platinum chemotherapy, other single-agent chemotherapies,
cetuximab, or other experimental treatments.
While antibodies directed towards the PD-(L)1 axis have revolutionized the
treatment of cancer, the majority of patients either do not respond or lose
response to these drugs. The mechanisms for failure of anti-PD-1 therapy are
poorly understood, but in some cases are likely due to existence of additional
checkpoint pathways that either abrogate a response when present or cause loss
of response when induced. This study aims to evaluate the clinical and
biological effects of blocking additional key checkpoint pathways, LAG-3 and
TIM-3, which have been implicated in the lack of/loss of response to PD-1
inhibitors.
Retifanlimab is a humanized, hinge-stabilized, IgG4* monoclonal antibody that
recognizes human PD-1. Retifanlimab contains a human IgG4 Fc domain to limit
effector function while retaining neonatal Fc receptor binding to extend
circulating half-life. Retifanlimab is designed to target PD-1-expressing
cells, including T cells, and sustain/restore their effector function by
blocking checkpoint inhibitory interactions between PD-1 and its 2 ligands,
PD-L1 and PD-L2.
INCAGN02385 is an Fc-modified IgG1* monoclonal antibody that binds to human
LAG-3 with an estimated affinity (KD) of 1.7 nM and was chosen for clinical
development based on its selectivity for human LAG-3 with no cross-reactivity
to related IgSF proteins. INCAGN02385 functions as a potent LAG-3 antagonist
antibody via its ability to inhibit LAG-3 binding to MHC class II, leading to
enhanced TCR signaling.
INCAGN02390 is a recombinant, aglycosylated fully human IgG1* monoclonal
antibody that binds to the ECD of the TIM-3 receptor. Antagonist TIM-3
antibodies have demonstrated enhanced antitumor activity in several mouse tumor
models when combined with blockade of the PD-(L)1 pathway.
This is a randomized, Phase 2 study to evaluate the efficacy and safety of the
combination of retifanlimab and INCAGN02385 and the triplet combination of
retifanlimab, INCAGN02385, and INCAGN02390 compared with retifanlimab alone in
participants with systemic therapy-naive, metastatic or with unresectable,
recurrent SCCHN whose tumors express PD-L1.

To determine the efficacy of the combinations of retifanlimab + INCAGN02385
(TG2) and retifanlimab + INCAGN02385 + INCAGN02390 (TG3) compared with
retifanlimab alone (TG1) in the overall study population.

Randomized, double-blind, multicenter study evaluating the efficacy and safety
of TG2 (retifanlimab + INCAGN02385) and TG3 (retifanlimab + INCAGN02385 +
INCAGN02390) compared with TG1 (retifanlimab alone)

This is a randomized, double-blind, Phase 2 study to evaluate the efficacy and
safety of the combination of retifanlimab plus INCAGN02385(TG2) and
retifanlimab plus INCAGN02385 and INCAGN02390 (TG3) compared with retifanlimab
alone as first-line treatment in participants with PD-L1-positive and systemic
therapy-naive R/M SCCHN.
Study treatment will begin on Day 1. Randomized participants will continue
study treatment in 4-week cycles for up to 2 years or until discontinuation
criteria are met. The duration for enrollment is expected to be approximately
12 months.
After 30 participants have been randomized and have received treatment for at
least 4 weeks (at least 2 doses), an interim analysis of safety will be
performed by an independent external DSMB.

- Treatment group 1 (TG1): retifanlimab and placebos for INCAGN02385 and
INCAGN02390
o Retifanlimab will be administered by vein once every 4 weeks.
o Placebo (for INCAGN02385) will be administered by vein once every 2 weeks.
o Placebo (for INCAGN02390) will be administered by vein once every 2 weeks.

- Treatment group 2 (TG2): retifanlimab + INCAGN02385 + Placebo for INCAGN02390
o Retifanlimab will be administered by vein once every 4 weeks.
o INCAGN02385 will be administered by vein once every 2 weeks.
o Placebo (for INCAGN02390) will be administered by vein once every 2 weeks.

- Treatment group 3 (TG3): retifanlimab + INCAGN02385 + INCAGN02390
o Retifanlimab will be administered by vein once every 4 weeks.
o INCAGN02385 will be administered by vein once every 2 weeks.
o INCAGN02390 will be administered by vein at once every 2 weeks.

Subjects will undergo the procedures and procedures indicated in Table 3 -
Table 5 of the study protocol. Subjects have additional blood tests, scans,
biopsies and multiple visits to the hospital. These will be more compared to
regular care.

Possible known side effects are described in the Investigators Brochure and
patient information and can also occur during this study. There is also a risk
that unknown side effects occur and there is a chance that the treatment will
not be efficacious for the patient. Please refer to IB and patient information
on details regarding possible side effects with the study treatments.
Additionally, the study procedures (blood draw, ECG, biopsy, CT/MRI Scan) may
also give discomforts, which are described in patient information.

Patients may benefit from treatment with investigational drugs and their
disease may improve.