Emerging data suggest that
LAG-3
upregulation may be a mechanism of resistance to
PD-1
or
PD-L1
therapy. A key observation is that therapeutic inhibition of the
checkpoint pathway leads to increased expression of
LAG-3,
which, in turn, may prevent responses to
therapy. Both
LAG-3
and
PD-1
become overexpressed on TILs in multiple preclinical tumor models and the combination of
LAG-3
and
PD-1
antibodies have demonstrated improvement of the anti-tumor response in murine models compared to blocking either one alone. The potential therapeutic benefit of the combination of traditional antibodies and bispecific antibodies targeting
PD-1
and
LAG-3
has been investigated in several clinical trials, and preliminary clinical results have indicated activity in
treatment naïve and resistant tumors.
Based on results generated using a combination of two traditional antibodies targeting
PD-1
and
LAG-3,
and the observation that an increase in
LAG-3
expression may contribute to resistance to
PD-1
checkpoint therapy, we believe that a bispecific antibody that targets both
PD-L1
and
LAG-3
simultaneously, such as FS118, has broad potential as an immuno-oncology therapeutic. Simultaneous targeting of
LAG-3
and
PD-L1
with a bispecific antibody not only releases the brakes of two immunosuppressive pathways, but it may also have advantages over a combination of traditional antibodies by focusing these effects at
PD-L1
positive sites in the tumor or by crosslinking between immune cells in the tumor microenvironment. Recently,
LAG-3
shedding was found to correlate with responsiveness to
PD-1
therapy in murine tumors and in the clinic high levels of
LAG-3
and low levels of
ADAM-10
correlated with a poor outcome of
PD-1
treatment. Therefore, increased shedding of
LAG-3
from the surface of the T cell, due to tetravalent bispecific-binding to
LAG-3
and
PD-L1,
may result in lower
LAG-3
levels in the tumor and potentially prevents one of the mechanisms of acquired resistance to
therapies.
Resistance to
regimens can come in two main forms. “Primary resistance” is where the cancer shows no sensitivity to treatment and continues to grow. “Acquired resistance” to
regimens, sometimes referred to as secondary resistance, is where there is initial sustained (greater than or equal to three months) clinical benefit (defined as a complete response, partial response, or stable disease) from therapy but the cancer then starts to grow again while the patient is still being treated. Our analysis of preliminary clinical data from the
study of FS118 indicates that FS118 may have greater clinical activity in patients with acquired resistance compared to primary resistance. While we have not assessed this, we also believe that FS118 will have clinical activity in cancer patients who have not previously been exposed to
therapy.
Tumor types with immuno-suppression or T cell exhaustion may
co-express
LAG-3
and
PD-L1
and could benefit from treatment with our dual checkpoint inhibitor product candidate, FS118. Examples of such tumors include head and neck, soft-tissue sarcoma, mesothelioma, ovarian, gastric cancer, anaplastic thyroid cancer and small cell lung cancer. Globally, this cancer population represents over 2.5 million new diagnoses annually. Our focus will be on patients with cancers whose tumors
co-express
LAG-3
and
PD-L1
and who have developed acquired resistance to
therapy or who have not yet received it.
Squamous cell carcinoma of the head and neck, otherwise known as head and neck cancer, includes cancers of the mouth (oral cavity, oral cancers, tongue) and throat (oropharynx and tonsils, nasopharynx and hypopharynx), as well as rarer cancers of the nasal cavity, sinuses, salivary glands and the middle ear. According to GLOBOCAN, in 2020 approximately 900,000 new head and neck cancer were estimated to have been diagnosed worldwide. Treatment of patients with advanced head and neck cancer consists of
PD-1
therapy alone or in combination with chemotherapy in the first-line, in the metastatic setting. Approximately
one-third
of these patients develop Acquired Resistance to
PD-1
therapy and, therefore, we plan to develop FS118 as a sequential treatment for these patients, either alone or in combination with standard of care therapies.
Malignant pleural mesothelioma (“MPM”) is a rare but aggressive cancer usually caused by asbestos exposure. According to GLOBOCAN, in 2020,
it estimates up to approximately 25,000 new patients were diagnosed with MPM. For patients ineligible for surgery, which represents the large majority of this patient population, the first-line treatment consists of chemotherapy. Recently, published data from a randomized