December 13, 2021
Monza (Italy) – Rottapharm Biotech announces dosing the first patient in the Phase 1/2 study of CR6086 in combination with Agenus’ balstilimab (anti-PD-1) in advanced colorectal cancer at the National Cancer Institute (Istituto Nazionale dei Tumori) – Milan (Italy).
Patients with colorectal cancers have limited treatment options, as most do not respond to PD-1 therapy or other immunotherapy regimens studied to date. Colorectal cancers represent one of the three most common cancers diagnosed, and the second leading cause of deaths across all cancer types globally. More than 80% of colorectal cancers are classified as mismatch repair-proficient (pMMR) and microsatellite stable (MSS) colorectal cancer (CRC), which correlates with low tumor mutation burden and poor immune cell infiltration within the tumor microenvironment (“cold tumors”). These patients generally do not benefit from PD-1 therapy alone and combination strategies with other immune-modulating therapies are necessary to address immune suppression in the tumor microenvironment and improve sensitivity to PD-1 therapy.
The involvement of prostaglandin E2 (PGE2) in cancerogenesis has been known for decades. There is now growing evidence about the role of PGE2, via its EP4 receptor on different immune cells, as a key effector for the impaired immune response within the tumor microenvironment and the potential for an EP4 receptor antagonist to turn the tumor microenvironment into an immune-responsive (“hot”) tissue.
Rottapharm Biotech is developing CR6086, a potent and selective small molecule antagonist of EP4. EP4 signaling broadly suppresses immune activity in the tumor microenvironment, contributing to treatment resistance and tumor progression. CR6086 is designed to increase the activity and infiltration of several different immune cell types – including T cells, natural killer cells, and dendritic cells – while blocking the immune suppressive role of PGE2 in the tumor microenvironment. Preclinical evidence suggests that CR6086 may work in combination with PD-1 therapy to promote durable, anti-tumor immune responses. CR6086 is a potential best-in-class EP4 receptor antagonist, based on its pharmacokinetics and pharmacodynamic profile, and has demonstrated a strong safety profile in >250 subjects treated to date.
Balstilimab is a monoclonal antibody developed by Agenus Inc., belonging to the immune checkpoint inhibitor class, and is an inhibitor of programmed cell death 1 (PD-1) protein. It has been evaluated in >400 patients to date and has demonstrated strong clinical activity and an excellent safety profile in several tumor types, including cervical cancer (results published in Gynecologic Oncology this year).
The Phase 1/2 clinical study aims at evaluating the safety and efficacy of CR6086 combined with balstilimab in patients with advanced pMMR/MSS metastatic CRC (mCRC). The primary endpoints are safety, tolerability, and preliminary efficacy, as determined by disease control rate. The secondary endpoints include objective response rate, duration of response, progression-free survival, and overall survival.
Rottapharm Biotech’s clinical collaboration with Agenus offers a promising new combination therapy for patients with advanced pMMR/MSS mCRC where there is a high unmet need, and for a further range of potential applications in other immunotherapy-resistant tumors.