Study Explores Anti-PVRIG Therapy Plus Nivolumab and Anti-TIGIT Therapy in Advanced Solid Tumors

The first patient with an advanced solid tumor has been dosed with the first-in-class anti-PVRIG antibody, COM701, in combination with nivolumab (Opdivo) and the anti-TIGIT antibody, BMS-986207, in a phase 1/2 clinical trial (NCT04570839), according to a press release from Compugen Ltd.

"We continue to push forward as leaders in the DNAM axis space and as the only company evaluating a potential synergistic triple blockade of PVRIG, TIGIT, and PD-1 in the clinic," said Anat Cohen-Dayag, PhD, president and chief executive officer, Compugen, in a press release. "We believe that the future of immuno-oncology will be driven by combination therapy and this study examining our three-pathway hypothesis is an important component of our overall strategy and a key differentiator for Compugen in the TIGIT space.

In the open-label trial, the safety, tolerability, and preliminary antitumor activity of COM701 combined with nivolumab and BMS-986207 will be assessed in about 100 patients. The study will first follow a sequential dose-escalation design. Then an expansion cohort will be evaluated after the recommended dose for expansion (RDFE) of COM701 in combination with BMS-986207 and nivolumab is determined.

“The study is designed to evaluate simultaneous blockade of 3 immune checkpoint pathways, PVRIG, TIGIT, and PD-1, and test the hypothesis that blockade of both PVRIG and TIGIT, parallel DNAM pathways, may be required in certain tumor types to generate or enhance an anti-tumor immune response. The initiation of the cohort expansion phase of the study, allowing us to focus with the selected dose for expansion on specific patient populations where we believe the DNAM axis is dominant, is an important step to examine the potential benefit of this unique immunotherapy combination in a broader range of patients,” stated Cohen-Dayag.

During the dose-escalation portion of the study, a maximum of 5 cohorts will receive the escalating dose of COM701 with fixed doses of nivolumab and BMS-986207. At the RDFE, expansion cohort 1 will assess the combination in patients with platinum-resistant/refractory epithelial ovarian cancer, primary peritoneal, or fallopian tube cancer, which will be compared with a nivolumab only group.

Cohorts 2 and 3 are both single arms. In cohort 2, patients with microsatellite stable endometrial cancer will be treated with the combination of COM701, nivolumab, and BMS-986207. Finally, in cohort 3, patients with high PVRL2 tumors will also receive COM701 in combination with nivolumab and BMS-986207. In all study arms, treatment will be administered by intravenous infusion every 4 weeks.

Multiple primary end points are to be investigated during the study including, the proportion of patients with adverse events (AEs), the number of patients who experience AEs in the 1st cycle during dose escalation within the dose limiting toxicity window, the RDFE of the combination, and the area under the curve of COM701 in subjects receiving the 3-drug combination.

The secondary end point of the study is the objective response rate per RECIST v 1.1 in patients treated in cohorts 1 through 3.

Per the general inclusion criteria, patients may be enrolled in the study if they have histologically or cytologically confirmed locally advanced or metastatic solid malignancy and have either exhausted standard therapy options or are not eligible to receive standard therapy. Patients are also required to have an ECOG performance status of 0-1. For inclusion in the expansion cohort, patients are required to have a diagnosis of advanced epithelial ovarian, fallopian tube, or primary peritoneal carcinoma for cohort 1, endometrial cancer for cohort 2, and a tumor with high expression of PVRL2 for cohort 3.

Inclusion in the expansion cohorts also calls for MSS disease proven by genetic testing or an immunohistochemistry test and prior receipt of 2 systemic cytotoxic therapies.

The study excludes patients with advanced solid tumors who have active autoimmune disease requiring systemic treatment, symptomatic interstitial lung disease or inflammatory pneumonitis, history of immune-related events that resulted in immunotherapy treatment discontinuation, and untreated or symptomatic central nervous system metastases. Patients who previously received COM701, another PVRIG inhibitor, or an anti-TIGIT antibody are not eligible to enroll. For cohort 1 of the dose-expansion phase, patients who have received prior therapy with an anti-PD-1/PD-L1/2, COM701, another PVRIG inhibitor, anti-TIGIT antibody, anti-CTLA-4 antibody, anti-OX-40 antibody, or anti-CD137 antibody are not eligible.

Patients are currently being recruiting for the phase 1/2 study of COM701 in combination with BMS-986207 and nivolumab in Illinois, Michigan, Tennessee, and Texas. The estimated primary completion date for the study is August 2022.

“We are on track to report preliminary data from the triple combination dose-escalation arm of the study in the fourth quarter of this year,” Cohen-Dayag said, in the press release.

_Reference:

_{Compugen doses first patient in phase 1/2 triple combination cohort expansion of COM701 with Opdivo® and Bristol Myers Squibb's anti-tigit antibody, BMS-986207. News release. Compugen Ltd. July 19, 2021. Accessed July 27, 2021. https://bit.ly/3BNqbRG}