COM701 With Nivolumab and BMS-986207 Show Preliminary Safety/Tolerability in Advanced Solid Tumors

Ecaterina E Dumbrava, MD

In patients with advanced solid tumors, the investigational combination of COM701 with nivolumab (Opdivo) and BMS-986207 was found to be well-tolerated with a favorable safety profile, according to preliminary results (NCT04570839) presented in a poster during the 2021 Society of Immunotherapy for Cancer (SITC) Annual Meeting.

COM701 is a novel 1st in-class immune checkpoint inhibitor. Its mechanism of action can lead to enhanced activation of T and natural killer (NK) cells. The reasoning behind combining COM701 with the anti-TIGIT therapy, BMS-986207, and the immune checkpoint inhibitor, nivolumab, is to block the DNAM axis, making treatment more tolerable.

A positive result in the final analysis of this trial could serve an unmet medical need for new treatment options for patients who are refractory to or relapse after treatment with an anti-PD-L1 regimen.

Thirteen patients were enrolled for the initial safety analysis. The study follows a 3 + 3 design by which COM701 is dosed at either 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, or 20 mg/kg. COM701 is combined with fixed doses of 480 mg nivolumab and BMS-986207. All therapies in the study are administered intravenously every 4 weeks. All therapies in the study are ongoing for 2 years except in cases of progressive disease (PD), toxicity, withdrawal of consent, according to the investigator’s discretion.

The primary objective of the study is to determine safety and tolerability of the combination, the maximum tolerated dose, and pharmacokinetics. Dose-limiting toxicity was evaluated in the first 28 days in the first cycle of dose escalation. The study is also investigating preliminary antitumor activity per RECIST v1.1 with CT imaging every 8 weeks.

Exploratory end point in the study included the immunogenicity of the immunotherapy triplet, as well as the COM701-mediated pharmacodynamic effect in blood and immune-related changes.

Enrollment in the study is contingent upon patients having histologically confirmed locally advanced or metastatic solid malignancy. Cancers can include platinum-resistant or refractory ovarian cancer, relapsed or refractory endometrial cancer, and head and neck squamous cell carcinoma (HNSCC). Patients must also have exhausted all available treatment options and presents with measurable disease and an ECOG performance status of 0 or 1. Patients with a history of inflammatory pneumonitis or interstitial lung disease history of immune-related toxicities on prior immunotherapy treatment leading to discontinuation were excluded from the study.

In addition to the ovarian, endometrial, and HNSCC cohorts, the study will include a basket cohort of patients with high expression of PVRL2 in their tumors. In the HNSCC cohort, both patients who are naïve to treatment with immunotherapy and those previously treated will be included.

Of those included in the preliminary analysis, 54% were below the age of 65, 46% were female, 54% were male, and the majority (61%) had an ECOG performance status of 1. The tumor types included 2 colorectal, 2 prostate, 2 melanoma, and 2 ovarian/fallopian tube tumors, along with 1 case each of non-small cell lung cancer, pancreatic cancer, esophageal cancer, and gastric cancer.

Results show no dose-limiting toxicities at any dose level, but the maximum tolderated dose has not yet been determined. In terms of preliminary anti-tumor activity, results showed stable disease in 3 patients.

Fatigue was the most frequently observed treatment-emergent adverse event (TEAE), having occurred in 50% of patients. The events of fatigue were grade 2 or lower in 43% and grade 3 in 7%. Serious AEs occurred in 2 or more patients and included 2 cases of grade 3 vomiting, and 2 cases of grade 3 abdominal pain.

Overall, 14% of the study population discontinued treatment. Of those who discontinued at the COM701 dose level of 1 mg/kg 1 patient experienced grade 3 vomiting and there was 1 case of serous grade 3 abdominal pain, but both cases were considered to be unrelated to any study drug. At the 10 mg/kg dose level of COM701, there was 1 case of grade 3 increased aspartate aminotransferase that was possibly caused by study drugs.

In terms of PK, the profiles of COM701 were generally dose proportional. There was an increased level of immune activation with study treatment, according to the peripheral pharmacodynamic analysis.

“The pharmacodynamic changes suggest synergistic immune activation following the triplet blockade as compared to COM701 monotherapy and combination results, as well as published data,” said Ecaterina E Dumbrava, MD, of The University of Texas MD Anderson Cancer Center.

The study is ongoing and recruiting at 7 locations across the United States. According to Dumbrava, “the expansion cohorts are enrolling patients currently with platinum-resistant ovarian cancer, endometrial cancer, and head and neck squamous cell carcinoma.”

_Reference:

_{Dumbrava EG, Sharma M, Fleming GF, et al. COM701 in combination with BMS-986207 (anti-TIGIT antibody) and nivolumab - preliminary results of safety, tolerability and pharmacokinetics in patients with advanced solid tumors (NCT04570839). Presented at SITC Annual Meeting 2021; November 10-14 2021; Washington, DC. Abstract 478.}