COM701, a novel, first-in-class immune checkpoint inhibitor, was found to demonstrate encouraging preliminary antitumor activity and good tolerability when used as either a monotherapy and in combination with nivolumab in a number of heavily pretreated patients with advanced or metastatic solid tumors, according to data from a phase 1 trial.
Ryan J. Sullivan, MD
COM701, a novel, first-in-class immune checkpoint inhibitor, was found to demonstrate encouraging preliminary antitumor activity and good tolerability when used as either a monotherapy and in combination with nivolumab (Opdivo) in a number of heavily pretreated patients with advanced or metastatic solid tumors, according to data from a phase 1 trial (NCT03667716) presented during the 2020 AACR Virtual Annual Meeting.1
Results showed that the inhibitor resulted in 2 confirmed partial responses (PRs). One of these responses occurred in a patient with primary peritoneal cancer who was receiving COM701 as a monotherapy given at 20 mg/kg intravenously every 4 weeks. The second PR occurred in a patient with microsatellite stable colorectal cancer who received COM701 at 0.3 mg/kg intravenously every 3 weeks plus nivolumab at 480 mg intravenously every 3 weeks.
Additionally, the disease control rate with single-agent COM701 was 69% (n = 11/16) and 75% with the combination (n = 9/12) across a variety of tumor types. Durable stable disease of ≥6 months was achieved in 6 of 28 patients, 2 of whom were on the single-agent arm and 4 were on the combination arm.
“Remarkable advances in tumor immunotherapy have been made over the past several years; however, a number of unmet needs remain,” said Ryan Sullivan, MD, an assistant professor of medicine at Harvard Medical School and Massachusetts General Hospital Cancer Center, in a virtual presentation during the meeting. “Particularly, finding better therapies for patients who are primarily refractory to, develop resistance on, or relapse following immune checkpoint inhibitors, is going to be critical.”
In preclinical models, inhibition of cell service receptors, such as PVRIG, has been shown to result in enhanced activation of T cells and natural killer (NK) cells as well as tumor growth inhibition.2 “COM701 is a novel monoclonal antibody against PVRIG,” said Sullivan. “We have previously shown preliminary safety and antitumor activity of COM701 monotherapy. Today, we update that monotherapy cohort data and report on preliminary safety and antitumor activity of the agent in combination with nivolumab.”
The phase 1 trial is broken into 2 parts. In arm A, investigators are evaluating monotherapy dose escalation in all-comers who progressed on standard-of-care (SOC) therapy, followed by a monotherapy cohort expansion of 20 patients who progressed on SOC and have either non—small cell lung cancer (NSCLC), ovarian cancer, breast cancer, endometrial cancer, or colorectal cancer (CRC). In arm B, investigators are examining escalating doses of COM701 with a fixed dose of nivolumab in up to 20 all-comers who progressed on SOC.
The objectives of the study are to analyze the safety and tolerability, describe the pharmacokinetics and pharmacodynamics, and report on the preliminary clinical activity of COM701 as a monotherapy and in combination with nivolumab.
With regard to the dose-escalation schema, investigators initially enrolled to single-patient dose cohorts for the first 4 dose levels. They then enrolled 3 patients each at 1 mg/kg, 3 mg/kg, 10 mg/kg, and 20 mg/kg dose levels for single-agent therapy.
“Once we cleared the 1-mg dose level, as monotherapy, we then opened the 0.3 mg/kg dose level in combination with nivolumab,” explained Sullivan. “In between the 10-mg to 20-mg dose level monotherapy and 3 mg- to 10 mg-dose level combination therapy, we modified the dosing schedule from every 3 weeks to every 4 weeks, based on pharmacokinetic data.”
A total of 28 patients were evaluable for the analysis; 16 of these patients were on arm A and 12 patients were on arm B of the trial. Nine of the patients on arm A and 9 of those on arm B were female. Thirteen patients were age ≤65 years in arm A versus 7 patients in arm B. The median number of prior therapies received across both arms was 5.
Notably, patients with many different cancers were enrolled on the trial. In arm A, 6 patients had CRC, 2 had pancreatic ductal adenocarcinoma, and 2 had ovarian/primary peritoneal serous carcinoma. Other cancers included NSCLC, adenoid cystic carcinoma, melanoma, mesothelioma, carcinoma of unknown primary treatment, and gallbladder carcinoma (n = 1 each). In arm B, tumor types included endometrial cancer (n =3), CRC (n = 2), NSCLC (n = 2), lung neuroendocrine tumor (n = 1), anal squamous cell carcinoma (n = 1), renal cell carcinoma (n = 1), mesothelioma (n = 1), and cervical cancer (n = 1).
To date, 2 patients on arm A and 6 patients on arm B remain on therapy, according to Sullivan. “Three patients on arm A and 3 on arm B were treated with the intravenous every-4-week dosing schedule and two-thirds of those patients remain on therapy in each arm,” he said. “The majority of patients who discontinued therapy did so because of disease progression either defined radiographically or clinically.”
With regard to safety, the majority of patients experienced at least 1 grade 1/2 toxicity (56% in arm A vs 54% in arm B). Five total patients in arm A experienced adverse events (AEs) that led to treatment discontinuation. One patient with pancreatic cancer experienced grade 5 cardiac arrest; another with pancreatic cancer presented with grade 3 vomiting; a patient with CRC experienced grade 3 pulmonary embolism and worsening ascites; another with CRC reported grade 3 worsening atrial fibrillation; and 1 patient with gallbladder carcinoma experienced grade 1 urinary retention, grade 2 blood bilirubin increase, and grade 3 diarrhea. Notably, however, all of these events were determined to be related to the disease rather than the study treatment per investigator assessment.
With regard to incidence of treatment-emergent AEs (TEAEs) in ≥3 patients in the monotherapy cohort (n = 18), 56% were grade 1/2 in severity and 39% were grade 3, 4, or 5. The most common, all-grade TEAE was fatigue (39%), followed by nausea (28%) and anxiety (22%). Incidence of TEAEs in ≥3 patients in the combination therapy cohort (n = 13) proved to be similar, with 54% of TEAEs being grade 1/2 in severity and 46% being grade 3, 4, or 5. Again, fatigue was most commonly reported (39%, all grades).
The incidence of serious TEAEs in all patients on the monotherapy arm was 39%, all grades, with ascites being the most commonly reported (11%, grades 3, 4, or 5). Notably, all serious TEAEs were determined to be related to the underlying disease per investigator assessment.
“However, pulmonary embolism, which occurred in 1 patient and was determined to be grade 3, was also felt to potentially be related to the study drug,” noted Sullivan.
Again, the data proved to be similar in the combination arm, as well. A total of 5 serious TEAEs were reported in this cohort and all 5 toxicities were believed to be related to the underlying disease; all were determined to be unrelated to the study treatment, according to Sullivan.
Additionally, the preliminary pharmacokinetic profiles in arm A and arm B indicated that COM701 “exhibits typical targeted mediated drug disposition, has greater clearance at lower doses where presumably target saturation is not yet achieved, and longer clearance at higher doses,” said Sullivan. At doses of greater than 1 mg/kg, COM701 is dose proportional. These data support the every-4-week dosing schedule, said Sullivan.
Based on promising preclinical data and the data from the study, a phase 1/2 trial is in development, and it will examine a triple combination approach that will target PVRIG, PD-1, and TIGIT with COM701, nivolumab, and an anti-TIGIT monoclonal antibody called N86207.
“In the near future, we plan on opening the COM701 monotherapy dose expansions in these diseases,” concluded Sullivan.