1. Nalley, Catlin

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COM701, a novel first-in-class immune checkpoint inhibitor, is well-tolerated alone and in combination with nivolumab among a variety of heavily pretreated patients with advanced or metastatic solid tumors, according to findings presented at the AACR 2020 Virtual Annual Meeting (Abstract CT031).


"Immune checkpoint inhibitors have been a remarkable advance in anti-cancer treatment in the past several years," noted study author Ecaterina Dumbrava, MD, Assistant Professor, Department of Investigational Cancer Therapeutics, MD Anderson Cancer Center. "However, the vast majority of patients still do not respond to immune checkpoint inhibitors, and even those that do eventually relapse."


"A number of unmet needs remain-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," emphasized study author Ryan Sullivan, MD, Assistant Professor, Medicine, Harvard Medical School, during his presentation.


"COM701 is a novel monoclonal antibody against PVRIG and we've previously shown preliminary safety and anti-tumor activity of COM701 monotherapy," he continued. "Today, we update this monotherapy cohort data and report on preliminary safety and anti-tumor activity of [this agent] in combination with nivolumab."


Methods & Findings

Researchers enrolled 28 patients with a variety of cancers in phase I of COM701. Eligible patients included those with performance status ECOG 0-1 and advanced or metastatic solid tumors who failed standard-of-care treatment. Prior immune checkpoint inhibitors were allowed.


The key objectives of the study include analysis of safety and tolerability, pharmacokinetics and pharmacodynamics, and the preliminary clinical activity of COM701 monotherapy as well as in combination with nivolumab.


"In Arm A (n=16), patients received COM701 monotherapy 0.01, 0.03, 0.1, 0.3, 1, 3, 10 mg/kg (all IV q3 weeks) and 20 mg/kg (IV q4 weeks)," according to the study authors. "In Arm B (n=12), patients received COM701 at 0.3, 1, or 3 mg/kg plus nivolumab 360 mg IV q3 weeks (three patients/dose cohort) and three patients received 10 mg/kg plus nivolumab 480 mg IV q4 weeks."


Eighteen of the 28 patients were female. In Arm A, 13 were 65 years or younger compared to seven in Arm B. The median number of prior therapies was six among patients in Arm A and four in Arm B. Patients with many different types of tumors were enrolled, including colorectal cancer, pancreatic ductal adenocarcinoma, endometrial, ovarian, and NSCLC.


"Dose-limiting toxicity was not seen in Arm A or Arm B," Sullivan reported. "Presently, two patients on Arm A and six patients on Arm B remain on therapy. Three patients each in Arm A and Arm B were treated with the IV q4 weekly dosing schedule and two of three of those patients remain on therapy in each arm. The majority of patients who discontinued therapy did so for disease progression either defined radiographically or clinically.


"The majority of patients had at least one grade 1 or grade 2 toxicity. Five patients had an adverse event that led to study discontinuation," he continued. "All five were deemed related to disease per investigator assessment and none of the five were deemed related to treatment."


The most frequent treatment emergent adverse events (TEAEs) in Arm A were fatigue, nausea, and anxiety-all grade 1 or 2. In Arm B, the most common TEAEs included fatigue, anemia, and constipation.


In the monotherapy arm, the incidence of serious TEAEs was 39 percent. Investigator assessment determined that these events were related to the underlying disease. "However, pulmonary embolism, which occurred in one patient and was determined to be grade 3, was also felt to potentially be related to the study drug," Sullivan noted.


The data for serious TEAEs in the combination cohort were similar. A total of five serious TEAEs were reported and all five toxicities were thought to be related to the underlying disease rather than the study treatment, according to Sullivan.


When discussing pharmacokinetics of Arms A and B, Sullivan noted, "COM701 exhibits typical target-mediated drug disposition, has greater clearance at lower doses where presumably target saturation is not yet achieved, and longer clearance at higher doses. Additionally, at doses of greater than 1 mg/kg, COM701 is dose-proportional. These data support the every-4-week dosing schedule.


"There was one partial response in Arm A and Arm B," he said. "The majority of patients had either a partial response or stable disease. [To date,] two patients in Arm A and four patients in Arm B have had durable stable disease lasting for greater than or equal to 6 months."


COM701 is well-tolerated with a manageable safety profile as a single agent and in combination with nivolumab, Sullivan noted. "The single agent MTD was declared at 20 mg/kg IV q4 weekly and the PK profile supports this dosing schedule. The combination dose escalation continues," he said. "In the near future, we plan on opening the COM701 monotherapy dose expansions in these diseases."


Key Takeaways, Next Steps

These preliminary results demonstrate the potential of COM701, alone and in combination, for patients with a variety of cancer types who have advanced or metastatic disease.


"The key message from these findings is that up to 69 percent of patients in the monotherapy arm and 75 percent of patients in the combination arm had either stable disease or a partial response," Dumbrava told Oncology Times. "So, we were able to control their disease with this treatment, which is remarkable for these patients who were heavily pretreated, especially when they are referred for a phase I clinical trial."


Beyond the efficacy of the treatment, the safety and dosing data hold promise for patients. The researchers did not observe any dose-limiting toxicities or serious immune-related adverse events, which according to Dumbrava is very reassuring. "Having a treatment that is very well-tolerated for these patients is very important."


Equally important is the current dosing schedule of every 4 weeks that is being explored in both arms. "Patients only have to receive treatment once every month," Dumbrava explained. "As a result, they're not spending their life in the hospital.


"This is a very promising compound," she concluded. "We are dedicated to bringing new treatment options to our patients that are safe and tolerable with a friendly schedule that allows them to have a good quality of life while controlling the disease."


Catlin Nalley is a contributing writer.