Before COVID19 - The AACR 2019 Annual Meeting during the opening plenary session at the American Association for Cancer Research Annual Meeting at the Georgia World Congress Center. Photo Courtesy: © AACR/Todd Buchanan.
Before COVID19 - The AACR 2019 Annual Meeting during the opening plenary session at the American Association for Cancer Research Annual Meeting at the Georgia World Congress Center. Photo Courtesy: © AACR/Todd Buchanan.

Results from an ongoing Phase I dose-escalation study of COM701 (NCT 03667716), a first-in-class anti-PVRIG antibody, in patients with advanced solid tumors who have exhausted all available standard therapies, were presented during the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting I. [Download]

The investigational drug is a humanized antibody that binds with high affinity to the poliovirus receptor-related immunoglobulin domain containing (PVRIG), a novel immune checkpoint, blocks the interaction with its ligand, PVRL2, and regulates the activity of T cells and natural killer cells through the DNAM/TIGIT axis.

Parallel immune checkpoint pathways
Discovered using Compugen‘s computational discovery platform that combines human biology derived from genome analysis with disease information derived from analysis of a vast amount of proprietary and publicly available data, PVRIG and TIGIT constitute parallel immune checkpoint pathways that counteract DNAM, a costimulatory molecule on T cells and NK cells with particularly high expression in lymphocytes that populate the tumor microenvironment (known as tumor-infiltrating lymphocytes or TILs).

In preclinical development, scientists found data to suggest that the blockade of PVRIG induces a robust anti-tumor immune response and demonstrates synergistic activity when used in combination with inhibitors of TIGIT and/or PD-1.

The PVRIG Pathway in the DNAM AXIS. Potential Molecular Interactions Between PVRIG/TIGIT and PD-1 Pathways Support Combination Approach to Overcome Immunotherapy Resistance. Image Courtesy: 2020 © Compugen.
The PVRIG Pathway in the DNAM AXIS. Potential Molecular Interactions Between PVRIG/TIGIT and PD-1 Pathways Support Combination Approach to Overcome Immunotherapy Resistance. PVRIG may serve as an alternative, targetable checkpoint in PD-L1 negative tumors, potentially addressing patient populations who are non-responsive to PD-1 therapies and improve outcomes in PD-1 responsive patient populations. Image Courtesy: 2020 © Compugen.

Furthermore, genetic ablation of the PVRIG gene in mice resulted in reduced tumor growth, which can be further enhanced by treatment with PD-1 pathway blockers. This combination effect is seen with antibody blockade of PVRIG together with PD-1 or TIGIT pathway inhibition, confirming the potential of a clinical combination of COM701with other checkpoint inhibitors. Initial results were presented in a poster presentation during the 2019 SITC Annual Meeting, National Harbor, Maryland on November 6 -10, 2019.[2]

Well-tolerated
In the ongoing phase I study COM701 is well-tolerated and demonstrated preliminary signals of anti-tumor activity in a heavily pretreated patient population. The researchers did not observe dose-limiting toxicities of the COM701 as a monotherapy and in combination with nivolumab (Opdivo®; Bristol-Myers Squibb). Furthermore, COM701 demonstrated encouraging signals of anti-tumor activity with high disease control rate in both the monotherapy and combination therapy arms (69% and 75%, respectively), including two confirmed partial responses and durable responses of over six months across cohorts, in the heavily pretreated patients enrolled in the study.

Ryan J. Sullivan, M.D. is
Assistant Professor, Medicine, Harvard Medical School and Assistant Professor, Hematology/Oncology, Massachusetts General Hospital. Photo Courtesy: © 2020 Dana-Farber / Harvard Cancer Center.

“I am highly encouraged by the safety profile and preliminary anti-tumor activity observed with COM701 both as a monotherapy and in combination with nivolumab,” noted Ryan J. Sullivan, M.D., Assistant Professor, Medicine, Harvard Medical School and Faculty Member of the Termeer Center for Targeted Therapy and Immunotherapy Programs at Massachusetts General Hospital Cancer Center, and presenting author.

“With a highly refractory and all comer* patient population, this trial enrolled patients that are difficult to treat including those who progressed on numerous prior therapies. Achieving durable disease control, including partial responses, is remarkable in this population and I am particularly enthusiastic about the proportion of patients in the combination arm, currently 50%, who remain on treatment. Taken together, these results support further investigation of targeting PVRIG with COM701 and suggest that targeting the PVRIG/TIGIT pathways may broaden the patient population that can benefit from immunotherapies.”

“We are thrilled to see durable responses in patients with extremely challenging cancer types with poor prognosis. These findings from the completed monotherapy dose-escalation and ongoing combination dose-escalation study arms continue to support the potential of COM701 as a monotherapy and in combination with nivolumab in patients who have exhausted all available treatment options. Notably, the ongoing responses in microsatellite stable colorectal cancer and primary peritoneal cancer, a type of ovarian cancer, are supportive of our biomarker-informed selection of indications for the monotherapy expansion cohorts,” explained Anat Cohen-Dayag, Ph.D., President and Chief Executive Officer of Compugen.

Ongoing study
The trial data for COM701, presented during AACR’s virtual annual meeting are from the monotherapy and combination arms of the ongoing, Phase I, open-label, dose-escalation study and include all eight cohorts from the monotherapy arm (n=16), and the first three of four cohorts of the combination arm (n=12).

The study was designed to assess the safety and tolerability of administering escalating doses of COM701 monotherapy as well as of combination administration with nivolumab in patients with advanced solid tumors. Additionally, secondary endpoints include preliminary antitumor activity, pharmacokinetics, and pharmacodynamics of COM701 monotherapy and in combination with nivolumab in patients with selected tumor types, including non-small cell lung cancer, ovarian cancer, breast cancer, endometrial cancer, and colorectal cancer.

Enrollment in the COM701 monotherapy dose-escalation arm is completed and enrollment in the combination dose-escalation arm at 20 mg/kg IV Q4 weeks is ongoing. The monotherapy expansion cohorts that will follow the monotherapy dose-escalation arm is based on a biomarker-informed selection of indications and will include non-small cell lung cancer, ovarian, breast, endometrial, and colorectal cancer. During this monotherapy expansion study, biopsies will be collected before and on COM701 treatment to allow retrospective analyses of Compugen’s DNAM axis biomarker approach.

Summary of preliminary Key findings
Key findings to be presented by Sullivan in an oral virtual presentation

  • COM701 was well-tolerated through 20 mg/kg IV Q4 weeks as a monotherapy and 10 mg/kg IV Q4 weeks in combination with nivolumab (480 mg IV Q4 weeks) with no dose-limiting toxicities reported.
     – No increased toxicity was observed in the combination arm.
     – No patients discontinued treatment due to toxicity of any study drug.
  • Preliminary COM701 pharmacokinetic data supports IV Q4 weeks dosing, allowing a dosing schedule with nivolumab.
  • Encouraging disease control rates of 69% (11/16) for monotherapy and 75% (9/12) for the combination arm.
     – 50% of patients (6/12) in the combination arm remain on study, some with continued responses observed beyond 200 days of treatment.
  • Across cohorts, durable responses of stable disease for over six months in six of 28 (21%) patients.
  • The two patients previously reported with confirmed partial responses, one from the monotherapy arm (microsatellite stable primary peritoneal cancer) and one from the combination arm (microsatellite stable colorectal cancer), remain on treatment.

* In the development of clinical trials an all-comers strategy all patients meeting the eligibility criteria are entered. This approach does not include a selection based on the specific status of the biomarker in question. In contrast, an enrichment design screens patients for the presence or absence of a marker or a panel of markers, and then only include patients who either have or do not have a certain marker characteristic or profile. [3]

Clinical trials
COM701 in Subjects With Advanced Solid Tumors – NCT03667716

Reference
[1] COM701 Demonstrates Antitumor Activity as Monotherapy and in Combination with Nivolumab in Patients with Advanced Malignancies. Abstract #9757 AACR 2020 Virtual Oral Presentation April 27-28, 2020 [Presentation]
[2] Dumbrava EI, Fleming GF, Hamilton E, Sullivan R, Patnaik A, Papadopoulos K, ElNaggar A, Hunter J, Olweny J, et al. Phase I Study of the Safety, Tolerability and Preliminary Anti-tumor Activity of COM701 Monotherapy in Patients with Advanced Solid Tumors. SITC Annual Meeting, National Harbor, Maryland in November 6 -10, 2019. Poster P241.
[3] Mandrekar SJ, Sargent DJ. Clinical trial designs for predictive biomarker validation: theoretical considerations and practical challenges. J Clin Oncol. 2009 Aug 20;27(24):4027–34.

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