Journal Article

Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer

Duffy, Austin G, Hrones, Donna Mabry, Myojin, Yuta, Cam, Maggie, Wang, Sophie, Homan, Philip, Wood, Bradford J, Levy, Elliot B, Figg, William D, Steinberg, Seth M, Greten, Tim F, Juburi, Israa, Hernandez, Jonathan M, Hewitt, Stephen M, Coffman, Kelley, Ruf, Benjamin, Kleiner, David E, Redd, Bernadette, Xie, Changqing, Monge, Cecilia

2023

Overview

BackgroundOncolytic immunotherapy represents a unique therapeutic platform for the treatment of cancer. Here, we evaluated the safety and efficacy of the combination of pexastimogene devacirepvec (PexaVec) plus durvalumab (anti-programmed death ligand 1) with and without tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4) in patients with standard chemotherapy refractory mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) in a phase I/II trial.MethodsAdult patients with histologically confirmed advanced pMMR mCRC, who had progressed on at least two prior lines of systemic chemotherapy were studied in four cohorts. Patients received four doses of PexaVec IV at a dose of 3×108 plaque forming units (pfu) (dose level 1) or 1×109 pfu (dose level 2) every 2 weeks. Twelve days after the first PexaVec administration, patients received either 1500 mg of durvalumab every 28 days alone or an additional single dose of 300 mg tremelimumab on day 1. Responses were assessed every 8 weeks by CT or MRI. AEs were recorded. The primary endpoints were safety and feasibility. Secondary endpoints included progression-free survival (PFS) and overall survival. Paired tumor samples and peripheral blood were collected to perform immune monitoring.ResultsThirty-four patients with mCRC enrolled on to the study: 16 patients in the PexaVec/durvalumab cohorts and 18 patients in the PexaVec/durvalumab/tremelimumab cohorts. Overall, the combination of PexaVec plus immune checkpoint inhibitors did not result in any unexpected toxicities. Most common toxicities observed were fever and chills after PexaVec infusion. Two cases of grade 3 colitis, one case of a grade 2 myositis and one case of grade 3 hypotension resulted in discontinuation of immune checkpoint inhibitor and PexaVec treatment, respectively. The median PFS in the PexaVec/durvalumab/tremelimumab cohorts was 2.3 months (95% CI: 2.2 to 3.2 months) vs 2.1 months (95% CI: 1.7 to 2.8 months; p=0.57) in the PexaVec/durvalumab cohorts. Flow cytometry analysis of peripheral blood mononuclear cells revealed an increase in Ki67+CD8+ T cells on treatment.ConclusionPexaVec in combination with durvalumab and tremelimumab is safe and tolerable. No unexpected toxicities were observed. The combination of PexaVec/durvalumab/tremelimumab demonstrated potential clinical activity in patients with pMMR mCRC, but further studies are needed to identify the predictive biomarkers.Trial registration numberNCT03206073.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adult / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Apoptosis / Biopsy / Cancer / Cancer therapies / CD8-Positive T-Lymphocytes / Chemotherapy / clinical trials, phase II as topic / Colorectal cancer / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - etiology / Cytotoxicity / Data analysis / Genes / Genomes / Granulocytes / Hematology / Humans / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / Immunotherapy / Leukocytes, Mononuclear / Metastasis / Monoclonal antibodies / Oncolytic and Local Immunotherapy / oncolytic viruses / Patients / Tumors / Vascular endothelial growth factor / Viruses