PT  - JOURNAL ARTICLE
AU  - Cecilia Monge
AU  - Changqing Xie
AU  - Yuta Myojin
AU  - Kelley Coffman
AU  - Donna Mabry Hrones
AU  - Sophie Wang
AU  - Jonathan M Hernandez
AU  - Bradford J Wood
AU  - Elliot B Levy
AU  - Israa Juburi
AU  - Stephen M Hewitt
AU  - David E Kleiner
AU  - Seth M Steinberg
AU  - William D Figg
AU  - Bernadette Redd
AU  - Philip Homan
AU  - Maggie Cam
AU  - Benjamin Ruf
AU  - Austin G Duffy
AU  - Tim F Greten
TI  - Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer
AID  - 10.1136/jitc-2022-005640
DP  - 2023 Feb 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e005640
VI  - 11
IP  - 2
4099  - http://jitc.bmj.com/content/11/2/e005640.short
4100  - http://jitc.bmj.com/content/11/2/e005640.full
SO  - J Immunother Cancer2023 Feb 01; 11
AB  - Background Oncolytic 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.Methods Adult 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.Results Thirty-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.Conclusion PexaVec 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 number NCT03206073.Data are available upon reasonable request.