Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer
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-cytotoxi...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-02-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/2/e005640.full |
| _version_ | 1811168472822972416 |
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| author | Stephen M Hewitt David E Kleiner Tim F Greten William D Figg Cecilia Monge Seth M Steinberg Maggie Cam Benjamin Ruf Austin G Duffy Jonathan M Hernandez Changqing Xie Yuta Myojin Kelley Coffman Donna Mabry Hrones Sophie Wang Bradford J Wood Elliot B Levy Israa Juburi Bernadette Redd Philip Homan |
| author_facet | Stephen M Hewitt David E Kleiner Tim F Greten William D Figg Cecilia Monge Seth M Steinberg Maggie Cam Benjamin Ruf Austin G Duffy Jonathan M Hernandez Changqing Xie Yuta Myojin Kelley Coffman Donna Mabry Hrones Sophie Wang Bradford J Wood Elliot B Levy Israa Juburi Bernadette Redd Philip Homan |
| author_sort | Stephen M Hewitt |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T16:26:57Z |
| format | Article |
| id | doaj.art-7d02b8ba4ef24ff8856cf44022b698f1 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-10T16:26:57Z |
| publishDate | 2023-02-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-7d02b8ba4ef24ff8856cf44022b698f12023-02-09T02:30:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-02-0111210.1136/jitc-2022-005640Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancerStephen M Hewitt0David E Kleiner1Tim F Greten2William D Figg3Cecilia Monge4Seth M Steinberg5Maggie Cam6Benjamin Ruf7Austin G Duffy8Jonathan M Hernandez9Changqing Xie10Yuta Myojin11Kelley Coffman12Donna Mabry Hrones13Sophie Wang14Bradford J Wood15Elliot B Levy16Israa Juburi17Bernadette Redd18Philip Homan19Aff2 grid.417768.b0000000404839129Laboratory of PathologyCenter for Cancer Research, National Cancer Institute 10 Center Drive, Building 10 Hatfield CRC, MSC 4605 20892-1201 Bethesda MD USA7 Laboratory of Pathology, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA1 Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAClinical Pharmacology Program, Center for Cancer Research, NCI, Bethesda, Maryland, USAAff1 0000 0004 1936 8075grid.48336.3aMedical Oncology Service, Center for Cancer ResearchNational Cancer Institute, National Institutes of Health Bethesda MD USABiostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USANational Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA1 Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA5 The Mater Hospital/University College Dublin, Dublin, IrelandNational Cancer Institute, Surgical Oncology Program, National Institutes of Health, Bethesda, Maryland, USAGastrointestinal Malignancies Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAGastrointestinal Malignancies Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAGastrointestinal Malignancies Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAGastrointestinal Malignancies Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAGastrointestinal Malignancies Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USACenter for Interventional Oncology, Radiology and Imaging Sciences, NIH Clinical Center & Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, USACenter for Interventional Oncology, Radiology and Imaging Sciences, NIH Clinical Center & Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, USANational Cancer Institute, National Institutes of Health, Bethesda, Maryland, USARadiology and Imaging Sciences, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAFrederick National Laboratory for Cancer Research, Frederick, Maryland, USABackground 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.https://jitc.bmj.com/content/11/2/e005640.full |
| spellingShingle | Stephen M Hewitt David E Kleiner Tim F Greten William D Figg Cecilia Monge Seth M Steinberg Maggie Cam Benjamin Ruf Austin G Duffy Jonathan M Hernandez Changqing Xie Yuta Myojin Kelley Coffman Donna Mabry Hrones Sophie Wang Bradford J Wood Elliot B Levy Israa Juburi Bernadette Redd Philip Homan Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer Journal for ImmunoTherapy of Cancer |
| title | Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer |
| title_full | Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer |
| title_fullStr | Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer |
| title_full_unstemmed | Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer |
| title_short | Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer |
| title_sort | phase i ii study of pexavec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer |
| url | https://jitc.bmj.com/content/11/2/e005640.full |
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