Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer
Background Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e004233.full |
| _version_ | 1797771609145081856 |
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| author | John Wright Stephanie Lheureux Ilaria Colombo Ramy Gadalla Pamela S Ohashi Xuan Li Lisa Wang Matthew S Block David G Brooks Andrea Jewell Carolyn McCourt Eugenia Girda Sarah Temkin Gini F Fleming Linda Duska Daniela E Matei Panagiotis A Konstantinopoulos Ben X Wang Stephanie L Gaillard Michael McHale Floor J Backes Theresa L Werner Siobhan Kehoe Rachel Wildman Shirin Soleimani Scott Lien Trevor Pugh |
| author_facet | John Wright Stephanie Lheureux Ilaria Colombo Ramy Gadalla Pamela S Ohashi Xuan Li Lisa Wang Matthew S Block David G Brooks Andrea Jewell Carolyn McCourt Eugenia Girda Sarah Temkin Gini F Fleming Linda Duska Daniela E Matei Panagiotis A Konstantinopoulos Ben X Wang Stephanie L Gaillard Michael McHale Floor J Backes Theresa L Werner Siobhan Kehoe Rachel Wildman Shirin Soleimani Scott Lien Trevor Pugh |
| author_sort | John Wright |
| collection | DOAJ |
| description | Background Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling.Patients and methods In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored.Results Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009).Conclusions Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation. |
| first_indexed | 2024-03-12T21:39:06Z |
| format | Article |
| id | doaj.art-0e5bfe1cd7414e458e3cfe2d6fbf3f50 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T21:39:06Z |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-0e5bfe1cd7414e458e3cfe2d6fbf3f502023-07-27T02:50:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-004233Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancerJohn Wright0Stephanie Lheureux1Ilaria Colombo2Ramy Gadalla3Pamela S Ohashi4Xuan Li5Lisa Wang6Matthew S Block7David G Brooks8Andrea Jewell9Carolyn McCourt10Eugenia Girda11Sarah Temkin12Gini F Fleming13Linda Duska14Daniela E Matei15Panagiotis A Konstantinopoulos16Ben X Wang17Stephanie L Gaillard18Michael McHale19Floor J Backes20Theresa L Werner21Siobhan Kehoe22Rachel Wildman23Shirin Soleimani24Scott Lien25Trevor Pugh26Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland, USAMedical Oncology & Hematology, Princess Margaret Hospital Cancer Centre/University Health Networks/Sinai Health Systems, Toronto, Ontario, CanadaDrug Development Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, CanadaImmune Profiling Team – Tumor Immunotherapy Program, Princess Margaret Cancer Centre, Toronto, Ontario, CanadaDepartment of Immunology, University of Toronto, Toronto, Ontario, CanadaDepartment of Vascular and Thyroid Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, ChinaDepartment of Pediatrics, Baylor College of Medicine, Houston, Texas, USADepartment of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USADepartment of Immunology, University of Toronto, Toronto, Ontario, CanadaDepartment of Gynecologic Oncology, University of Kansas Medical Center, Kansas City, Kansas, USADepartment of Gynecology Oncology, Washington University School of Medicine, St Louis, Missouri, USADepartment of Gynecology Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USADepartment of Gynecology Oncology, Virginia Commonwealth University, Richmond, Virginia, USADepartment of Medicine, University of Chicago Medicine, Chicago, Illinois, USADepartment of Gynecology Oncology, University of Virginia, Charlottesville, Virginia, USADepartment of Obstetrics and Gynecology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Illinois, USADepartment of Gynecologic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USAImmune Profiling Team – Tumor Immunotherapy Program, Princess Margaret Cancer Centre, Toronto, Ontario, CanadaDepartment of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, Maryland, USA4 Obstetrics, Gynecology, and Reproductive Sciences, University of California San Diego, La Jolla, California, USADepartment of Gynecologic Oncology, Ohio State University, Columbus, Ohio, USA2 University of Utah Health Huntsman Cancer Institute, Salt Lake City, Utah, USADepartment of Gynecology Oncology, NYU Langone, New York City, New York, USADrug Development Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, CanadaDepartment of Medical Biophysics, University of Toronto, Toronto, Ontario, CanadaDrug Development Program, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, CanadaCancer Genomics Program, Princess Margaret Cancer Centre, Toronto, Ontario, CanadaBackground Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling.Patients and methods In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored.Results Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009).Conclusions Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.https://jitc.bmj.com/content/10/3/e004233.full |
| spellingShingle | John Wright Stephanie Lheureux Ilaria Colombo Ramy Gadalla Pamela S Ohashi Xuan Li Lisa Wang Matthew S Block David G Brooks Andrea Jewell Carolyn McCourt Eugenia Girda Sarah Temkin Gini F Fleming Linda Duska Daniela E Matei Panagiotis A Konstantinopoulos Ben X Wang Stephanie L Gaillard Michael McHale Floor J Backes Theresa L Werner Siobhan Kehoe Rachel Wildman Shirin Soleimani Scott Lien Trevor Pugh Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer Journal for ImmunoTherapy of Cancer |
| title | Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer |
| title_full | Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer |
| title_fullStr | Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer |
| title_full_unstemmed | Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer |
| title_short | Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer |
| title_sort | translational randomized phase ii trial of cabozantinib in combination with nivolumab in advanced recurrent or metastatic endometrial cancer |
| url | https://jitc.bmj.com/content/10/3/e004233.full |
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