Biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma: analysis of a phase II clinical trial and a cohort of long-term responders
Background Recent trials suggest that programmed cell death 1 (PD-1)-directed immunotherapy may be beneficial for some patients with anal squamous cell carcinoma and biomarkers predictive of response are greatly needed.Methods This multicenter phase II clinical trial (NCT02919969) enrolled patients...
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2024-01-01
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| author | Jeffrey A Meyerhardt Sunil Kumar Jessica A Zerillo Aparna Parikh James M Cleary Scott Rodig Benjamin Schlechter Kimmie Ng Stephanie K Dougan Nora Horick Glenn J Hanna Andrew L Coveler Anuj K Patel Nadine J McCleary Douglas A Rubinson Jeffrey W Clark Kent Mouw Kathleen Pfaff Thomas A Abrams Matthew B Yurgelun Eliezer M Van Allen S Jennifer Wang Leah H Biller Harshabad Singh Emma L Welsh Brandon M Huffman Lestat R Ali Megan T Hoffman Katherine A Metayer Shayla Murray Alexandra Bird Jennifer A Chan Wolfram Goessling Jeffrey S Wisch Brendan Reardon Robert J Mayer Catherine Del Vecchio Fitz Charlotte Kuperwasser |
| author_facet | Jeffrey A Meyerhardt Sunil Kumar Jessica A Zerillo Aparna Parikh James M Cleary Scott Rodig Benjamin Schlechter Kimmie Ng Stephanie K Dougan Nora Horick Glenn J Hanna Andrew L Coveler Anuj K Patel Nadine J McCleary Douglas A Rubinson Jeffrey W Clark Kent Mouw Kathleen Pfaff Thomas A Abrams Matthew B Yurgelun Eliezer M Van Allen S Jennifer Wang Leah H Biller Harshabad Singh Emma L Welsh Brandon M Huffman Lestat R Ali Megan T Hoffman Katherine A Metayer Shayla Murray Alexandra Bird Jennifer A Chan Wolfram Goessling Jeffrey S Wisch Brendan Reardon Robert J Mayer Catherine Del Vecchio Fitz Charlotte Kuperwasser |
| author_sort | Jeffrey A Meyerhardt |
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| description | Background Recent trials suggest that programmed cell death 1 (PD-1)-directed immunotherapy may be beneficial for some patients with anal squamous cell carcinoma and biomarkers predictive of response are greatly needed.Methods This multicenter phase II clinical trial (NCT02919969) enrolled patients with metastatic or locally advanced incurable anal squamous cell carcinoma (n=32). Patients received pembrolizumab 200 mg every 3 weeks. The primary endpoint of the trial was objective response rate (ORR). Exploratory objectives included analysis of potential predictive biomarkers including assessment of tumor-associated immune cell populations with multichannel immunofluorescence and analysis of circulating tumor tissue modified viral-human papillomavirus DNA (TTMV-HPV DNA) using serially collected blood samples. To characterize the clinical features of long-term responders, we combined data from our prospective trial with a retrospective cohort of patients with anal cancer treated with anti-PD-1 immunotherapy (n=18).Results In the phase II study, the ORR to pembrolizumab monotherapy was 9.4% and the median progression-free survival was 2.2 months. Despite the high level of HPV positivity observed with circulating TTMV-HPV DNA testing, the majority of patients had low levels of tumor-associated CD8+PD-1+ T cells on pretreatment biopsy. Patients who benefited from pembrolizumab had decreasing TTMV-HPV DNA scores and a complete responder’s TTMV-HPV DNA became undetectable. Long-term pembrolizumab responses were observed in one patient from the trial (5.3 years) and three patients (2.5, 6, and 8 years) from the retrospective cohort. Long-term responders had HPV-positive tumors, lacked liver metastases, and achieved a radiological complete response.Conclusions Pembrolizumab has durable efficacy in a rare subset of anal cancers. However, despite persistence of HPV infection, indicated by circulating HPV DNA, most advanced anal cancers have low numbers of tumor-associated CD8+PD-1+ T cells and are resistant to pembrolizumab. |
| format | Article |
| id | doaj-art-3355b66d86a3433d9514838bcb4205a5 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-01-01 |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-3355b66d86a3433d9514838bcb4205a52025-02-02T09:35:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-01-0112110.1136/jitc-2023-008436Biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma: analysis of a phase II clinical trial and a cohort of long-term respondersJeffrey A Meyerhardt0Sunil Kumar1Jessica A Zerillo2Aparna Parikh3James M Cleary4Scott Rodig5Benjamin Schlechter6Kimmie Ng7Stephanie K Dougan8Nora Horick9Glenn J Hanna10Andrew L Coveler11Anuj K Patel12Nadine J McCleary13Douglas A Rubinson14Jeffrey W Clark15Kent Mouw16Kathleen Pfaff17Thomas A Abrams18Matthew B Yurgelun19Eliezer M Van Allen20S Jennifer Wang21Leah H Biller22Harshabad Singh23Emma L Welsh24Brandon M Huffman25Lestat R Ali26Megan T Hoffman27Katherine A Metayer28Shayla Murray29Alexandra Bird30Jennifer A Chan31Wolfram Goessling32Jeffrey S Wisch33Brendan Reardon34Robert J Mayer35Catherine Del Vecchio Fitz36Charlotte Kuperwasser37Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA1 Department of General Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Sawangi Meghe, Wardha, Maharashtra, IndiaHarvard Medical School, Boston, Massachusetts, USADepartment of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USADepartment of Medicine, Harvard Medical School, Boston, Massachusetts, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA5Dana-Farber Cancer Institute, Boston, MA, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USAMassachusetts General Hospital, Boston, Massachusetts, USADepartment of Medicine, Harvard Medical School, Boston, Massachusetts, USAUniversity of Washington School of Medicine, Seattle, Washington, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts, USAHarvard Medical School, Boston, Massachusetts, USACenter for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA28 Harvard Medical School, Boston, Massachusetts, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medicine, Harvard Medical School, Boston, Massachusetts, USADana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medicine, Harvard Medical School, Boston, Massachusetts, USADepartment of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USAMassachusetts General Hospital, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USANaveris, Inc, Waltham, Massachusetts, USANaveris, Inc, Waltham, Massachusetts, USABackground Recent trials suggest that programmed cell death 1 (PD-1)-directed immunotherapy may be beneficial for some patients with anal squamous cell carcinoma and biomarkers predictive of response are greatly needed.Methods This multicenter phase II clinical trial (NCT02919969) enrolled patients with metastatic or locally advanced incurable anal squamous cell carcinoma (n=32). Patients received pembrolizumab 200 mg every 3 weeks. The primary endpoint of the trial was objective response rate (ORR). Exploratory objectives included analysis of potential predictive biomarkers including assessment of tumor-associated immune cell populations with multichannel immunofluorescence and analysis of circulating tumor tissue modified viral-human papillomavirus DNA (TTMV-HPV DNA) using serially collected blood samples. To characterize the clinical features of long-term responders, we combined data from our prospective trial with a retrospective cohort of patients with anal cancer treated with anti-PD-1 immunotherapy (n=18).Results In the phase II study, the ORR to pembrolizumab monotherapy was 9.4% and the median progression-free survival was 2.2 months. Despite the high level of HPV positivity observed with circulating TTMV-HPV DNA testing, the majority of patients had low levels of tumor-associated CD8+PD-1+ T cells on pretreatment biopsy. Patients who benefited from pembrolizumab had decreasing TTMV-HPV DNA scores and a complete responder’s TTMV-HPV DNA became undetectable. Long-term pembrolizumab responses were observed in one patient from the trial (5.3 years) and three patients (2.5, 6, and 8 years) from the retrospective cohort. Long-term responders had HPV-positive tumors, lacked liver metastases, and achieved a radiological complete response.Conclusions Pembrolizumab has durable efficacy in a rare subset of anal cancers. However, despite persistence of HPV infection, indicated by circulating HPV DNA, most advanced anal cancers have low numbers of tumor-associated CD8+PD-1+ T cells and are resistant to pembrolizumab.https://jitc.bmj.com/content/12/1/e008436.full |
| spellingShingle | Jeffrey A Meyerhardt Sunil Kumar Jessica A Zerillo Aparna Parikh James M Cleary Scott Rodig Benjamin Schlechter Kimmie Ng Stephanie K Dougan Nora Horick Glenn J Hanna Andrew L Coveler Anuj K Patel Nadine J McCleary Douglas A Rubinson Jeffrey W Clark Kent Mouw Kathleen Pfaff Thomas A Abrams Matthew B Yurgelun Eliezer M Van Allen S Jennifer Wang Leah H Biller Harshabad Singh Emma L Welsh Brandon M Huffman Lestat R Ali Megan T Hoffman Katherine A Metayer Shayla Murray Alexandra Bird Jennifer A Chan Wolfram Goessling Jeffrey S Wisch Brendan Reardon Robert J Mayer Catherine Del Vecchio Fitz Charlotte Kuperwasser Biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma: analysis of a phase II clinical trial and a cohort of long-term responders Journal for ImmunoTherapy of Cancer |
| title | Biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma: analysis of a phase II clinical trial and a cohort of long-term responders |
| title_full | Biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma: analysis of a phase II clinical trial and a cohort of long-term responders |
| title_fullStr | Biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma: analysis of a phase II clinical trial and a cohort of long-term responders |
| title_full_unstemmed | Biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma: analysis of a phase II clinical trial and a cohort of long-term responders |
| title_short | Biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma: analysis of a phase II clinical trial and a cohort of long-term responders |
| title_sort | biomarkers of pembrolizumab efficacy in advanced anal squamous cell carcinoma analysis of a phase ii clinical trial and a cohort of long term responders |
| url | https://jitc.bmj.com/content/12/1/e008436.full |
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