Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer
Background The immunosuppressive desmoplastic stroma of pancreatic cancer represents a major hurdle to developing an effective immune response. Preclinical studies in pancreatic cancer have demonstrated promising anti-tumor activity with Bruton tyrosine kinase (BTK) inhibition combined with programm...
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BMJ Publishing Group
2020-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/1/e000587.full |
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| author | Al B Benson Anirban Maitra Milind Javle Michael Overman Richard E Davis Pankaj Vats Chandan Kumar-Sinha Lianchun Xiao Niharika B Mettu Edwin R Parra Charles D Lopez Veerendra Munugalavadla Priti Patel Lin Tao Sattva Neelapu |
| author_facet | Al B Benson Anirban Maitra Milind Javle Michael Overman Richard E Davis Pankaj Vats Chandan Kumar-Sinha Lianchun Xiao Niharika B Mettu Edwin R Parra Charles D Lopez Veerendra Munugalavadla Priti Patel Lin Tao Sattva Neelapu |
| author_sort | Al B Benson |
| collection | DOAJ |
| description | Background The immunosuppressive desmoplastic stroma of pancreatic cancer represents a major hurdle to developing an effective immune response. Preclinical studies in pancreatic cancer have demonstrated promising anti-tumor activity with Bruton tyrosine kinase (BTK) inhibition combined with programmed cell death receptor-1 (PD-1) blockade.Methods This was a phase II, multicenter, open-label, randomized (1:1) clinical trial evaluating the BTK inhibitor acalabrutinib, alone (monotherapy) or in combination with the anti-PD-1 antibody pembrolizumab (combination therapy). Eligible patients were adults with histologically confirmed metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1 who had received at least one prior systemic therapy. Oral acalabrutinib 100 mg twice daily was administered with or without intravenous pembrolizumab 200 mg on day 1 of each 3-week cycle. Peripheral blood was analyzed for changes in immune markers, and tumors from exceptional responders were molecularly analyzed.Results A total of 77 patients were enrolled (37 monotherapy; 40 combination therapy) with a median age of 64 years; 77% had an ECOG PS of 1. The median number of prior therapies was 3 (range 1–6). Grade 3–4 treatment-related adverse events were seen in 14.3% of patients in the monotherapy arm and 15.8% of those in the combination therapy arm. The overall response rate and disease control rate were 0% and 14.3% with monotherapy and 7.9% and 21.1% with combination therapy, respectively. Median progression-free survival was 1.4 months in both arms. Peripheral blood flow analysis demonstrated consistent reductions in granulocytic (CD15+) myeloid-derived suppressor cells (MDSCs) over time. Two exceptional responders were found to be microsatellite stable with low tumor mutation burden, low neoantigen load and no defects in the homologous DNA repair pathway.Conclusions The combination of acalabrutinib and pembrolizumab was well tolerated, but limited clinical activity was seen with either acalabrutinib monotherapy or combination therapy. Peripheral reductions in MDSCs were seen. Efforts to understand and target the pancreatic tumor microenvironment should continue.Trial registration number NCT02362048. |
| format | Article |
| id | doaj-art-50d0394471cc4ce4983fa47de5d9edeb |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-05-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-50d0394471cc4ce4983fa47de5d9edeb2025-08-20T02:13:11ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-05-018110.1136/jitc-2020-000587Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancerAl B Benson0Anirban Maitra1Milind Javle2Michael Overman3Richard E Davis4Pankaj Vats5Chandan Kumar-Sinha6Lianchun Xiao7Niharika B Mettu8Edwin R Parra9Charles D Lopez10Veerendra Munugalavadla11Priti Patel12Lin Tao13Sattva Neelapu145 Department of Medicine, Northwestern University Division of Hematology/Oncology, Chicago, Illinois, USATranslational Molecular Pathology, UTMDACC, Houston, Texas, USADepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Gastrointestinal Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USASurgery, AIC Kijabe Hospital, Kijabe, Kenya3 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA3 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan, USA4 Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA5 Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, North Carolina, USA1The University of Texas MD Anderson Cancer Center, Houston, TX, USA8 Department of Oncology, School of Medicine, Oregon Health and Science University Foundation, Portland, Oregon, USA9 Acerta Pharma LLC, Redwood City, California, USA9 Acerta Pharma LLC, Redwood City, California, USACancer Day-Care Unit, Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University/ West China School of Nursing, Sichuan University, Chengdu, ChinaDepartment of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas, USABackground The immunosuppressive desmoplastic stroma of pancreatic cancer represents a major hurdle to developing an effective immune response. Preclinical studies in pancreatic cancer have demonstrated promising anti-tumor activity with Bruton tyrosine kinase (BTK) inhibition combined with programmed cell death receptor-1 (PD-1) blockade.Methods This was a phase II, multicenter, open-label, randomized (1:1) clinical trial evaluating the BTK inhibitor acalabrutinib, alone (monotherapy) or in combination with the anti-PD-1 antibody pembrolizumab (combination therapy). Eligible patients were adults with histologically confirmed metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1 who had received at least one prior systemic therapy. Oral acalabrutinib 100 mg twice daily was administered with or without intravenous pembrolizumab 200 mg on day 1 of each 3-week cycle. Peripheral blood was analyzed for changes in immune markers, and tumors from exceptional responders were molecularly analyzed.Results A total of 77 patients were enrolled (37 monotherapy; 40 combination therapy) with a median age of 64 years; 77% had an ECOG PS of 1. The median number of prior therapies was 3 (range 1–6). Grade 3–4 treatment-related adverse events were seen in 14.3% of patients in the monotherapy arm and 15.8% of those in the combination therapy arm. The overall response rate and disease control rate were 0% and 14.3% with monotherapy and 7.9% and 21.1% with combination therapy, respectively. Median progression-free survival was 1.4 months in both arms. Peripheral blood flow analysis demonstrated consistent reductions in granulocytic (CD15+) myeloid-derived suppressor cells (MDSCs) over time. Two exceptional responders were found to be microsatellite stable with low tumor mutation burden, low neoantigen load and no defects in the homologous DNA repair pathway.Conclusions The combination of acalabrutinib and pembrolizumab was well tolerated, but limited clinical activity was seen with either acalabrutinib monotherapy or combination therapy. Peripheral reductions in MDSCs were seen. Efforts to understand and target the pancreatic tumor microenvironment should continue.Trial registration number NCT02362048.https://jitc.bmj.com/content/8/1/e000587.full |
| spellingShingle | Al B Benson Anirban Maitra Milind Javle Michael Overman Richard E Davis Pankaj Vats Chandan Kumar-Sinha Lianchun Xiao Niharika B Mettu Edwin R Parra Charles D Lopez Veerendra Munugalavadla Priti Patel Lin Tao Sattva Neelapu Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer Journal for ImmunoTherapy of Cancer |
| title | Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer |
| title_full | Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer |
| title_fullStr | Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer |
| title_full_unstemmed | Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer |
| title_short | Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer |
| title_sort | randomized phase ii study of the bruton tyrosine kinase inhibitor acalabrutinib alone or with pembrolizumab in patients with advanced pancreatic cancer |
| url | https://jitc.bmj.com/content/8/1/e000587.full |
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