Durvalumab and tremelimumab in patients with advanced rare cancer: a multi-centre, non-blinded, open-label phase II basket trialResearch in context
Summary: Background: Dual inhibition of cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed death ligand 1 (PD-L1) has been shown to be an effective treatment strategy in many cancers. We sought to determine the objective response rate of combination durvalumab (D) plus tremelimumab...
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Elsevier
2025-01-01
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| Series: | EClinicalMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589537024005704 |
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| author | Abha A. Gupta Anna Tinker Derek Jonker Rahma Jamal Hal Hirte Eric W. Winquist Quincy Chu Christian Kollmannsberger Ralph Wong Thierry Alcindor Torsten O. Nielsen Ming Tsao Tricia R. Cottrell Diane Provencher John Hilton Monika K. Krzyżanowska Christine Elser Sebastien Hotte Joana Sederias Siwei Zhang Wei Tu Janet Dancey |
| author_facet | Abha A. Gupta Anna Tinker Derek Jonker Rahma Jamal Hal Hirte Eric W. Winquist Quincy Chu Christian Kollmannsberger Ralph Wong Thierry Alcindor Torsten O. Nielsen Ming Tsao Tricia R. Cottrell Diane Provencher John Hilton Monika K. Krzyżanowska Christine Elser Sebastien Hotte Joana Sederias Siwei Zhang Wei Tu Janet Dancey |
| author_sort | Abha A. Gupta |
| collection | DOAJ |
| description | Summary: Background: Dual inhibition of cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed death ligand 1 (PD-L1) has been shown to be an effective treatment strategy in many cancers. We sought to determine the objective response rate of combination durvalumab (D) plus tremelimumab (TM) in parallel cohorts of patients with carefully selected rare cancer types in which these agents had not previously been evaluated in phase II trials and for which there was clinical or biological rationale for dual immune checkpoint inhibitor therapy to be active. Methods: We designed a multi-centre, non-blinded, open-label phase II basket trial with each of the following 8 rare cancers considered a separate phase II trial: salivary carcinoma, carcinoma of unknown primary (CUP) with tumour infiltrating lymphocytes and/or expressing PD-L1, mucosal melanoma, acral melanoma, osteosarcoma, undifferentiated pleomorphic sarcoma, clear cell carcinoma of the ovary (CCCO) or squamous cell carcinoma of the anal canal (SCCA). The primary objective was to evaluate the response rate of the combination of D and TM, and the secondary objectives were to evaluate the tolerability and safety of D and TM combination. Eligible patients had advanced, metastatic or recurrent, or unresectable cancer with no known life-prolonging treatment option, age ≥16 years, ECOG performance status 0 or 1. Patients received D (1500 mg IV) + TM (75 mg IV) on Day 1 q4 weeks for 4 cycles followed by D q4 weeks until disease progression. This trial is registered with ClinicalTrials.gov, NCT02879162. Findings: From December 14th, 2016, to August 14, 2019, 140 patients enrolled into seven cohorts. The rare melanoma cohorts were closed due to lack of accrual. Of the 140 patients enrolled, 138 were eligible, 138 were evaluable for toxicity and 128 (91%) were evaluable for response. Durable responses were noted in all cohorts except for osteosarcoma. The overall response rate for eligible patients was 16% (95% CI: 10–23%). The response rates in each cancer cohort were undifferentiated pleomorphic sarcoma 15% (n = 3/20; 95% CI 3–38%), salivary carcinoma 20% (n = 4/20; 95% CI: 6–44%), CUP 17% (n = 3/18; 95% CI 4–41%), SCCA 10% (n = 2/20; 95% CI 12–32%) and CCCO 21% (n = 8/39; 95% CI 9–37%). Grade 3/4 adverse events were rare, where 4 patients experienced grade 4 related events and39 patients experienced grade 3 events. Interpretation: Durvalumab + tremelimumab treatment resulted in meaningful responses in salivary carcinoma and CCCO and deserves further exploration in front-line studies. Funding: AstraZeneca and Canadian Cancer Society. |
| format | Article |
| id | doaj-art-029e681d31af4c2f8ad0424f9ac223e7 |
| institution | Kabale University |
| issn | 2589-5370 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EClinicalMedicine |
| spelling | doaj-art-029e681d31af4c2f8ad0424f9ac223e72025-01-22T05:43:24ZengElsevierEClinicalMedicine2589-53702025-01-0179102991Durvalumab and tremelimumab in patients with advanced rare cancer: a multi-centre, non-blinded, open-label phase II basket trialResearch in contextAbha A. Gupta0Anna Tinker1Derek Jonker2Rahma Jamal3Hal Hirte4Eric W. Winquist5Quincy Chu6Christian Kollmannsberger7Ralph Wong8Thierry Alcindor9Torsten O. Nielsen10Ming Tsao11Tricia R. Cottrell12Diane Provencher13John Hilton14Monika K. Krzyżanowska15Christine Elser16Sebastien Hotte17Joana Sederias18Siwei Zhang19Wei Tu20Janet Dancey21University Health Network, Princess Margaret Cancer Centre, Toronto, ON, Canada; Corresponding author.CAVA - BCCA - Vancouver, BC, CanadaOttawa Hospital Research Institute, Ottawa, ON, CanadaCHUM-Centre Hospitalier de l'Universite de Montreal, Montreal, QC, CanadaJuravinski Cancer Centre at Hamilton Health Sciences, Hamilton, ON, CanadaLondon Regional Cancer Program, London, ON, CanadaCancerCare Manitoba, Winnipeg, MB, CanadaCAVA - BCCA - Vancouver, BC, CanadaCancerCare Manitoba, Winnipeg, MB, CanadaThe Research Institute of the McGill University, Montreal, QC, CanadaBC Cancer and Molecular and Advanced Pathology Centre, University of British Columbia, Vancouver, BC, CanadaUniversity Health Network, Princess Margaret Cancer Centre, Toronto, ON, CanadaCanadian Cancer Trials Group, Queen's University, Kingston, ON, CanadaCHUM-Centre Hospitalier de l'Universite de Montreal, Montreal, QC, CanadaOttawa Hospital Research Institute, Ottawa, ON, CanadaUniversity Health Network, Princess Margaret Cancer Centre, Toronto, ON, CanadaUniversity Health Network, Princess Margaret Cancer Centre, Toronto, ON, CanadaJuravinski Cancer Centre at Hamilton Health Sciences, Hamilton, ON, CanadaCanadian Cancer Trials Group, Queen's University, Kingston, ON, CanadaCanadian Cancer Trials Group, Queen's University, Kingston, ON, CanadaCanadian Cancer Trials Group, Queen's University, Kingston, ON, CanadaCanadian Cancer Trials Group, Queen's University, Kingston, ON, CanadaSummary: Background: Dual inhibition of cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed death ligand 1 (PD-L1) has been shown to be an effective treatment strategy in many cancers. We sought to determine the objective response rate of combination durvalumab (D) plus tremelimumab (TM) in parallel cohorts of patients with carefully selected rare cancer types in which these agents had not previously been evaluated in phase II trials and for which there was clinical or biological rationale for dual immune checkpoint inhibitor therapy to be active. Methods: We designed a multi-centre, non-blinded, open-label phase II basket trial with each of the following 8 rare cancers considered a separate phase II trial: salivary carcinoma, carcinoma of unknown primary (CUP) with tumour infiltrating lymphocytes and/or expressing PD-L1, mucosal melanoma, acral melanoma, osteosarcoma, undifferentiated pleomorphic sarcoma, clear cell carcinoma of the ovary (CCCO) or squamous cell carcinoma of the anal canal (SCCA). The primary objective was to evaluate the response rate of the combination of D and TM, and the secondary objectives were to evaluate the tolerability and safety of D and TM combination. Eligible patients had advanced, metastatic or recurrent, or unresectable cancer with no known life-prolonging treatment option, age ≥16 years, ECOG performance status 0 or 1. Patients received D (1500 mg IV) + TM (75 mg IV) on Day 1 q4 weeks for 4 cycles followed by D q4 weeks until disease progression. This trial is registered with ClinicalTrials.gov, NCT02879162. Findings: From December 14th, 2016, to August 14, 2019, 140 patients enrolled into seven cohorts. The rare melanoma cohorts were closed due to lack of accrual. Of the 140 patients enrolled, 138 were eligible, 138 were evaluable for toxicity and 128 (91%) were evaluable for response. Durable responses were noted in all cohorts except for osteosarcoma. The overall response rate for eligible patients was 16% (95% CI: 10–23%). The response rates in each cancer cohort were undifferentiated pleomorphic sarcoma 15% (n = 3/20; 95% CI 3–38%), salivary carcinoma 20% (n = 4/20; 95% CI: 6–44%), CUP 17% (n = 3/18; 95% CI 4–41%), SCCA 10% (n = 2/20; 95% CI 12–32%) and CCCO 21% (n = 8/39; 95% CI 9–37%). Grade 3/4 adverse events were rare, where 4 patients experienced grade 4 related events and39 patients experienced grade 3 events. Interpretation: Durvalumab + tremelimumab treatment resulted in meaningful responses in salivary carcinoma and CCCO and deserves further exploration in front-line studies. Funding: AstraZeneca and Canadian Cancer Society.http://www.sciencedirect.com/science/article/pii/S2589537024005704Checkpoint inhibitorsRare cancersOvarian carcinoma |
| spellingShingle | Abha A. Gupta Anna Tinker Derek Jonker Rahma Jamal Hal Hirte Eric W. Winquist Quincy Chu Christian Kollmannsberger Ralph Wong Thierry Alcindor Torsten O. Nielsen Ming Tsao Tricia R. Cottrell Diane Provencher John Hilton Monika K. Krzyżanowska Christine Elser Sebastien Hotte Joana Sederias Siwei Zhang Wei Tu Janet Dancey Durvalumab and tremelimumab in patients with advanced rare cancer: a multi-centre, non-blinded, open-label phase II basket trialResearch in context EClinicalMedicine Checkpoint inhibitors Rare cancers Ovarian carcinoma |
| title | Durvalumab and tremelimumab in patients with advanced rare cancer: a multi-centre, non-blinded, open-label phase II basket trialResearch in context |
| title_full | Durvalumab and tremelimumab in patients with advanced rare cancer: a multi-centre, non-blinded, open-label phase II basket trialResearch in context |
| title_fullStr | Durvalumab and tremelimumab in patients with advanced rare cancer: a multi-centre, non-blinded, open-label phase II basket trialResearch in context |
| title_full_unstemmed | Durvalumab and tremelimumab in patients with advanced rare cancer: a multi-centre, non-blinded, open-label phase II basket trialResearch in context |
| title_short | Durvalumab and tremelimumab in patients with advanced rare cancer: a multi-centre, non-blinded, open-label phase II basket trialResearch in context |
| title_sort | durvalumab and tremelimumab in patients with advanced rare cancer a multi centre non blinded open label phase ii basket trialresearch in context |
| topic | Checkpoint inhibitors Rare cancers Ovarian carcinoma |
| url | http://www.sciencedirect.com/science/article/pii/S2589537024005704 |
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