Safety, immunologic and clinical activity of Durvalumab in combination with Olaparib or Cediranib in advanced leiomyosarcoma: Results of the DAPPER clinical trial

Non-inflamed (cold) tumors such as leiomyosarcoma (LMS) do not benefit from immune checkpoint blockade (ICB) monotherapy. Combining ICB with angiogenesis-, or poly-ADP ribose polymerase (PARP) inhibitors may increase tumor immunogenicity by altering the immune cell composition of the tumor microenvi...

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Veröffentlicht in:Clinical cancer research 2023-10, Vol.29 (20), p.4128-4138
Hauptverfasser: Salawu, Abdulazeez, Wang, Ben X, Han, Ming, Geady, Caryn, Heirali, Alya, Berman, Hal K, Pfister, Thomas D, Hernando-Calvo, Alberto, Al-Ezzi, Esmail Mutahar, Stayner, Lee-Anne, Gupta, Abha A, Ayodele, Olubukola, Lam, Bernard, Hansen, Aaron R, Spreafico, Anna, Bedard, Philippe L, Butler, Marcus O, Avery, Lisa, Coburn, Bryan, Haibe-Kains, Benjamin, Siu, Lillian L, Abdul Razak, Albiruni R
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Sprache:eng
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Zusammenfassung:Non-inflamed (cold) tumors such as leiomyosarcoma (LMS) do not benefit from immune checkpoint blockade (ICB) monotherapy. Combining ICB with angiogenesis-, or poly-ADP ribose polymerase (PARP) inhibitors may increase tumor immunogenicity by altering the immune cell composition of the tumor microenvironment (TME). The DAPPER phase II study evaluated the safety, immunologic, and clinical activity of ICB-based combinations in pre-treated LMS patients. Patients were randomized to receive durvalumab 1500mg IV q4w with either Olaparib 300mg bid PO (Arm A) or Cediranib 20mg qd PO on 5 days/week (Arm B) until unacceptable toxicity or disease progression. Paired tumor biopsies, serial radiological assessments and stool collections were performed. Primary endpoints were safety, and immune cell changes in the TME. Objective responses and survival were correlated with transcriptomic, radiomic and microbiome parameters. Among 30 heavily pre-treated patients (15 on each arm), grade ≥ 3 toxicity occurred in 3 (20%) and 2 (13%) on Arms A and B, respectively. On arm A, 1 patient achieved partial response (PR) with increase in CD8 T-cells and macrophages in the TME during treatment, while 4 had stable disease ≥ 6 months (SD-6m). No patients on Arm B achieved PR or SD-6m. Transcriptome analysis showed that baseline M1-macrophage and B-cell activity were associated with overall survival. Durvalumab plus olaparib increased immune cell infiltration of TME with clinical benefit in some LMS patients. Baseline M1-macrophage and B-cell activity may identify LMS patients with favorable outcomes on immunotherapy and should be further evaluated.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-23-1137