Clinical cancer research : an official journal of the American Association for Cancer Research · 2025
Clinical and Translational Results from PORTER, a Multicohort Phase I Platform Trial of Combination Immunotherapy in Metastatic Castration-Resistant Prostate Cancer.
СтатьяКлиническое исследование I фазыМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Galsky Matthew D, Autio Karen A, Cabanski Christopher R, Wentzel Kristopher, Graff Julie N, Friedlander Terence W, Howes Timothy R, Shotts Kristin M, Densmore Julie, Spasic Marko, Da Silva Diane M, Chen Richard O, Lata Jennifer, Skolnik Jeffrey, Keler Tibor, Yellin Michael J, LaVallee Theresa M, Fairchild Justin, Boffo Silvia, O'Donnell-Tormey Jill, Dugan Ute, Bhardwaj Nina, Subudhi Sumit K, Fong Lawrence
Аннотация
PURPOSE: Current immune checkpoint therapies offer limited benefits for metastatic castration-resistant prostate cancer. Novel combinations may enhance immunotherapy efficacy.
PATIENTS AND METHODS: We conducted an open-label, noncomparative platform trial (NCT03835533) in metastatic castration-resistant prostate cancer to assess nivolumab-based combinations. The cohorts were as follows: (A) bempegaldesleukin 0.006 mg/kg and nivolumab 360 mg i.v. every 3 weeks; (B) stereotactic body radiotherapy 30 to 50 Gy, CDX-301 75 μg/kg s.c. for 5 days, poly-ICLC 1 mg intramuscularly weekly twice for 3 weeks, and nivolumab 480 mg every 4 weeks; and (C) CDX-301 75 μg/kg for 10 days, INO-5151 3 mg intramuscularly on lead-in day 8, day 1 of cycles 1 to 3, and then every 12 weeks, and nivolumab 480 mg every 4 weeks. The primary endpoint was safety; secondary endpoints included composite response rate (radiographic, PSA, or circulating tumor cell responses), 6-month disease control rate, progression-free survival, and overall survival. Serial blood and tissue samples were analyzed for pharmacodynamics and association with disease control.
RESULTS: A total of 43 patients were enrolled (n = 14, 15, and 14 in cohorts A, B, and C, respectively). Grade 3 to 4 treatment-related adverse events occurred in 10 (71%), 2 (13%), and 2 (14%) patients, respectively, with one grade 5 treatment-related adverse event in cohort A. Composite response rates were 7% (1/14), 33% (5/15), and 7% (1/14). Across cohorts, 6-month disease control was associated with preexisting memory/regulatory T cells, TNFα, and other inflammatory pathways.
CONCLUSIONS: Cohort B, which combined radiotherapy with CDX-301, poly-ICLC, and nivolumab, demonstrated encouraging clinical activity. Preexisting rather than treatment-induced immune activation was associated with clinical benefit across cohorts, highlighting the importance of baseline immune fitness.
PATIENTS AND METHODS: We conducted an open-label, noncomparative platform trial (NCT03835533) in metastatic castration-resistant prostate cancer to assess nivolumab-based combinations. The cohorts were as follows: (A) bempegaldesleukin 0.006 mg/kg and nivolumab 360 mg i.v. every 3 weeks; (B) stereotactic body radiotherapy 30 to 50 Gy, CDX-301 75 μg/kg s.c. for 5 days, poly-ICLC 1 mg intramuscularly weekly twice for 3 weeks, and nivolumab 480 mg every 4 weeks; and (C) CDX-301 75 μg/kg for 10 days, INO-5151 3 mg intramuscularly on lead-in day 8, day 1 of cycles 1 to 3, and then every 12 weeks, and nivolumab 480 mg every 4 weeks. The primary endpoint was safety; secondary endpoints included composite response rate (radiographic, PSA, or circulating tumor cell responses), 6-month disease control rate, progression-free survival, and overall survival. Serial blood and tissue samples were analyzed for pharmacodynamics and association with disease control.
RESULTS: A total of 43 patients were enrolled (n = 14, 15, and 14 in cohorts A, B, and C, respectively). Grade 3 to 4 treatment-related adverse events occurred in 10 (71%), 2 (13%), and 2 (14%) patients, respectively, with one grade 5 treatment-related adverse event in cohort A. Composite response rates were 7% (1/14), 33% (5/15), and 7% (1/14). Across cohorts, 6-month disease control was associated with preexisting memory/regulatory T cells, TNFα, and other inflammatory pathways.
CONCLUSIONS: Cohort B, which combined radiotherapy with CDX-301, poly-ICLC, and nivolumab, demonstrated encouraging clinical activity. Preexisting rather than treatment-induced immune activation was associated with clinical benefit across cohorts, highlighting the importance of baseline immune fitness.