PD-1/PD-L1 inhibitors have shown clinical benefit in mUC; however, the ORR is 15-25%, highlighting the need for more effective therapies. Gunderson, et al 2015 showed activation of Bruton tyrosine kinase (BTK) in myeloid cells of the pancreatic tumor microenvironment. As myeloid suppression impairs T-cell anti-tumor function, BTK inhibition may augment checkpoint inhibitor T-cell activation. This study assessed safety and efficacy of the PD-1 inhibitor pembrolizumab (P) alone or with the BTK inhibitor acalabrutinib (PA) in mUC.
Patients (pts) with mUC who progressed with ≥1 line of platinum chemotherapy were randomized 1:1 to P (200 mg Q3W IV) or PA (200 mg Q3W+100 mg BID PO). Pts who progressed (irRECIST) with monotherapy were permitted to cross over to combination therapy. Primary objectives were safety and ORR (local review, RECIST 1.1). Secondary endpoints included PFS and OS. Tumor PD-L1 expression was evaluated by Q2Solutions.
Between Jun 2015 and Jan 2016, 75 pts were treated with P (n = 35) or PA (n = 40); cross over, n = 10. Median age, 66 y; men, 76%; ECOG PS 0-1, 97%; median prior therapies, 2 (range, 1-4). In P/PA median (mos) time on study treatment, 2.96/1.94; median follow-up, 11.2/6.1. Grade 3-4 treatment-emergent AEs (%) in ≥ 15% of P or PA was anemia (20) in P and fatigue (23), increased alanine aminotransferase (23), urinary tract infection (18), and anemia (15) in PA. There were 3 fatal AEs in PA: hemoptysis and sepsis (unrelated); pneumonia (P-related). ORR was 26% (CR, 9%) with P and 20% (CR, 10%) with PA. Median PFS was similar between treatment arms; median OS was 11.4 and 6.3 mos in P vs PA (Table). Most pts (49/60) had PD-L1+ tumors; expression was not associated with improved ORR (Table).Table:
|Pembrolizumab n = 35||Pembrolizumab + acalabrutinib n = 40|
|Safety, n (%) (excluding events after cross over)|
|Any grade 3-4 AE||17 (49)||29 (73)|
|Any treatment-related grade 3-4 AE||6 (17)||21 (53)|
|Any grade 3-4 SAE||12 (34)||20 (50)|
|Any treatment-related 3-4 SAE||0 (0)||6 (15)|
|AE leading to study drug discontinuation||7 (20)||15 (38)|
|Grade 5 AE||0 (0)||3 (8)|
|Treatment-emergent AEs, n (%) (any grade, ≥30% of all pts)|
|Fatigue||16 (46)||33 (83)|
|Decreased appetite||13 (37)||17 (43)|
|Diarrhea||7 (20)||15 (38)|
|Anemia||7 (20)||14 (35)|
|Vomiting||10 (29)||12 (30)|
|ORR, % (95% CI) [n/N]|
|Overall population||26 (13, 43) [9/35]||20 (9, 36) [8/40]|
|PD-L1+ population||23 (8, 45) [5/22]||22 (9, 42) [6/27]|
|Median PFS, mo (95% CI)||1.6 (1.4, 4.2)||2.2 (1.4, 3.5)|
|Median OS, mo (95% CI)||11.4 (5.7, NE)||6.3 (3.6, 12.3)|
|12 mo OS, % (95% CI)||44.1 (27.2, 59.8)||38.5 (23.5, 53.3)|
AE, adverse event; CI, confidence interval; mo, month; NE, not estimable; ORR, overall response rate; PFS, progression-free survival; SAE, serious adverse event; OS, overall survival.
Most pts tolerated the study treatment, although more PA-treated pts had grade 3-4 AEs. Acalabrutinib plus pembrolizumab did not improve ORR over pembrolizumab alone in pts with mUC, regardless of PD-L1 status.
Clinical trial identification
Legal entity responsible for the study
T. Zhang: Stock ownership: Capio Biosciences; Consulting/Advisory Role: Bayer, GI Therapeutics; Research Funding: Janssen, Acerta Pharma, Pfizer, Merrimack, StemCentrX. M. Harrison: Research Funding: Acerta, Bristol-Myers Squib, Genentech, Merck, Pfizer; Consulting/Advisory Role: AstraZeneca, Exelixis, Genentech; Speaker\'s Bureau: AstraZeneca, Exelixis, Genentech. P. O\'Donnell: Stock: DVA, PrescriptIQ, AGN; Honoraria: Algeta ASA, Genentech/ROG, NVS, American Medical Forum, MRK, AstraZeneca, Astellas, Seattle Genetics, INO, Janssen, PRXL; Rsrch Fund: BI, MRK, Genentech/ROG, AZN/Medimmune, Acerta, Janssen; Exprt Testmny: Trinity Health. A. Alva: Speakers Bureau: AstraZeneca; Research Funding: Bayer, Merck, Genentech, and Progenics. N. Hahn: Advisory: OncoGeneX, AstraZeneca, Merck, Bristol-Myers Squib, Genentech, Inovio, Principia Biopharma, Champions Oncology, Health Advances, TARIS Biomedical, Seattle Genetics; Research Funding: Novartis, OncoGeneX, Mirati, Merck, Genentech, Bristol-Myers Squib, Heat Biologics, Acerta, AstraZeneca, Principia Biopharma. L.J. Appleman: Research Funding: Acerta Pharma. J. Burke: Consulting or Advisory Role: Pfizer, Incyte, Celgene, Genentech, Bayer; Travel Expenses: TG Therapeutics. M. Fleming: Speaker\'s bureau: Genentech. M. Milowsky: Advisory: Inovio Pharmaceuticals, Genentech, AstraZeneca; Research Funding: Mirati, Pfizer, Cerulean, Merck, Seattle Genetics, Acerta, BioClin, Roche/Genentech, Bristol-Myers Squibb, X4 Pharma, MedImmune, Incyte, Innocrin Pharma, Inovio Pharma. A. Mortazavi: Research Funding: Acerta Pharma, Genentech, Merck, Novartis; Honoraria: Motive Medical Intelligence; Consultancy/Advisory Role: Genentech-Roche. N. Shore: Consulting or Advisory Role: Amgen, Astellas, Bayer, Dendreon, Ferring Pharmaceuticals, Janssen, Medivation, Sanofi, Tolmar, Inc; Speaker\'s Bureau: Janssen, Bayer, Dendreon. E.V. Schmidt: Employment: MSD, Merck; Stock: MSD. C. Kresja, T. Chen, A. Hamdy: Employment: Acerta Pharma. B. Bitman: Employment: Acerta Pharma; Stock: AstraZeneca. R. Izumi: Employment/Equity Ownership/Patents: Acerta Pharma. D.J. George: Rsrch Suprt and Cnsltnt: Astellas/Mediviation, Byr, Bristol-Myers Squib, Exelixis, J&J, Novartis, Pfizer, Viamet/Innocrin Rshrch Suprt: Acerta, Gntech, Millennium Cnsltnt: Acceleron, Clovis, Dendreon/Valeant, Merck, Myovant Spker: Byr, Dendreon/Valeant, Snofi-Avnts. All other authors have declared no conflicts of interest.