Pembrolizumab plus dinaciclib in patients with hematologic malignancies: the phase 1b KEYNOTE-155 study
Gareth P Gregory, Shaji Kumar, Ding Wang, Daruka Mahadevan, Patricia Walker, Nina Wagner-Johnston, Carolina Escobar, Rajat Bannerji, Divaya Bhutani, Julie Chang, Francisco J Hernandez-Ilizaliturri, Andreas Klein, John M Pagel, Witold Rybka, Andrew J Yee, Anne Mohrbacher, Mo Huang, Mohammed Farooqui, Patricia Marinello, Hang Quach, Gareth P Gregory, Shaji Kumar, Ding Wang, Daruka Mahadevan, Patricia Walker, Nina Wagner-Johnston, Carolina Escobar, Rajat Bannerji, Divaya Bhutani, Julie Chang, Francisco J Hernandez-Ilizaliturri, Andreas Klein, John M Pagel, Witold Rybka, Andrew J Yee, Anne Mohrbacher, Mo Huang, Mohammed Farooqui, Patricia Marinello, Hang Quach
Abstract
Preclinical data demonstrated that combining an anti-programmed cell death 1 (PD-1) inhibitor with a cyclin-dependent kinase 9 (CDK9) inhibitor provided enhanced antitumor activity with no significant toxicities, suggesting this combination may be a potential therapeutic option. The multicohort, phase 1 KEYNOTE-155 study evaluated the safety and antitumor activity of the PD-1 inhibitor pembrolizumab plus the CDK9 inhibitor dinaciclib in patients with relapsed or refractory (rr) chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Patients enrolled were ≥18 years of age with a confirmed diagnosis of CLL, DLBCL, or MM. The study included 2 phases: a dose-evaluation phase to determine dose-limiting toxicities and a signal-detection phase. Patients received pembrolizumab 200 mg every 3 weeks plus dinaciclib 7 mg/m2 on day 1 and 10 mg/m2 on day 8 of cycle 1 and 14 mg/m2 on days 1 and 8 of cycles 2 and later. Primary endpoint was safety, and a key secondary endpoint was objective response rate (ORR). Seventy-two patients were enrolled and received ≥1 dose of study treatment (CLL, n = 17; DLBCL, n = 38; MM, n = 17). Pembrolizumab plus dinaciclib was generally well tolerated and produced no unexpected toxicities. The ORRs were 29.4% (5/17, rrCLL), 21.1% (8/38, rrDLBCL), and 0% (0/17, rrMM), respectively. At data cutoff, all 72 patients had discontinued treatment, 38 (52.8%) because of progressive disease. These findings demonstrate activity with combination pembrolizumab plus dinaciclib and suggest that a careful and comprehensive approach to explore anti-PD-1 and CDK9 inhibitor combinations is warranted. This trial was registered at www.clinicaltrials.gov as NCT02684617.
© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
Figures
References
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Version 1.2021. Chronic Lymphocytic leukemia/Small Lymphocytic Lymphoma. Vol. 2020. Plymouth Meeting, PA: National Comprehensive Cancer Network; 2020.
- Shi L, Chen S, Yang L, Li Y. The role of PD-1 and PD-L1 in T-cell immune suppression in patients with hematological malignancies. J Hematol Oncol. 2013;6(1):74.
- Bose P, Simmons GL, Grant S. Cyclin-dependent kinase inhibitor therapy for hematologic malignancies. Expert Opin Investig Drugs. 2013;22(6):723-738.
- Li L, Pongtornpipat P, Tiutan T, et al. . Synergistic induction of apoptosis in high-risk DLBCL by BCL2 inhibition with ABT-199 combined with pharmacologic loss of MCL1. Leukemia. 2015;29(8):1702-1712.
- Gregory GP, Hogg SJ, Kats LM, et al. . CDK9 inhibition by dinaciclib potently suppresses Mcl-1 to induce durable apoptotic responses in aggressive MYC-driven B-cell lymphoma in vivo. Leukemia. 2015;29(6):1437-1441.
- Hossain DMS, Javaid S, Cai M, et al. . Dinaciclib induces immunogenic cell death and enhances anti-PD1-mediated tumor suppression. J Clin Invest. 2018;128(2):644-654.
- Chen R, Zinzani PL, Lee HJ, et al. . Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087. Blood. 2019;134(14):1144-1153.
- Armand P, Rodig S, Melnichenko V, et al. . Pembrolizumab in relapsed or refractory primary mediastinal large b-cell lymphoma. J Clin Oncol. 2019;37(34):3291-3299.
- Flynn J, Jones J, Johnson AJ, et al. . Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia. Leukemia. 2015;29(7):1524-1529.
- Gojo I, Sadowska M, Walker A, et al. . Clinical and laboratory studies of the novel cyclin-dependent kinase inhibitor dinaciclib (SCH 727965) in acute leukemias. Cancer Chemother Pharmacol. 2013;72(4):897-908.
- Kumar SK, LaPlant B, Chng WJ, et al. ; Mayo Phase 2 Consortium . Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood. 2015;125(3):443-448.
- Baiocchi RA, Flynn JM, Jones JA, et al. . Early evidence of anti-lymphoma activity of the cyclin dependent kinase inhibitor dinaciclib (sch 727965) in heavily pre-treated low grade lymphoma and diffuse large cell lymphoma patients. Blood. 2010;116(21):3966.
- Badros A, Hyjek E, Ma N, et al. . Pembrolizumab, pomalidomide, and low-dose dexamethasone for relapsed/refractory multiple myeloma. Blood. 2017;130(10):1189-1197.
- Ji Y, Wang SJ. Modified toxicity probability interval design: a safer and more reliable method than the 3 + 3 design for practical phase I trials. J Clin Oncol. 2013;31(14):1785-1791.
- Hallek M, Cheson BD, Catovsky D, et al. ; International Workshop on Chronic Lymphocytic Leukemia . Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456.
- Cheson BD, Pfistner B, Juweid ME, et al. ; International Harmonization Project on Lymphoma . Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-586.
- Durie BG, Harousseau JL, Miguel JS, et al. ; International Myeloma Working Group . International uniform response criteria for multiple myeloma [published corrections appear in Leukemia. 2006;20(12):2220 and 2007;21(5):1134]. Leukemia. 2006;20(9):1467-1473.
- Ribrag V, Avigan DE, Green DJ, et al. . Phase 1b trial of pembrolizumab monotherapy for relapsed/refractory multiple myeloma: KEYNOTE-013. Br J Haematol. 2019;186(3):e41-e44.
- Usmani SZ, Schjesvold F, Oriol A, et al. ; KEYNOTE-185 Investigators . Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019;6(9):e448-e458.
- Mateos MV, Blacklock H, Schjesvold F, et al. ; KEYNOTE-183 Investigators . Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019;6(9):e459-e469.
- Armand P, Lesokhin A, Borrello I, et al. . A phase 1b study of dual PD-1 and CTLA-4 or KIR blockade in patients with relapsed/refractory lymphoid malignancies. Leukemia. 2021;35(3):777-786.
- Zinzani PL, Santoro A, Gritti G, et al. . Nivolumab combined with brentuximab vedotin for relapsed/refractory primary mediastinal large B-cell lymphoma: efficacy and safety from the phase ii checkmate 436 study. J Clin Oncol. 2019;37(33):3081-3089.
- Godfrey J, Tumuluru S, Bao R, et al. . PD-L1 gene alterations identify a subset of diffuse large B-cell lymphoma harboring a T-cell-inflamed phenotype. Blood. 2019;133(21):2279-2290.
- Wright GW, Huang DW, Phelan JD, et al. . A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications. Cancer Cell. 2020;37(4):551-568.e14.
Source: PubMed