PS1075 ANTITUMOR ACTIVITY OF PEMBROLIZUMAB PLUS DINACICLIB IN PATIENTS WITH DIFFUSE LARGE B CELL LYMPHOMA: THE PHASE 1B KEYNOTE‐155 STUDY
Authors: Gregory G. , Walker P. , Mahadevan D. , Wang D. , Chang J. , Hernandez‐Ilizaliturri F. , Klein A. , Rybka W. , Wagner‐Johnston N. , Escobar C. , Pagel J.M. , Mohrbacher A. , Opat S. , Shortt J. , Ma H. , Gwo J. , Farooqui M. , Quach H. 
Published: June 2019

Background:The cyclin‐dependent kinase inhibitor dinaciclib induces apoptosis by CDK9 inhibition with antitumor activity in preclinical syngeneic lymphoma models and early phase trials of hematologic malignancies including diffuse large B‐cell lymphoma (DLBCL). Murine syngeneic tumor models (MC‐38) showed combined anti‐tumor activity of anti‐PD‐1 antibody and dinaciclib via enhanced dinaciclib‐induced immunogenic cell death. KEYNOTE‐155 (NCT02684617) evaluated the antitumor activity of pembrolizumab plus dinaciclib in patients (pts) with relapsed/refractory (rr) CLL, MM, and DLBCL.Aims:To present data from an interim analysis of safety and efficacy in pts with rrDLBCL.Methods:In this phase 1b, two‐part, non‐randomized, open‐label study, pts with rrDLBCL who received ≥2 prior therapies were enrolled into an initial dose‐evaluation phase (two 21‐day cycles of pembrolizumab 200 mg [day 1] and dinaciclib 7 mg/m2 [day 1], 10 mg/m2 [day 8] in cycle 1 and 14 mg/m2 [day 1, day 8] from cycle 2 onwards). The DLBCL expansion cohort was opened for the signal‐detection phase (≥30 patients) if ≤4 pts had dose‐limiting toxicities (DLTs) in the dose‐evaluation phase. Treatment continued for up to 35 cycles or until disease progression (PD) or unacceptable toxicity. Response was assessed every 3 cycles for DLBCL (Revised Response Criteria for Malignant Lymphoma 2007). Pts who discontinued before PD were followed Q12W until documented PD, new anticancer treatment, or death. The primary endpoint was safety and tolerability. Secondary endpoints included ORR by investigator, DOR, PFS, and OS. AEs were graded per National Cancer Institute Common Terminology Criteria for AEs. Efficacy and safety were assessed in all pts who received ≥1 dose of pembrolizumab or dinaciclib.Results:As of Apr 25, 2018, 38 pts with rrDLBCL were enrolled and treated. Median age was 64.5 years (range, 39–85), 22 (58%) pts had ECOG PS 1, and 22 (58%) had ≥3 prior therapies. After a median follow‐up of 2.79 mo (range, 1.5–6.8), 36 (95%) pts discontinued treatment: 21 (55%) PD, 12 (32%) physician decision (10 [26%] clinical progression, 1[3%] logistics, 1 [3%] new therapy), 2 (5%) pt decision, and 1 (3%) AE. Median time on treatment was 51 days (range, 1–471). Among the 12 pts in all disease cohorts enrolled in the dose‐evaluation phase, DLTs occurred in 1 of 6 (17%) evaluable pts (grade 4 thrombocytopenia) with rrDLBCL. Of 38 pts with rrDLBCL, 24 (63%) had a treatment‐related AE. The most common treatment‐related AEs included decreased platelets (21%), lymphopenia (16%), nausea (13%), anemia (13%), diarrhea (13%), and pyrexia (13%). 12 (32%) pts had a grade 3–4 treatment‐related AE. The most common grade 3–4 treatment‐related AEs included lymphopenia (13%), decreased neutrophils (11%), decreased platelets (8%), leukopenia (8%), and laboratory tumor lysis syndrome (5%). There was no clinical TLS and no treatment‐related deaths. ORR was 18% (95% CI, 8–34) (3 CR and 4 PR) and median DOR was 4.9 mo (range, 2.1–13.8); 2 pts remained on treatment at data cutoff. With 36 (95%) events, median PFS was 2.1 mo (95% CI, 2–3) with 6‐mo and 12‐mo PFS rates of 13% and 8%, respectively. 19 (50%) pts died, with median OS of 9.8 mo (95% CI, 3 to not reached), and 12‐mo OS rate of 43%.Summary/Conclusion:Despite limited overall response, the observed CRs and durability (up to 13 mo) provide proof of concept for activity of this combination in rrDLBCL and rationale for further studies to define optimal dosing of dinaciclib, given the brevity of CDK9 inhibition observed in preclinical models.