Pembrolizumab plus dinaciclib in patients with hematologic malignancies: the phase 1b KEYNOTE-155 study

Area of Science:

• Oncology
• Immunotherapy
• Pharmacology

Background:

• Preclinical studies indicated that combining anti-programmed cell death 1 (PD-1) inhibitors with cyclin-dependent kinase 9 (CDK9) inhibitors enhances antitumor activity.
• This combination strategy showed potential with no significant toxicities observed in preclinical models.

Purpose of the Study:

• To evaluate the safety and antitumor activity of pembrolizumab (a PD-1 inhibitor) combined with dinaciclib (a CDK9 inhibitor).
• The study focused on patients with relapsed or refractory (rr) chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM).

Main Methods:

• A phase 1, multicohort study (KEYNOTE-155) enrolled 72 patients with confirmed diagnoses of CLL, DLBCL, or MM.
• Patients received pembrolizumab (200 mg every 3 weeks) plus dinaciclib at escalating doses (7 mg/m2 on day 1 and 10 mg/m2 on day 8 of cycle 1, then 14 mg/m2 on days 1 and 8 of subsequent cycles).
• The study included dose-evaluation and signal-detection phases, with safety and objective response rate (ORR) as primary and key secondary endpoints, respectively.

Main Results:

• The combination of pembrolizumab and dinaciclib was generally well-tolerated, with no unexpected toxicities.
• Objective response rates (ORRs) were observed in 29.4% of rrCLL patients (5/17) and 21.1% of rrDLBCL patients (8/38).
• No responses were observed in the rrMM cohort (0/17); 52.8% of all patients discontinued treatment due to progressive disease.

Conclusions:

• The combination of pembrolizumab and dinaciclib demonstrated activity in patients with relapsed/refractory CLL and DLBCL.
• The safety profile was acceptable, supporting further investigation of this therapeutic combination.
• Comprehensive exploration of anti-PD-1 and CDK9 inhibitor combinations is warranted in hematologic malignancies.