A phase Ib trial of the cyclin-dependent kinase inhibitor dinaciclib (dina) in combination with pembrolizumab (P) in patients with advanced triple-negative breast cancer (TNBC).

Abstract

1072 Background: Increased expression of the MYC transcriptional oncogene is found in 70% of TNBC and is associated with poor prognosis. In MYC-overexpressing TN xenografts, CDK1 inhibition with dina results in synthetic lethality, and attenuates distant metastasis. In syngeneic models, the combination of dina with anti-PD1 therapy is synergistic and increases immune cell tumor infiltration and activation. Methods: Patients (pts) with advanced TNBC were enrolled. Pts received intravenous dina day 1 and 8 in combination with fixed dose P 200 mg once every 21 days. Dina was dose escalated using a toxicity probability interval design targeting a dose limiting toxicity (DLT) rate of 25%. Evaluable disease and pre-treatment metastatic biopsies were required. After 17 pts were enrolled, eligibility was amended to require ≤2 lines of prior chemotherapy, and LDH ≤1.5x normal. Results: 22 pts were enrolled (median age 50, median 2 prior lines of therapy, 10 pts (45%) had disease which was previously ER+). Dina was dose escalated from 12 to 33 mg/m2 in 4 cohorts. No DLTs were observed. Of the first 5 patients in the 33 mg/m2 cohort, 2 pts required a dose reduction (1 pt due to recurrent grade (G) 3 fever and G2 chills; 1 pt due to recurrent G2 diarrhea, chills, fatigue), and 1 pt discontinued due to G3 hemolytic anemia. 4 additional pts were treated at 33 mg/m2 without DLT or dose reduction. G ≥3 adverse events (AEs) in all pts included neutropenia (ntp) (36.3%), febrile ntp (13.6%), and fatigue (13.6%). Most common all-grade AEs included fatigue (73%), diarrhea (59%), nausea (50%), ntp (45%), mucositis (32%), anorexia (23%). Immune-related AEs included sinusitis (3 pts), hemolytic anemia (1 pt), pneumonitis (1pt), and rash (2 pts). Of 21 pts evaluable for response, 1 pt had complete response (4.8%), 2 pts had partial response (9.5%), and 5 pts had stable disease (23.8%). Dose expansion and correlative biomarker studies are ongoing. Conclusions: The recommended phase 2 dose of dinaciclib given in combination with pembrolizumab is 33 mg/m2 on D1, 8 of 21-day cycle. Toxicities are generally manageable with dose reduction and dose delay. Clinical trial information: NCT01676753.