Randomized phase II trial of two dosing schedules of BI 2536, a novel Plk-1 inhibitor, in patients with relapsed advanced or metastatic non-small-cell lung cancer (NSCLC)

Abstract

8030 Background: BI 2536 is a novel, highly selective, potent inhibitor of Polo-like kinase 1 (Plk1), a key regulator of mitotic progression; BI 2536 has demonstrated favorable tolerability and antitumor activity in Phase I trials. We investigated the efficacy, safety and pharmacokinetics (PK) of two dosing schedules of BI 2536 in patients with relapsed advanced or metastatic NSCLC. Methods: Patients with NSCLC Stage IIIB/IV and ECOG performance status ≤2 who had relapsed after 1st- or 2nd-line therapy were randomized to receive BI 2536 on Day 1 (200 mg) or Days 1–3 (3×50 mg/3×60 mg) of 21-day treatment courses. Primary endpoint was objective response according to RECIST. Secondary endpoints were progression-free and overall survival (PFS and OS). Adverse events (AEs) were evaluated using common terminology criteria for AEs. Doses were escalated every other treatment course if well tolerated. Plasma was collected for population PK analysis. Results: Of 95 patients, four had partial responses (three in the Day-1 and one in the Day 1–3 schedule). PFS and OS were 58 days (95% CI: 48–85) and 189 days (95% CI: 176–304; 47 patients censored). Grade 4 neutropenia occurred in 36% of patients; one had febrile neutropenia. Two deaths (due to sepsis and pulmonary hemorrhage) were potentially related to BI 2536. Common, generally mild, non-hematological AEs were fatigue (30%) and nausea (26%). Preliminary model-based PK analyses indicate BI 2536 is a high-clearance compound (>1,000 mL/min) which quickly distributes in multiple compartments in a large volume of distribution (>1,000 litres). Estimated elimination half-life was >20 hours. Conclusion: Preliminary results show moderate efficacy and acceptable safety of BI 2536 monotherapy in relapsed NSCLC, thus validating Plk1 as a promising target for this novel class of antiproliferatives. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Boehringer Ingelheim, Boehringer Ingelheim Pharma GmbH & Co. KG Boehringer Ingelheim Pharma, Boehringer Ingelheim Pharma GmbH & Co. KG, Hoffman-La Roche, Lilly Oncology Bayer HealthCare, Boehringer Ingeheim Pharma, Hoffman-La Roche, Lilly Oncology