Phase II Study of Single-Agent Navitoclax (ABT-263) and Biomarker Correlates in Patients with Relapsed Small Cell Lung Cancer

• Type of Material: Article
• Authors: Charles M. Rudin, Johns Hopkins University; Christine L. Hann, Johns Hopkins University; Edward B. Garon, University of California, Los Angeles; Moacyr Ribeiro de Oliveira, Northwest Medical Specialties; Philip D. Bonomi, Rush University; D. Ross Camidge, UC Davis Cancer Center; Quincy Chu, University of Alberta; Giuseppe Giaccone, National Cancer Institute; Divis Khaira, Sunterra Oncology Associates; Suresh S Ramalingam, Emory University; Malcolm R. Ranson, Christie NHS Foundation Trust; Caroline Dive, University of Manchester; Evelyn M. McKeegan, Abbott Laboratories; Brenda J. Chyla, Abbott Laboratories; Barry L. Dowell, Abbott Laboratories; Arunava Chakravartty, Abbott Laboratories; Cathy E. Nolan, Abbott Laboratories; Niki Rudersdorf, Abbott Laboratories; Todd A. Busman, Abbott Laboratories; Mack H. Mabry, Abbott Laboratories; Andrew P. Krivoshik, Abbott Laboratories; Rod A. Humerickhouse, Abbott Laboratories; Geoffrey I. Shapiro, Dana Farber Cancer Institute; Leena Gandhi, Dana Farber Cancer Institute
• Language: Serbian
• Date: 2012-06-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2012 AACR.
• Final Published Version (URL): http://dx.doi.org/10.1158/1078-0432.CCR-11-3090
• Title of Journal or Parent Work: Clinical Cancer Research
• ISSN: 1078-0432
• Volume: 18
• Issue: 11
• Start Page: 3163
• End Page: 3169
• Keywords: APOPTOSIS PROTEIN XIAP; Science & Technology; X-LINKED INHIBITOR; Life Sciences & Biomedicine; CLINICAL-EFFICACY; PROGNOSTIC-FACTORS; CARCINOMA-CELLS; SMALL-MOLECULE INHIBITOR; SOLID TUMORS; GENE-EXPRESSION; Oncology; CIRCULATING TUMOR-CELLS; BCL-2 FAMILY INHIBITOR
• Research Categories: Health Sciences, Oncology

Abstract

Purpose: Bcl-2 is a critical regulator of apoptosis that is overexpressed in the majority of small cell lung cancers (SCLC). Nativoclax (ABT-263) is a potent and selective inhibitor of Bcl-2 and Bcl-xL. The primary objectives of this phase IIa study included safety at the recommended phase II dose and preliminary, exploratory efficacy assessment in patients with recurrent and progressive SCLC after at least one prior therapy. Experimental Design: Thirty-nine patients received navitoclax 325 mg daily, following an initial lead-in of 150 mg daily for 7 days. Study endpoints included safety and toxicity assessment, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates. Results: The most common toxicity associated with navitoclax was thrombocytopenia, which reached grade III-IV in 41% of patients. Partial response was observed in one (2.6%) patient and stable disease in 9 (23%) patients. Median PFS was 1.5 months and median OS was 3.2 months. A strong association between plasma pro-gastrin-releasing peptide (pro-GRP) level and tumor Bcl-2 copy number (R = 0.93) was confirmed. Exploratory analyses revealed baseline levels of cytokeratin 19 fragment antigen 21-1, neuronspecific enolase, pro-GRP, and circulating tumor cell number as correlates of clinical benefit. Conclusion: Bcl-2 targeting by navitoclax shows limited single-agent activity against advanced and recurrent SCLC. Correlative analyses suggest several putative biomarkers of clinical benefit. Preclinicalmodels support that navitoclaxmay enhance sensitivity of SCLC and other solid tumors to standard cytotoxics. Future studies will focus on combination therapies.