Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer

Charles M. Rudin, Christine L. Hann, Edward B. Garon, Moacyr Ribeiro De Oliveira, Philip D. Bonomi, D. Ross Camidge, Quincy Chu, Giuseppe Giaccone, Divis Khaira, Suresh S. Ramalingam, Malcolm R. Ranson, Caroline Dive, Evelyn M. McKeegan, Brenda J. Chyla, Barry L. Dowell, Arunava Chakravartty, Cathy E. Nolan, Niki Rudersdorf, Todd A. Busman, Mack H. MabryAndrew P. Krivoshik, Rod A. Humerickhouse, Geoffrey I. Shapiro, Leena Gandhi

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)3163-3169
Number of pages7
JournalClinical Cancer Research
Volume18
Issue number11
DOIs
StatePublished - Jun 1 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Rudin, C. M., Hann, C. L., Garon, E. B., Ribeiro De Oliveira, M., Bonomi, P. D., Camidge, D. R., Chu, Q., Giaccone, G., Khaira, D., Ramalingam, S. S., Ranson, M. R., Dive, C., McKeegan, E. M., Chyla, B. J., Dowell, B. L., Chakravartty, A., Nolan, C. E., Rudersdorf, N., Busman, T. A., ... Gandhi, L. (2012). Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clinical Cancer Research, 18(11), 3163-3169. https://doi.org/10.1158/1078-0432.CCR-11-3090