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

被引：459

作者：

Rudin, Charles M. ^{[1
]}

Hann, Christine L. ^{[1
]}

Garon, Edward B. ^{[3
]}

de Oliveira, Moacyr Ribeiro ^{[4
]}

Bonomi, Philip D. ^{[5
]}

Camidge, D. Ross ^{[7
]}

Chu, Quincy ^{[8
]}

Giaccone, Giuseppe ^{[2
]}

Khaira, Divis ^{[9
]}

Ramalingam, Suresh S. ^{[10
]}

Ranson, Malcolm R. ^{[11
]}

Dive, Caroline ^{[12
]}

McKeegan, Evelyn M. ^{[6
]}

Chyla, Brenda J. ^{[6
]}

Dowell, Barry L. ^{[6
]}

Chakravartty, Arunava ^{[6
]}

Nolan, Cathy E. ^{[6
]}

Rudersdorf, Niki ^{[6
]}

Busman, Todd A. ^{[6
]}

Mabry, Mack H. ^{[6
]}

Krivoshik, Andrew P. ^{[6
]}

Humerickhouse, Rod A. ^{[6
]}

Shapiro, Geoffrey I. ^{[13
]}

Gandhi, Leena ^{[13
]}

机构：

[1] Johns Hopkins Univ, Baltimore, MD 21218 USA

[2] NCI, Baltimore, MD USA

[3] Univ Calif Los Angeles, Los Angeles, CA USA

[4] PLLC, Tacoma, WA USA

[5] Rush Univ, Med Ctr, Chicago, IL USA

[6] Abbott Labs, Chicago, IL USA

[7] UC Davis Canc Ctr, Sacramento, CA USA

[8] Univ Alberta, Cross Canc Inst, Alberta Hlth Serv, Edmonton, AB T6G 2M7, Canada

[9] Sunterra Oncol Associates, Phoenix, AZ USA

[10] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA

[11] Christie NHS Fdn Trust, Manchester, Lancs, England

[12] Univ Manchester, Paterson Inst Canc Res, Manchester, Lancs, England

[13] Dana Farber Canc Inst, Boston, MA 02115 USA

来源：

CLINICAL CANCER RESEARCH | 2012年 / 18卷 / 11期

关键词：

SMALL-MOLECULE INHIBITOR; CIRCULATING TUMOR-CELLS; BCL-2 FAMILY INHIBITOR; APOPTOSIS PROTEIN XIAP; X-LINKED INHIBITOR; CARCINOMA-CELLS; PROGNOSTIC-FACTORS; CLINICAL-EFFICACY; GENE-EXPRESSION; SOLID TUMORS;

D O I：

10.1158/1078-0432.CCR-11-3090

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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-x(L). 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, neuron-specific 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. Preclinical models support that navitoclax may enhance sensitivity of SCLC and other solid tumors to standard cytotoxics. Future studies will focus on combination therapies. Clin Cancer Res; 18(11); 3163-9. (C) 2012 AACR.

引用

页码：3163 / 3169

页数：7

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