In preclinical models, the proteasome inhibitor bortezomib (PS-341) inhibits the growth of small cell lung cancer (SCLC) by inhibiting the antiapoptotic Bcl-2 signaling pathway. We conducted a phase II trial of PS-341 in previously treated patients with platinum-sensitive and -refractory extensive stage SCLC to determine response rate, toxicity, and survival. Methods: Patients with histologically confirmed SCLC, measurable disease, Zubrod performance status 0 -1, and previous treatment with

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... inum-based therapy were enrolled. They were stratified by platinum-sensitivity status: sensitive (relapse Ͼ90 days after platinum) or refractory (progression during or Յ90 days after platinum). PS-341 was administered at 1.3 mg/m 2 intravenously on days 1, 4, 8, and 11 every 21 days. Results: Of 56 eligible patients, 28 were platinum sensitive and 28 refractory. Twenty-nine patients (52%) had received two or more previous chemotherapy regimens. One platinum-refractory patient had a confirmed partial response. A majority of assessable patients (91%) progressed. Median progression-free survival and overall survival were 1 month and 3 months, respectively. Ten patients (18%) discontinued treatment due to adverse events or side effects. Conclusion: Although PS-341 induced a response in a patient with platinum-refractory disease, it has limited single-agent activity in this heavily pretreated cohort. As shown in preclinical models, testing of PS-341 in combination with an apoptotic trigger such as chemotherapy, is a rational clinical approach. A trial of topotecan plus PS-341 has been initiated to test this concept. FIGURE 1. Confirmed partial response to PS-341 in a patient with platinum-refractory small cell lung cancer. FIGURE 2. Kaplan-Meier overall survival curves.