Bortezomib (PS-341) in Relapsed or Refractory Extensive Stage Small Cell Lung Cancer: A Southwest Oncology Group Phase II Trial (S0327).
J Thorac Oncol. 2006 Nov;1(9):996-1001.
Lara PN Jr, Chansky K, Davies AM, Franklin WA, Gumerlock PH, Guaglianone PP, Atkins JN, Farneth N, Mack PC, Crowley JJ, Gandara DR.
*University of California, Davis Cancer Center, Sacramento, CA; daggerVeterans Administration of Northern California, Martinez, CA; double daggerSouthwest Oncology Group Statistical Center, Seattle, WA; section signUniversity of Colorado Health Sciences Center, Denver, CO; ||Central Illinois Community Clinical Oncology Program, Decatur, IL; paragraph signSoutheastern CCC Community Clinical Oncology Program, Goldsboro, NC.
BACKGROUND:: 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 platinum-based therapy were enrolled. They were stratified by platinum-sensitivity status: sensitive (relapse >90 days after platinum) or refractory (progression during or </=90 days after platinum). PS-341 was administered at 1.3 mg/m 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. |
