Bortezomib (PS-341) in relapsed or refractory extensive stage small cell lung cancer: a Southwest Oncology Group phase II trial (S0327).
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 < 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.


CONCLUSIONS
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.
Lara
Primo N
PN
University of California, Davis Cancer Center, Sacramento, CA 95817, USA. primo.lara@ucdmc.ucdavis.edu
Chansky
Kari
K
Davies
Angela M
AM
Franklin
Wilbur A
WA
Gumerlock
Paul H
PH
Guaglianone
Perry P
PP
Atkins
James N
JN
Farneth
Nichole
N
Mack
Philip C
PC
Crowley
John J
JJ
Gandara
David R
DR
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D000069286:Bortezomib; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016001:Confidence Intervals; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011336:Probability; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects; D012074:Remission Induction; D018570:Risk Assessment; D016019:Survival Analysis
D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib