Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma.
BACKGROUND
The authors evaluated the safety, tolerability, and efficacy of treatment using lonafarnib, a novel farnesyltransferase inhibitor (FTI), in combination with paclitaxel in patients with metastatic (Stage IIIB/V), taxane-refractory/resistant nonsmall cell lung carcinoma (NSCLC).


METHODS
Patients with NSCLC who experienced disease progression while receiving previous taxane therapy or who had disease recurrence within 3 months after taxane therapy cessation were treated with continuous lonafarnib 100 mg orally twice per day beginning on Day 1 and paclitaxel 175 mg/m(2) intravenously over 3 hours on Day 8 of each 21-day cycle.


RESULTS
A total of 33 patients were enrolled, 29 of whom were evaluable for response. Partial responses (PR) and stable disease (SD) were observed in 3 (10%) and 11 patients (38%), respectively. Thus, 48% (14 of 29) experienced clinical benefit (PR or SD). The updated and final median overall survival time was 39 weeks and the median disease progression-free survival time was 16 weeks. The combination of lonafarnib and paclitaxel was well tolerated with minimal toxicity. Grade 3 toxicities included fatigue (9%), diarrhea (6%), and dyspnea (6%). Grade 3 neutropenia occurred in only 1 patient (3%). Grade 4 adverse events included respiratory insufficiency in 2 patients (6%) and acute respiratory failure in 1 patient (3%).


CONCLUSIONS
Lonafarnib plus paclitaxel demonstrated clinical activity in patients with taxane-refractory/resistant metastatic NSCLC. In addition, the combination of lonafarnib and paclitaxel was well tolerated with minimal toxicity. Evaluation of this combination therapy in additional clinical trials is warranted.
Kim
Edward S
ES
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77401, USA. edkim@mdanderson.org
Kies
Merrill S
MS
Fossella
Frank V
FV
Glisson
Bonnie S
BS
Zaknoen
Sara
S
Statkevich
Paul
P
Munden
Reginald F
RF
Summey
Carmen
C
Pisters
Katherine M W
KM
Papadimitrakopoulou
Vali
V
Tighiouart
Mourad
M
Rogatko
Andre
A
Khuri
Fadlo R
FR
D000328:Adult; D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001952:Bridged-Ring Compounds / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D051231:Farnesyltranstransferase; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D012074:Remission Induction; D015996:Survival Rate; D043823:Taxoids / Q000627:therapeutic use; D016896:Treatment Outcome; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D017239:Paclitaxel; D010880:Piperidines; D011725:Pyridines; D043823:Taxoids; C080625:taxane; C115354:lonafarnib; D003986:Dibenzocycloheptenes