Randomized phase III trial comparing bexarotene (L1069-49)/cisplatin/vinorelbine with cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT I.
OBJECTIVE
This study evaluated whether the combination of the synthetic rexinoid bexarotene with first-line cisplatin/vinorelbine therapy provides additional survival benefit in patients with advanced non-small-cell lung cancer (NSCLC).


METHODS
Patients with stage IIIB with pleural effusion or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to open-label bexarotene 400 mg/m(2)/d with cisplatin/vinorelbine or to cisplatin/vinorelbine alone. Antilipid agents were initiated on or before day 1 in the bexarotene arm. Primary efficacy end point was overall survival. Primary, secondary and supportive efficacy analyses were conducted.


RESULTS
A total of 623 patients (312 control, 311 bexarotene) were enrolled. Overall, no significant difference in survival occurred between the two treatment groups. However, an unplanned retrospective analysis showed that a subpopulation of bexarotene patients (n = 98 of 306) who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had longer median survival compared with control patients (12.3 v 9.9 months; log-rank P = .08). Within that subgroup, those who benefited the most included males, smokers, those with stage IV disease, and those with a 6-month prior weight loss of 5% or more. Incidence, type and severity of grade 3/4 adverse events were comparable between arms, except for leukopenia (higher in chemotherapy arm) and hyperlipemia, hypothyroidism, dyspnea, and headache (higher in chemotherapy/bexarotene arm).


CONCLUSIONS
The addition of bexarotene to first-line chemotherapy did not increase survival in patients with advanced NSCLC. However, a subgroup (32%) of bexarotene-treated patients developing high-grade hypertriglyceridemia appeared to have better survival (12.3 months) than controls; thus triglyceride response may be a biomarker of survival benefit with bexarotene.
Ramlau
Rodryg
R
Lung Disease Centre, Oncology Department, ul.Szamarzewskiego, Poznań, Poland. rramlau@wcchpig.pl
Zatloukal
Petr
P
Jassem
Jacek
J
Schwarzenberger
Paul
P
Orlov
Sergei V
SV
Gottfried
Maya
M
Pereira
Jose Rodrigues
JR
Temperley
Guillermo
G
Negro-Vilar
Rosa
R
Rahal
Samia
S
Zhang
Joseph K
JK
Negro-Vilar
Andres
A
Dziewanowska
Zofia E
ZE
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000077610:Bexarotene; D014408:Biomarkers, Tumor / Q000097:blood*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology / Q000556:secondary; D002945:Cisplatin / Q000008:administration & dosage; D018450:Disease Progression; D005260:Female; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood / Q000139:chemically induced / Q000401:mortality; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016019:Survival Analysis; D015996:Survival Rate; D013764:Tetrahydronaphthalenes / Q000009:adverse effects; D014280:Triglycerides / Q000097:blood*; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
D014408:Biomarkers, Tumor; D013764:Tetrahydronaphthalenes; D014280:Triglycerides; D014747:Vinblastine; D000077610:Bexarotene; D002945:Cisplatin; D000077235:Vinorelbine