A Randomized Phase III Trial Comparing Bexarotene/Carboplatin/Paclitaxel vs. Carboplatin/Paclitaxel in Chemotherapy-Naive Patients with Advanced or Metastatic NSCLC (SPIRIT II Trial)
Reviewer: S. Jack Wei, MD
University of Pennsylvania School of Medicine
Last Modified: May 15, 2005
Presenter: G.R. Blumenschein, Jr., MD
Presenter's Affiliation: SPIRIT II Trial Group
Type of Session: Scientific
- High RXR-beta expression has been shown to be correlated with increased survival in patients with non-small cell lung cancer (NSCLC).
- Bexarotene (Targretin) is an RXR-selective rexinoid which forms homodimers and heterodimers with a number of molecular partners that ultimately lead to increased apoptosis and alters cell cycle control, differentiation, anti-metastatic activity, and anti-angiogenic activity.
- The use of bexarotene in patients with NSCLC has been shown to lead to disease stabilization and increased survival in several phase I and phase II trials.
- Bexarotene has also been found to result in increased triglyceride (TGC) levels and decreased thyroid stimulating hormone levels in a number of patients.
- This trial, in conjunction with the SPIRIT I Trial, was designed to determine if the addition of bexarotene to standard chemotherapy improved outcomes in patients with advanced or metastatic NSCLC.
Materials and Methods
- Patients with NSCLC who were stage IIIB with pleural effusion or stage IV were randomized to:
- Eligible patients were ECOG performance status 0 or 1 and had not received a prior chemotherapy.
- Patients receiving bexarotene were allowed to continue bexarotene until disease progression after completion of chemotherapy.
- Anti-lipid therapy was started on day one for patients receiving bexarotene.
- Primary endpoint was overall survival (OS) with secondary endpoint of 2-year survival.
- Additional endpoints included progression-free survival (PFS), time to progression (TTP), safety, population pharmacokinetics, and biochemical and genetic biomarkers.
- A total of 612 patients were enrolled.
- Treatment groups were well-balanced with respect to gender, stage, performance status, age, histopathology, ethnicity, smoking history, and degree of weight loss.
- Median survival was no different between the control group and the bexarotene group (9.2 mo vs. 8.5 mo, p=0.2).
- 2-year survival was no different between the two groups (16.3% vs. 12.4%, p=0.2).
- There was no difference in median PFS (4.9 mo vs. 4.1 mo, p=0.06).
- There were significant increases with the use of bexarotene with respect to grade 3/4 neutropenia, asthenia, leukopenia, and dehydration.
- 32% of patients receiving bexarotene experienced grade 3/4 hypertriglyceridemia compared to 0% in the control arm.
- Retrospective subgroup analysis showed that patients hypertriglyceridemia correlated with improved outcome with the use of bexarotene.
- It was hypothesized that hypertriglyceridemia served as a surrogate biomarker for response to treatment and this was analyzed further.
- Patients with NCI grade 3 or 4 hypertriglyceridemia had improved survival with bexarotene with a hazard ratio of 0.82 (p=0.0002).
- When separated by triglyceride level, patients with NCI grade 3 or 4 triglycerides had a median survival of 12.4 mo vs. 9.2 mo for the control group (p=0.014)
- Patients with NCI grade 0-2 triglycerides had a median survival of 6.6 mo vs. 9.2 mo for the control group (p=0.001).
- The correlation of high triglycerides with improved outcomes was found for all patient subgroups.
- Bexarotene added to carboplatin/paclitaxel in the first-line setting did not improve overall survival.
- Retrospective subset analysis suggests that elevated triglycerides in patients treated with bexarotene correlates with survival.
- The relationship between hypertriglyceridemia and response to bexarotene warrants further study.
- Additional biochemical and genetic marker analyses could help identify likely responders to treatment with bexarotene.