Phase III Trial Comparing Carboplatin, Paclitaxel, and Bexarotene With Carboplatin and Paclitaxel in Chemotherapy-Naïve Patients With Advanced or Metastatic Non–Small-Cell Lung Cancer: SPIRIT II

Abstract

Purpose The purpose of this study was to determine whether addition of the synthetic rexinoid bexarotene (Targretin; Eisai Inc, Woodcliff Lake, NJ) to standard first-line carboplatin and paclitaxel therapy provides additional survival benefit in patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with stage IIIB disease with pleural effusion, or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1, were randomly assigned to bexarotene 400 mg/m2/d combined with carboplatin and paclitaxel, or assigned to carboplatin and paclitaxel alone. Bexarotene patients also received lipid-lowering agents on or before day 1. The primary efficacy end point was overall survival; secondary efficacy and supportive analyses were also conducted. Results A total of 612 patients (306 per arm) were enrolled onto the study. In the intent-to-treat population, no significant difference in survival occurred between the two arms. However, a subpopulation (approximately 40%) of bexarotene-treated patients who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had significantly longer median survival than control patients (12.4 v 9.2 months; log-rank, P = .014). Bexarotene-treated patients with grade 3/4 hypertriglyceridemia who received the most benefit included those who were male, were smokers, experienced 6-month prior weight loss ≥ 5%, and had stage IV disease. The incidence and severity of most adverse events were similar between arms, although hyperlipidemia, neutropenia, fatigue, leukopenia, arthralgia, and diarrhea were more frequent in the bexarotene arm. Conclusion Although the addition of bexarotene to chemotherapy did not improve survival in the overall study population, occurrence of high-grade hypertriglyceridemia in bexarotene-treated patients strongly correlated with increased survival, suggesting that bexarotene may benefit a segment of first-line NSCLC patients.

Cotargeting Cyclin D1 Starts a New Chapter in Lung Cancer Prevention and Therapy

“…An important finding of the Dmitrovsky group's phase II trial was a significant survival benefit associated with bexarotene-induced hypertriglyceridemia (P ¼ 0.001), consistent with prior studies of bexarotene alone or combined with chemotherapy in NSCLC (4,5,19). Hypertriglyceridemia generally developed within 2 to 4 weeks in all these studies, and, long known in association with retinoids such as 13cRA (20), it does not seem to have adverse clinical effects.…”

“…Chemotherapy in general for this disease has been limited by toxicity and a lack of specificity and did not improve when combined with the epidermal growth factor receptor (EGFR) inhibitor erlotinib (2,3) or with the rexinoid bexarotene (4,5). Lung cancer chemoprevention has foundered heretofore for a variety of reasons, although very recent clinical data suggest promise in this setting (6).…”

The Rexinoids LG100268 and LG101506 Inhibit Inflammation and Suppress Lung Carcinogenesis in A/J Mice

“…Bexarotene is currently the only rexinoid approved by the FDA, for treatment of cutaneous T-cell lymphoma. Notably, bexarotene, either alone or in combination with erlotinib and various chemotherapeutic agents, has been tested in a variety of clinical trials for lung cancer (4)(5)(6)(7)(8)(9). Although bexarotene failed to increase overall survival as a single agent, subsets of patients responded to the drug, with highgrade hypertriglyceridemia identified as a biomarker of efficacy.…”

Therapeutic Potential of “Rexinoids” in Cancer Prevention and Treatment

“…A recent clinical trial with RXR ligand as a single therapeutic regimen has shown a favorable clinical outcome with mild toxicity for a selected subgroup of advanced lung cancer patients (11), suggesting that the downstream target of RXR would provide a mechanistic understanding of the anticancer effect of RXR ligands. One of the affected downstream pathways by liganded RXR is the p21 through RXR homodimer bindings to the two sequential RXREs, which overlap with an RARE (Fig.…”

“…11). However, rexinoid therapy significantly improved the overall survival in certain patient subgroups (i.e., males, smokers, and patients with stage IV disease) compared with the control group (11). The molecular mechanisms underlying this subgroup-dependent response and the molecular basis of rexinoid resistance remains to be understood.…”