Background: EGFR inhibition is an established therapy for previously treated NSCLC. Estrogen receptors (ER) and aromatase are expressed in most NSCLC specimens in both men and women. In preclinical models, estrogen stimulates NSCLC growth, an effect blocked by F, a pure ER antagonist. Preclinical models show enhanced anti-tumor effects by combining EGFR inhibitors with F.

Methods: We conducted a Phase II clinical study to evaluate whether addition of F enhances antitumor efficacy of E. Men and women with advanced NSCLC and > 1 prior chemotherapy regimen (unless patient refused) were randomized 2:1 to receive E (150 mg PO qd) + F (500 mg IM q2wk x 3, then q4wk) or E alone. Stratification for gender and ECOG (0, 1 vs. 2) was performed. Response rate (RR) was the primary endpoint. Secondary endpoints included progression free survival (PFS), overall survival (OS) and correlation between clinical endpoints and tumor tissue and blood-based biomarkers.

Results: 106 patients (pts) were randomized from March 2006 to June 2010. 100 (evaluated population) received E +/- F. E + F was well tolerated, with adverse events well balanced between arms. For E + F and E respectively, RR (23.6% vs. 14.8%, p = 0.35), PFS [1.9 vs. 1.8 months, hazard ratio (HR) 0.85, 95% confidence interval 0.55, 1.33] and OS [9.4 vs. 5.7 months, HR 0.96 (0.6, 1.55)] were similar between arms. EGFR mutational data could be obtained on 69 pts. EGFR mutations were more prevalent in the E arm (35% vs. 20%). EGFR mutations strongly predicted best response, PFS and OS (p < 0.0002 for each). RR, PFS and OS were similar among EGFR mutants between arms in this small subset (17 patients). Among the 52 pts with EGFR WT tumors, 3 partial responses (PR) were seen with E + F vs. none for E alone. Clinical benefit rate [CBR (RR + stable disease): 54.8% vs. 8.3%, p = 0.0056] was significantly higher among pts with WT tumors treated with E + F. Trends were observed in favor of E + F in PFS [2.0 vs. 1.6 months, HR 0.56 (0.29, 1.07)] and OS [7.4 vs. 5.9 months, HR 0.69 (0.36, 1.31)].

Conclusion: E + F was well tolerated in previously treated NSCLC pts, including men and pre- and post-menopausal women. The study showed a high RR (23.6%) for E + F, that was not adequately explained by EGFR mutations. Among EGFR WT pts, a significantly higher CBR that included 3 PRs was seen with trends towards improved PFS and OS with E + F as compared to E alone. Evaluation of tumor tissue biomarkers (including ER-α and -β, aromatase), blood estrogen levels and EGFR ligands known to be induced by ER signaling is ongoing to determine NSCLC subpopulations most likely to benefit from antiestrogens. [Supported by 1K23CA149079, P50 CA090440, V Foundation for Cancer Research, Jonsson Comprehensive Cancer Center, Wolfen Family Lung Cancer Research Program, Stiles Program in Oncology, National Lung Cancer Partnership and One Ball Matt Memorial Golf Tournament]

Citation Format: Edward B. Garon, Jill M. Siegfried, Steven M. Dubinett, Robert M. Elashoff, David J. Park, Rupesh J. Parikh, Ravi Patel, Eddie H. Hu, Karen L. Reckamp, Brad Adams, Diego Martinez, He-Jing Wang, Fairooz Kabbinavar, Sanja Dacic, Meghan Brennan, Isett Laux, Diana C. Marquez-Garban, Laura P. Stabile, Dennis J. Slamon, Richard J. Pietras. Result of TORI L-03, a randomized, multicenter phase II clinical trial of erlotinib (E) or E + fulvestrant (F) in previously treated advanced non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4664. doi:10.1158/1538-7445.AM2013-4664