Investigation of Combination Treatment With an Aromatase Inhibitor Exemestane and Carboplatin- Based Therapy for Postmenopausal Women With Advanced NSCLC

Introduction: Estrogen receptors (ER) (ERa, ERb) and aromatase (key enzyme for estrogen synthesis) are expressed in most human NSCLCs. High intratumoral es-trogen levels and elevated aromatase expression in NSCLC predict poor outcome. This open-label, phase 1b, single -center study evaluated the safety and tolerability of esca-lating doses of the aromatase inhibitor, exemestane, in combination with carboplatin and pemetrexed in post-menopausal women with stage IV nonsquamous NSCLC. Methods: Patients received exemestane (starting 1-wk before chemotherapy) at 25 mg orally (PO) daily (cohort 1) or 50 mg PO daily (cohort 2) combined with carboplatin (area under the curve 6 mg x min/mL) and pemetrexed (500 mg/m2) intravenously every 3 weeks for four cycles. Thereafter, patients were eligible for continued therapy with exemestane and pemetrexed or pemetrexed alone. Results: A total of 10 patients consented for therapy, and two patients failed in the screening. Four patients completed the therapy in cohort 1 and four patients in cohort 2. The median number of cycles administered was 15 (range: 1-54). Maximum tolerated dose was exemestane 50 mg PO daily with combination chemotherapy. Intention-to -treat analysis revealed an objective response rate (ORR) of 62.5% (five of eight patients with partial response) and a clinical benefit rate of 87.5% (seven of eight patients with either stable disease or partial response). ORR was associ-ated with aromatase expression (p = 0.02). Circulating es-trogen levels decreased with exemestane use, and quality of life measurements did not significantly change during the treatment. There were no adverse events. Conclusions: The combination of carboplatin, pemetrexed, and exemestane in postmenopausal women with metastatic NSCLC is safe and well tolerated. Biomarker studies revealed that ORR correlates with tumor aromatase expression. These findings support future clinical trials to confirm the antitumor efficacy with this combination therapy. (c) 2020 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).