JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Benjamin J. Solomon, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Federico Cappuzzo, Istituto Toscano Tumori, Livorno; Jolanda Paolini, Jennifer Tursi, and Tiziana Usari, Pfizer Oncology, Milan, Italy; Enriqueta Felip, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology, Barcelona, Spain; Fiona H. Blackhall, The Christie Hospital and Institute of Cancer Sciences, Manchester University, Manchester, United Kingdom; Daniel B. Costa, Beth Israel Deaconess Center, Boston, MA; Tarek Mekhail, Florida Hospital Cancer Institute, Orlando, FL; Keith D. Wilner and Paulina Selaru, Pfizer Oncology, La Jolla, CA; Dong-Wan Kim, Seoul National University Hospital, Seoul, South Korea; Kazuhiko Nakagawa, Kinki University, Osaka, Japan; Yi-Long Wu, Guangdong Lung Cancer Institute, Guangzhou, China; and Tony S.K. Mok, State Key Laboratory of South China, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Shatin, China. Published online ahead of print at www.jco.org on March 28, 2016. Supported by Pfizer. Presented in part at the 2014 European Society for Medical Oncology Congress, Madrid, Spain, September 26-30, 2014. Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article. Clinical trial information: NCT01154140. Corresponding author: Benjamin J. Solomon, MBBS, PhD, FRACP, Department of Medical Oncology, Peter MacCallum Cancer Centre, St Andrew’s Place, East Melbourne, Victoria 3002, Australia; e-mail: ben.solomon@ petermac.org. © 2016 by American Society of Clinical Oncology 0732-183X/16/3424w-2858w/$20.00 DOI: 10.1200/JCO.2015.63.5888 Intracranial Efficacy of Crizotinib Versus Chemotherapy in Patients With Advanced ALK-Positive Non–Small-Cell Lung Cancer: Results From PROFILE 1014 Benjamin J. Solomon, Federico Cappuzzo, Enriqueta Felip, Fiona H. Blackhall, Daniel B. Costa, Dong-Wan Kim, Kazuhiko Nakagawa, Yi-Long Wu, Tarek Mekhail, Jolanda Paolini, Jennifer Tursi, Tiziana Usari, Keith D. Wilner, Paulina Selaru, and Tony S.K. Mok See accompanying article on page 2814 A B S T R A C T Purpose Intracranial efficacy of first-line crizotinib versus chemotherapy was compared prospectively in the phase III PROFILE 1014 study in ALK-positive non–small-cell lung cancer. Patients and Methods Patients were randomly assigned to receive crizotinib (250 mg twice daily; n = 172) or chemotherapy (pemetrexed 500 mg/m 2 plus cisplatin 75 mg/m 2 or carboplatin at area under the curve 5 to 6, every 3 weeks for # six cycles; n = 171). Patients with stable treated brain metastases (tBM) were eligible. Intracranial ef ficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases (BM), respectively; intracranial time to tumor progression (IC-TTP; per protocol) and intracranial disease control rate (IC-DCR; post hoc) were measured. The intent-to-treat population was also assessed. Results Of 343 patients in the intent-to-treat population, 23% had tBM at baseline. A nonsigni ficant IC-TTP improvement was observed with crizotinib in the intent-to-treat population (hazard ratio [HR], 0.60; P = .069), patients with tBM (HR, 0.45; P = .063), and patients without BM (HR, 0.69; P = .323). Among patients with tBM, IC-DCR was signi ficantly higher with crizotinib versus chemotherapy at 12 weeks (85% v 45%, respectively; P , .001) and 24 weeks (56% v 25%, respectively; P = .006). Progression-free survival was signi ficantly longer with crizotinib versus chemotherapy in both subgroups (tBM present: HR, 0.40; P , .001; median, 9.0 v 4.0 months, respectively; BM absent: HR, 0.51; P , .001; median, 11.1 v 7.2 months, respectively) and in the intent-to-treat population (HR, 0.45; P , .001; median, 10.9 v 7.0 months, respectively). Conclusion Compared with chemotherapy, crizotinib demonstrated a significantly higher IC-DCR in patients with tBM. Improvements in IC-TTP were not statistically significant in patients with or without tBM, although sensitivity to detect treatment differences in or between the two subgroups was low. J Clin Oncol 34:2858-2865. © 2016 by American Society of Clinical Oncology INTRODUCTION Crizotinib, an oral small-molecule inhibitor of anaplastic lymphoma kinase (ALK), MET, and ROS1 receptor tyrosine kinases, 1,2 has demon- strated significant antitumor efficacy in patients with advanced ALK-positive non–small-cell lung cancer (NSCLC). 3 The ongoing international, multicenter, randomized, open-label phase III study PROFILE 1014 recently demonstrated superior progression-free survival (PFS), objec- tive response rate (ORR), and patient-reported outcomes for crizotinib versus pemetrexed- platinum combination chemotherapy in patients with previously untreated advanced ALK-positive NSCLC, establishing crizotinib as standard first- line therapy in this population. 4 Although the development of targeted thera- pies has improved outcomes for selected patient populations with oncogenic driver mutations, 5,6 brain metastases (BM) are frequent and result in significant morbidity and mortality in patients with lung cancer. Metastatic spread to the brain occurs in at least 30% of patients with NSCLC 7 and 23% to 31% of patients with ALK-positive disease. 8-10 2858 © 2016 by American Society of Clinical Oncology VOLUME 34 • NUMBER 24 • AUGUST 20, 2016 Downloaded from ascopubs.org by 52.73.204.196 on May 17, 2022 from 052.073.204.196 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.