Phase III, Randomized, Placebo-Controlled, Double-Blind

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Phase III, Randomized, Placebo-Controlled, Double-Blind JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT Phase III, Randomized, Placebo-Controlled, Double-Blind Trial of Motesanib (AMG-706) in Combination With Paclitaxel and Carboplatin in East Asian Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer Kaoru Kubota, Hiroshige Yoshioka, Fumihiro Oshita, Toyoaki Hida, Kiyotaka Yoh, Hidetoshi Hayashi, Terufumi Kato, Hiroyasu Kaneda, Kazuhiko Yamada, Hiroshi Tanaka, Yukito Ichinose, Keunchil Park, Eun Kyung Cho, Kyung-Hee Lee, Chih-Bin Lin, James Chih-Hsin Yang, Kaori Hara, Takayuki Asato, and Kazuhiko Nakagawa Author affiliations and support information (if applicable) appear at the end of this ABSTRACT article. Purpose Published at jco.org on September 13, This phase III, randomized, placebo-controlled, double-blind study determined whether motesanib 2017. improved progression-free survival (PFS) compared with placebo in combination with paclitaxel and K.K. and H.Y. contributed equally to this carboplatin (P/C) in East Asian patients with stage IV/recurrent nonsquamous non–small-cell lung work. cancer. Clinical trial information: JPRN-JapicCTI- 121887. Patients and Methods Corresponding author: Kaoru Kubota, MD, Patients were randomly assigned (1:1) to receive oral motesanib 125 mg or placebo once daily plus 2 Department of Pulmonary Medicine and paclitaxel 200 mg/m IV and carboplatin area under the concentration-time curve 6 mg/mL $ min IV Oncology, Graduate School of Medicine, for up to six 3-week cycles. Random assignment was stratified by epidermal growth factor receptor Nippon Medical School, 1-1-5, Sendagi, status, region, and weight loss in the 6 months before assignment. The primary end point was PFS, Bunkyo-ku, Tokyo 113-8603, Japan; e-mail: [email protected]. the key secondary end point was overall survival, and other secondary end points were objective response rate, time to tumor response, duration of response, and adverse events (AEs). © 2017 by American Society of Clinical Oncology Results 0732-183X/17/3599-1/$20.00 Four hundred one patients were assigned to receive motesanib plus P/C (n = 197) or placebo plus P/C (n = 204). Median PFS was 6.1 v 5.6 months for motesanib versus placebo (stratified log-rank test P = .0825; stratified hazard ratio, 0.81; 95% CI, 0.64 to 1.03; P = .0820); median overall survival was not reached versus 21.6 months (P = .5514). In secondary analyses, the objective response rate was 60.1% v 41.6% (P , .001); median time to tumor response, 1.4 v 1.6 months, and median duration of response, 5.3 v 4.1 months. Incidence of grade $ 3AEs(86.7%v 67.6%) and AEs that led to drug discontinuation (32.7% v 14.2%) were higher with motesanib than with placebo. AEs reported more frequently with motesanib were GI disorders, hypertension, and gallbladder related. Conclusion Motesanib plus P/C did not significantly improve PFS versus placebo plus P/C in East Asian patients with stage IV/recurrent nonsquamous non–small-cell lung cancer. J Clin Oncol 35. © 2017 by American Society of Clinical Oncology (NSCLC) indicated that the efficacy of motesanib is INTRODUCTION comparable with the anti-VEGF-A monoclonal antibody bevacizumab when both therapies are Motesanib, a selective, oral, small-molecule inhib- used in combination with paclitaxel and carboplatin itor of vascular endothelial growth factor (VEGF) (P/C).5 In the phase III, randomized, placebo- receptors 1, 2, and 3; platelet-derived growth factor controlled, double-blind Motesanib NSCLC Ef- 1 fi ASSOCIATED CONTENT receptor; and Kit receptor, has demonstrated an- cacy and Tolerability (MONET1) study, mote- titumor activity as monotherapy2-4 and in com- sanib plus P/C did not significantly improve overall Data Supplement DOI: https://doi.org/10.1200/JCO. bination with chemotherapy in advanced solid survival (OS) versus placebo plus P/C in patients 5,6 2017.72.7297 tumors. A phase II, randomized, open-label with advanced nonsquamous NSCLC or in a ı 6 DOI: https://doi.org/10.1200/JCO.2017. study in chemotherapy-na¨ve patients with ad- subset of patients with adenocarcinoma ; how- 72.7297 vanced nonsquamous non–small-cell lung cancer ever, a preplanned exploratory subgroup analysis © 2017 by American Society of Clinical Oncology 1 Downloaded from ascopubs.org by Serena Stockwell on September 18, 2017 from 024.090.166.239 Copyright © 2017 American Society of Clinical Oncology. All rights reserved. Kubota et al of 227 East Asian patients in this study demonstrated a median OS The primary end point was investigator-assessed PFS, which was of 20.9 months in the motesanib plus P/C arm and 14.5 months in defined as the time from random assignment to the first objective tumor the placebo plus P/C arm (P = .0223); median progression-free progression or death as a result of any cause. The key secondary end point was OS, which was defined as the time from random assignment to death. survival (PFS) was 7.0 and 5.3 months, respectively (P , .001), Other secondary end points were ORR by investigator, time to tumor re- and the objective response rate (ORR) was 62% and 27%, re- sponse, duration of response (DOR), and incidence of adverse events (AEs). spectively (P , .001).7 Mounting evidence shows differences between Asian and white patients with lung cancer in terms of epidemiology, etiology, treat- Assessments 8 Tumor response was assessed by computed tomography and mag- ment outcomes, and toxicities. A higher incidence of epidermal netic resonance imaging scans every 6 6 1 weeks by the investigators and growth factor receptor (EGFR) mutations has been reported in Asian by an independent imaging assessment committee per RECIST 1.1 until 8-10 versus non-Asian patients with NSCLC (32% to 51.4% v 6%). progressive disease. Safety was assessed through 30 days after the last dose. Improved efficacy and higher levels of toxicity with P/C also have been AEs were graded according to the National Cancer Institute Common reported for patients with NSCLC in Japan versus the United States, Terminology Criteria for Adverse Events (version 3.0). Interim analyses of which may be explained by population-related pharmacogenomics.11 safety were conducted by the data monitoring committee after 50 and 150 On the basis of the MONET1 Asian subgroup analysis7 and successful patients had been randomly assigned and had completed one or more cycles of study treatment. An additional exclusion criterion for patients exploratory modeling and simulations that were based on MONET1 12 with interstitial lung disease on computed tomography scan was added, but data, the primary objective of the current phase III, randomized, interim analyses are not reported because no recommendations were made placebo-controlled, double-blind MONET-A study was to determine to modify or stop treatment or to suspend random assignment. whether motesanib plus P/C improved PFS versus placebo plus P/C in East Asian patients with advanced/recurrent nonsquamous NSCLC. Statistical Analysis A sample size of 400 patients (200 per arm) was determined to provide 90% power (overall one-sided 2.5% significance level) to detect a hypoth- PATIENTS AND METHODS esized PFS hazard ratio (HR) of 0.67 and an increase in median PFS from 5.3 months in the placebo plus P/C arm to 7.9 months in the motesanib plus Patients P/C arm after the occurrence of a minimum of 260 PFS events. An interim analysis of OS was planned at the same time as this primary analysis but was Patients age $ 18 years with histologically or cytologically confirmed conditional on demonstrating a significant improvement in PFS. stage IV/recurrent nonsquamous NSCLC were eligible. Other inclusion PFS and OS were analyzed in all randomly assigned patients. Safety criteria were measurable or nonmeasurable lesion per Response Evaluation was analyzed in all patients who received one or more doses of motesanib Criteria in Solid Tumors version 1.1 (RECIST 1.1); Eastern Cooperative or placebo. ORR was analyzed in all patients with one or more unidi- Oncology Group performance status 0 or 1; life expectancy $ 3 months; and mensionally measurable lesion at baseline per RECIST 1.1. PFS, OS, and adequate renal, hepatic, coagulation, and hematologic function. Patients with DOR distributions were estimated by using the Kaplan-Meier method. The antigen-negative hepatitis B who were hepatitis B antibody positive were primary end point of PFS and key secondary end point of OS were eligible. Key exclusion criteria were adenosquamous histology or an unclear compared between arms by using log-rank tests stratified by randomi- histology subtype (. 10% squamous cells); symptomatic CNS metastases zation factors; stratified Cox proportional hazards (PH) regression models (clinically stable patients with asymptomatic brain metastases were eligible if were used to define HRs. Unstratified Cox PH regression models with definitive therapy had been administered, and the patient was not receiving descriptive P values were used for the preplanned, exploratory PFS and OS corticosteroids for $ 2 weeks before random assignment); history of pul- subgroup analyses; no adjustments were made for multiple comparisons. monary hemorrhage or gross hemoptysis (approximately $ 3 mL of bright- The following baseline covariates were used to examine selected efficacy red blood) within 6 months of random assignment; prior chemotherapy, and safety end points in subgroup or multivariable analyses: the three including adjuvant chemotherapy within 1 year of random assignment; prior stratification factors; histology (adenocarcinoma v nonadenocarcinoma); targeted therapy; major surgery within 28 days or anticoagulation therapy disease status at enrollment (initial v recurrent); prior adjuvant chemo- within 7 days of random assignment; uncontrolled hypertension; and arterial therapy (yes v no); sex (male v female); prior radiation therapy (yes v no); or venous thrombosis within 12 months or bleeding diathesis or bleeding brain metastases (yes v no); age at enrollment (, 65 v $ 65 years); smoking within 14 days of random assignment.
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