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.

(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

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%, response, 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. The study was conducted in ac- history ($ 100 v , 100 cigarettes in lifetime); and baseline Eastern cordance with the Declaration of Helsinki and Good Clinical Practice, and Cooperative Oncology Group performance status (0 v 1). A stratified study procedures were approved by the institutional review board at each Cochran-Mantel-Haenszel test was used for the primary comparison of site. All patients provided written informed consent. ORR. Descriptive statistics are presented for safety data.

Study Design and Treatments This phase III, randomized, placebo-controlled, double-blind study RESULTS was conducted at 52 sites in Japan (n = 24), Korea (n = 17), Taiwan (n = 10), and Hong Kong (n = 1) between July 2012 and March 2015. Patients were randomly assigned (1:1) by interactive Web response system to ei- Patients ther once-daily oral motesanib 125 mg or matching placebo; all patients In total, 401 patients were randomly assigned to motesanib also received paclitaxel 200 mg/m2 IV and carboplatin area under the plus P/C (n = 197) or placebo plus P/C (n = 204). Demographic concentration-time curve 6 mg/mL $ min IVon day 1 of each 3-week cycle characteristics were similar between arms and representative of the ﬁ for up to six cycles. Random assignment was strati ed by EGFR status population under study (Table 1). At study entry, the overall (mutant v wild type or unknown), region (Japan v non-Japan), and weight median age was 65.0 years (range, 25 to 80 years), 71.8% of patients loss in the 6 months before assignment (, 5% v $ 5%). Patients who discontinued P/C before completing or as a result of the protocol-speciﬁed were male, and 70.6% were enrolled in Japan; the majority had six cycles could continue to receive motesanib or placebo monotherapy until previously smoked (59.6%) or were current smokers (12.2%) and disease progression, unacceptable toxicity, withdrawal of consent, or death. had wild-type or unknown-type EGFR (79.3%). Except for one

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. Motesanib, Paclitaxel, and Carboplatin in NSCLC: Phase III Study patient in the motesanib plus P/C arm who did not receive motesanib At this cutoff, 143 patients (72.6%) in the motesanib plus P/C arm or P/C and one patient in the placebo plus P/C arm who did not and 152 (74.5%) in the placebo plus P/C arm had experienced a PFS receive carboplatin, all patients received concomitant P/C. At the time event (death or disease progression). After a median follow-up of of the PFS primary analysis, 165 patients (83.8%) in the motesanib 10.3 months (range, 0.5 to 25.5 months) for the motesanib plus P/C plus P/C arm and 166 (81.4%) in the placebo plus P/C arm had arm and 10.1 months (range, 0.5 to 26.7 months) for the placebo plus discontinued motesanib or placebo (Fig 1). P/Carm,medianPFSwas6.1months(95%CI,5.65to7.13months) v 5.6months(95%CI,5.36to5.91months)formotesanibplusP/C fi Treatment Exposure and placebo plus P/C, respectively (strati ed log-rank test P = .0825; stratified Cox PH regression model HR, 0.81; 95% CI, 0.64 to 1.03; By the data cutoff date of September 30, 2014, median daily P = .0820; Fig 2A). The hypothesized improvement in PFS was not doses of motesanib and placebo were 125 mg. Patients received demonstrated, and on the basis of this result plus data on OS, other motesanib for a median of 4.5 months (range, 0.1 to 24.6 months) secondary efficacy end points, and the safety profile, the study was and placebo for a median of 4.3 months (range, 0.03 to 23.7 months). terminated (final data cutoff, March 31, 2015). P/C was administered for a median of four cycles (range, one to six Prespecified subgroup analyses showed a trend toward cycles) in the motesanib plus P/C arm and five cycles (range, one to a consistent PFS benefit with motesanib plus P/C across subgroups six cycles) in the placebo plus P/C arm. In the maintenance except for patients with recurrent disease at enrollment and pa- (monotherapy) phase, patients received motesanib for a median tients who had undergone prior adjuvant therapy (Fig 2B). Of of 2.8 months (range, 0.03 to 21.0 months) and placebo for note, a PFS benefit (HR , 1 and 95% CI that did not overlap unity) 2.1 months (range, 0.03 to 19.1 months). was observed for patients with mutant-type EGFR (HR, 0.57 by unstratified Cox PH regression model; 95% CI, 0.33 to 0.98; Efficacy P = .0413), $ 5% weight loss before random assignment (HR, 0.64; PFS by investigator: Primary end point. The data cutoff date for 95% CI, 0.43 to 0.96; P = .0299), no prior adjuvant therapy (HR, the PFS primary analysis was September 30, 2014; unless otherwise 0.77; 95% CI, 0.61 to 0.97; P = .0261), and prior radiation therapy stated, efficacy and safety data are reported from this primary analysis. (HR, 0.58; 95% CI, 0.34 to 0.98; P = .0418).

Table 1. Baseline Demographics and Disease Characteristics Characteristic Motesanib + P/C, No. (%) Placebo + P/C, No. (%) Total, No. (%) No. of patients 197 204 401 Median age, years (upper, lower quartile) 65 (59, 70) 64 (58, 69) 65 (58, 70) Male sex 141 (71.6) 147 (72.1) 288 (71.8) Region Japan 140 (71.1) 143 (70.1) 283 (70.6) Korea, Taiwan, and Hong Kong 57 (28.9) 61 (29.9) 118 (29.4) ECOG performance status 0 93 (47.2) 89 (43.6) 182 (45.4) 1 104 (52.8) 115 (56.4) 219 (54.6) Cigarette smoking history Never 49 (24.9) 64 (31.4) 113 (28.2) Past 131 (66.5) 108 (52.9) 239 (59.6) Present 17 (8.6) 32 (15.7) 49 (12.2) Disease status/stage at study entry Initial, stage IV 171 (86.8) 194 (95.1) 365 (91.0) Recurrent 26 (13.2) 10 (4.9) 36 (9.0) Histology Adenocarcinoma 189 (95.9) 191 (93.6) 380 (94.8) Large-cell carcinoma 3 (1.5) 0 (0) 3 (0.7) Undifferentiated 1 (0.5) 3 (1.5) 4 (1.0) Other 4 (2.0) 10 (4.9) 14 (3.5) EGFR status*† Mutant type 41 (20.8) 42 (20.6) 83 (20.7) Wild type or unknown 156 (79.2) 162 (79.4) 318 (79.3) Weight loss in previous 6 months† , 5% 136 (69.0) 136 (66.7) 272 (67.8) $ 5% 61 (31.0) 67 (32.8) 128 (31.9) Prior therapy Prior adjuvant chemotherapy 6 (3.0) 4 (2.0) 10 (2.5) Prior radiotherapy 37 (18.8) 38 (18.6) 75 (18.7) Median time since primary diagnosis, 1 (0.6, 1.6) 1 (0.6, 1.4) 1 (0.6, 1.5) months (upper, lower quartile)

Abbreviations: ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; P/C, paclitaxel and carboplatin. *Data missing for one patient in the placebo + P/C arm. †Data shown from clinical report forms rather than from interactive Web response system.

Assessed for eligibility (N = 507)

Patients who did not meet inclusion criteria (n = 106)

Patients randomly assigned (n = 401)

Motesanib once daily + P/C (n = 197) Placebo + P/C (n = 204) Received motesanib (n = 196) Received placebo (n = 204) Did not receive motesanib (n = 1) Did not receive placebo (n = 0)

Maintenance (monotherapy) phase (n = 119) Maintenance (monotherapy) phase (n = 139)

PFS PA cutoff Final data cutoff PFS PA cutoff Final data cutoff Sept 30, 2014 Mar 31, 2015 Sept 30, 2014 Mar 30, 2015 Motesanib Placebo Ongoing (n = 31) (n = 3) Ongoing (n = 38) (n = 4) Discontinued (n = 165) (n = 193) Discontinued (n = 166) (n = 200) Disease progression (n = 84) (n = 97) Disease progression (n = 125) (n = 147) Adverse event (n = 63) (n = 67) Adverse event (n = 28) (n = 30) Patient request (n = 10) (n = 10) Patient request (n = 6) (n = 6) Consent withdrawn (n = 5) (n = 6) Consent withdrawn (n = 2) (n = 5) Administrative decision (n = 2) (n = 9) Administrative decision (n = 3) (n = 7) Death (n = 1) (n = 2) Death (n = 1) (n = 1) Noncompliance (n = 0) (n = 0) Noncompliance (n = 1) (n = 1) Other (n = 0) (n = 2) Other (n = 0) (n = 3) Paclitaxel Paclitaxel Completed (n = 69) (n = 71) Completed (n = 87) (n = 92) Discontinued (n = 123) (n = 125) Discontinued (n = 106) (n = 112)

Carboplatin Carboplatin Completed (n = 69) (n = 71) Completed (n = 87) (n = 92) Discontinued (n = 123) (n = 125) Discontinued (n = 105) (n = 111)

Analyzed for efficacy (n = 197) Analyzed for efficacy (n = 204) Analyzed for safety (n = 196) Analyzed for safety (n = 204)

Fig 1. CONSORT diagram. PA, primary analysis; P/C, paclitaxel and carboplatin; PFS, progression-free survival.

OS: Key secondary end point. Interim analysis of OS was for the placebo plus P/C arm, the estimated median OS was conditional on demonstrating a significant improvement in PFS. 22.8 months (95% CI, 18.33 months to NR) and 21.6 months Formal statistical testing of OS and other secondary end points, (95% CI, 17.48 months to NR) for motesanib plus P/C and therefore, was not performed; results are descriptive and not placebo plus P/C, respectively (stratified log-rank test P = .9356; intended for inferential purposes. stratified Cox PH regression model HR, 1.01; 95% CI, 0.74 to At the time of the PFS primary analysis, 56 patients (28.4%) in 1.38; P = .9347). Prespecified subgroup analyses showed a trend the motesanib plus P/C arm experienced an event (death) versus 62 toward an OS benefit(HR, 1) in patients with mutant-type (30.4%) in the placebo plus P/C arm. The estimated median OS EGFR (HR, 0.45 by unstratified Cox PH regression model; 95% was not reached (NR; 95% CI, 18.33 months to NR) in the CI, 0.14 to 1.47; P = .1863). motesanib plus P/C arm versus 21.6 months (95% CI, 17.48 to NR) Tumor response by investigator. Overall, 193 patients in the in the placebo plus P/C arm (stratified log-rank test P = .5514; motesanib plus P/C arm and 197 in the placebo plus P/C arm had stratified Cox PH regression model HR, 0.90; 95% CI, 0.62 to 1.29; measurable disease. The ORR was 60.1% v 41.6% for the mote- P = .5536; Fig 3). At final data cutoff (March 31, 2015), 82 patients sanib plus P/C versus placebo plus P/C arms, respectively (dif- (41.6%) in the motesanib plus P/C arm experienced an event ference in rate, 18.5%; 95% CI, 8.21% to 28.74%; P , .001). The versus 80 (39.2%) in the placebo plus P/C arm. After a median median time to tumor response was 1.4 v 1.6 months, and the follow-up of 13.6 months (range, 0.5 to 30.4 months) for the estimated median DOR was 5.3 v 4.1 months with motesanib plus motesanib plus P/C arm and 12.6 months (range, 0.5 to 31.3 months) P/C versus placebo plus P/C, respectively (Table 2).

A 100 Treatment Group No. Events Median (95% CI) 90 Motesanib + P/C 197 143 6.1 (5.65 to 7.13) 80 Placebo + P/C 204 152 5.6 (5.36 to 5.91)

70 HR, 0.81; 95% CI, 0.64 to 1.03 Stratified log-rank P = .0825 60

10 Patients Alive and Progression Free (%) Free Progression and Alive Patients

0 6 1218 24 Time (months) No. at risk: Motesanib + P/C 197 74 14 7 0 Placebo + P/C 204 68 10 3 0

B Fig 2. (A) Kaplan-Meier plot of progression- free survival by investigator. (B) Forest plot of No. HR 95% CI hazard ratios of progression-free survival across EGFR status subsets. EGFR, epidermal growth factor receptor; Mutant type 85 0.57 0.33 to 0.98 HR,hazardratio;P/C,paclitaxelandcarboplatin. Wild type or unknown type 316 0.88 0.68 to 1.13

Region Japan 283 0.82 0.63 to 1.07 Korea, Taiwan, and Hong Kong 118 0.73 0.46 to 1.17

Weight loss < 5% 265 0.88 0.66 to 1.16 ≥ 5% 136 0.64 0.43 to 0.96

Histology Adenocarcinoma 380 0.80 0.63 to 1.02 Nonadenocarcinoma 21 0.63 0.20 to 2.03

Disease status at enrollment Initial 365 0.80 0.63 to 1.02 Recurrent 36 1.35 0.56 to 3.24

Prior adjuvant chemotherapy Yes 10 4.89 0.56 to 43.03 No 391 0.77 0.61 to 0.97

Prior radiation therapy Yes 75 0.58 0.34 to 0.98 No 326 0.84 0.65 to 1.09

0.1 1 10 HR Favors motesanib + P/C Favors placebo + P/C

Safety were higher in the motesanib plus P/C arm versus the placebo plus The safety analysis set consisted of 196 patients who received P/C arm (Table 3). motesanib plus P/C and 204 who received placebo plus P/C. Overall, Most common AEs in the motesanib plus P/C arm were the incidence of AEs (100% v 99.5%), motesanib/placebo-related decreased appetite (n = 116; 59.2%), diarrhea (n = 114; 58.2%), AEs (93.4% v 79.4%), grade $ 3 AEs (86.7% v 67.6%), serious AEs alopecia (n = 113; 57.7%), peripheral sensory neuropathy (n = 107; (48% v 32.4%), and AEs that led to permanent discontinuation of 54.6%), and nausea (n = 103; 52.6%) and in the placebo plus P/C motesanib or placebo (32.7% v 14.2%) and P/C (37.8% v 25.5%) arm, alopecia (n = 132; 64.7%), peripheral sensory neuropathy jco.org © 2017 by American Society of Clinical Oncology 5

Treatment Group No. Events Median (95% CI) 100 Motesanib + P/C 197 56 NR (18.33 to NR) 90 Placebo + P/C 204 62 21.6 (17.48 to NR)

40 Fig 3. Kaplan-Meier plot of overall survival. HR, hazard ratio; NR, not reached; P/C, pacli-

Patients Alive (%) Alive Patients 30 taxel and carboplatin.

20 HR, 0.90; 95% CI, 0.62 to 1.29 10 Stratified log-rank P = .5514

0 6 1218 24 Time (months) No. at risk: Motesanib + P/C 197 153 78 41 8 Placebo + P/C 204 148 80 36 4

(n = 113; 55.4%), decreased appetite (n = 101; 49.5%), constipation of the subgroup analysis of Asian patients.7 The results add to the (n = 97; 47.5%), and nausea (n = 89; 43.6%). A low incidence of body of evidence that suggests that in general (with the possible thromboembolic events in the motesanib plus P/C and placebo- exception of the tyrosine kinase inhibitor [TKI] nintedanib and the P/C arms was observed (arterial, n = 4 [2.0%] v 1[, 1%]; venous, monoclonal antibodies bevacizumab and ramucirumab, which n=9[4.6%]v 5 [2.5%]). Mainly gallbladder-related AEs resulted in have achieved small incremental increases in OS),13-15 VEGF motesanib discontinuation (cholecystitis, n = 6 [3.1%]; gallbladder pathway inhibitors in combination with chemotherapy do not enlargement, n = 3 [1.5%]; liver disorder, n = 2 [1.0%]). The most provide a significant clinical benefit to unselected (ie, in terms of common grade $ 3 AEs in the motesanib plus P/C arm were biomarkers) patients with advanced nonsquamous NSCLC.16 neutropenia (n = 51; 26.0%), decreased neutrophil count (n = 34; The prognostic relevance of the baseline covariates for PFS 17.3%), and hypertension (n = 32; 16.3%) and in the placebo plus P/ was investigated and showed a treatment effect in patient sub- C arm, neutropenia (n = 53; 26.0%), decreased neutrophil count groups defined by mutant-type EGFR, $ 5% weight loss, no prior (n = 24; 11.8%), and leukopenia (n = 10; 4.9%). All-grade AEs and adjuvant therapy, and prior radiation therapy (Fig 2B). These grade $ 3 AEs with at least a five-percentage-point difference in subgroup analyses may offer an explanation for the differing results incidence rates between treatment arms are listed in Table 4.The between our study and the MONET1 Asian subgroup analysis. A most common serious AEs in the motesanib plus P/C group were higher incidence of EGFR mutations has been reported in Asian pneumonia (n = 13; 6.6%), decreased appetite (n = 8; 4.1%), cholecystitis (n = 7; 3.6%), and febrile neutropenia (n = 6; 3.1%) and in the placebo plus P/C arm, decreased appetite, pneumonia, Table 2. Tumor Response by Investigator pulmonary embolism, and pleural effusion (each n = 4; 2.0%). Motesanib + P/C, Placebo + P/C, Thirteen AEs were fatal (eight in the motesanib plus P/C arm, Response No. (%) No. (%) five in the placebo plus P/C arm). Three deaths in the motesanib plus No. of patients 193 197 P/C arm as a result of congestive cardiac failure, interstitial lung Response ORR (CR + PR) 116 (60.1) 82 (41.6) disease, and peritonitis (each n = 1) were considered to be related to CR 1 (0.5) 0 (0) motesanib plus P/C. An additional death as a result of acute PR 115 (59.6) 82 (41.6) myocardial infarction and acute renal failure in the motesanib plus Stable disease 64 (33.2) 87 (44.2) P/C arm was considered related to the P/C component of therapy. Progressive disease 5 (2.6) 16 (8.1) Not estimable 8 (4.1) 12 (6.1) Difference in ORR, 18.5* (8.21 to 28.74) % (95% CI) Median TTR, months 1.4 (1.3, 2.7) 1.6 (1.4, 2.8) DISCUSSION (upper, lower quartile) Median DOR, months 5.3 (4.30 to 5.88) 4.1 (2.96 to 4.37) (95% CI) In this phase III randomized, placebo-controlled, double-blind study, motesanib plus P/C did not significantly improve PFS versus Abbreviations: CR, complete response; DOR, duration of response; ORR, overall response rate; P/C, paclitaxel and carboplatin; PR, partial response; TTR, placebo plus P/C in East Asian patients with stage IV/recurrent time to tumor response. nonsquamous NSCLC. The findings are consistent with overall *P , .001. findings of the phase III MONET1 study6 but do not replicate those

literature for Asian patients with NSCLC19 possibly because these Table 3. Safety Overview patients selected EGFR TKIs as first-line treatment. Although Motesanib + P/C, Placebo + P/C, EGFR mutational status was not presented in the MONET1 Asian AE No. (%) No. (%) subgroup analysis, a higher number of Asian patients with EGFR No. of patients 196 204 mutations in the MONET1 study could have explained the dif- Any AEs 196 (100.0) 203 (99.5) Motesanib/placebo-related AEs 183 (93.4) 162 (79.4) ferential activity observed versus in the current study. Finally, Grade $ 3 AEs 170 (86.7) 138 (67.6) subgroup analyses can generate misleading results; therefore, al- Motesanib/placebo-related 106 (54.1) 39 (19.1) though trials are adequately powered for their main end points, grade $ 3 AEs fi Serious AEs 94 (48.0) 66 (32.4) they may not be suf ciently powered to detect differences in ef- 20 Motesanib/placebo-related 56 (28.6) 23 (11.3) ficacy between subgroups as a result of multiple comparisons. serious AEs The current findings demonstrate this risk of failure when per- AEs that led to discontinuation 64 (32.7) 29 (14.2) fi of motesanib/placebo forming a con rmatory study designed on the basis of results from AEs that led to discontinuation 74 (37.8) 52 (25.5) a subgroup analysis. Unless the prior subanalysis is statistically of P/C powered or associated with sufficient scientific rationale for bio- Deaths as a result of AEs 8 (4.1) 5 (2.5) marker data or tumor pathology that could explain the effects in Abbreviations: AE, adverse event; P/C, paclitaxel and carboplatin. a specific subset of patients, a risk exists that the prior results were mistakenly positive. Motesanib plus P/C was associated with increased toxicity versus non-Asian patients with NSCLC.8-10 EGFR mutations have versus placebo plus P/C. The incidences of grade $ 3 AEs and AEs been shown to be a good predictor of clinical benefit after that led to permanent discontinuation of motesanib or placebo treatment with EGFR TKIs,17 and preclinical and clinical studies were higher in the motesanib plus P/C arm. AEs reported more have suggested a synergistic effect with the combination of VEGF frequently in the motesanib plus P/C arm were GI disorders and EGFR inhibitors.18 In the current study, most East Asian (diarrhea, nausea, vomiting, abdominal pain); hypertension; and patients had wild-type or unknown-type EGFR status (79.3%); the gallbladder related (cholecystitis, gallbladder enlargement, liver EGFR mutant rate was substantially lower than that reported in the disorder), which were the main AEs that resulted in motesanib

Table 4. AEs With at Least a Five-Percentage-Point Difference in Incidence Between Treatment Arms in Overall Rate and/or Grade $ 3 Rate Motesanib + P/C, No. (%) Placebo + P/C, No. (%) AE All Grades Grade $ 3 All Grades Grade $ 3 No. of patients 196 204 Nonhematologic toxicity Alopecia 113 (57.7) 0 (0) 132 (64.7) 0 (0) Decreased appetite 116 (59.2) 18 (9.2) 101 (49.5) 9 (4.4) Nausea 103 (52.6) 7 (3.6) 89 (43.6) 6 (2.9) Myalgia 83 (42.3) 1 (0.5) 72 (35.3) 0 (0) Diarrhea 114 (58.2) 12 (6.1) 40 (19.6) 3 (1.5) Hypertension 86 (43.9) 32 (16.3) 29 (14.2) 4 (2.0) Vomiting 57 (29.1) 5 (2.6) 42 (20.6) 2 (1.0) ALT increased 58 (29.6) 20 (10.2) 27 (13.2) 2 (1.0) AST increased 51 (26.0) 13 (6.6) 21 (10.3) 1 (0.5) GGT increased 44 (22.4) 21 (10.7) 20 (9.8) 2 (1.0) Weight decreased 35 (17.9) 2 (1.0) 13 (6.4) 0 (0) Epistaxis 32 (16.3) 0 (0) 14 (6.9) 0 (0) Dysgeusia 27 (13.8) 0 (0) 17 (8.3) 0 (0) Blood ALP increased 29 (14.8) 2 (1.0) 8 (3.9) 0 (0) Proteinuria 31 (15.8) 3 (1.5) 6 (2.9) 1 (0.5) Abdominal pain 26 (13.3) 0 (0) 8 (3.9) 0 (0) Pneumonia 19 (9.7) 12 (6.1) 8 (3.9) 4 (2.0) Dyspepsia 19 (9.7) 0 (0) 6 (2.9) 0 (0) Gallbladder enlargement 23 (11.7) 1 (0.5) 0 (0) 0 (0) Cholecystitis 11 (5.6) 3 (1.5) 1 (0.5) 0 (0) Hematologic toxicity Anemia 44 (22.4) 19 (9.7) 41 (20.1) 9 (4.4) Platelet count decreased 43 (21.9) 17 (8.7) 34 (16.7) 8 (3.9) Neutrophil count decreased 43 (21.9) 34 (17.3) 31 (15.2) 24 (11.8) Thrombocytopenia 39 (19.9) 17 (8.7) 18 (8.8) 4 (2.0) WBC count decreased 24 (12.2) 12 (6.1) 14 (6.9) 7 (3.4) Leukopenia 7 (3.6) 5 (2.6) 24 (11.8) 10 (4.9)

NOTE. AEs are listed in descending frequency on the basis of the sum of all-grade AEs in both arms. AEs are deﬁned according to Medical Dictionary for Regulatory Activities preferred terms. Abbreviations: AE, adverse event; ALP, alkaline phosphatase; GGT, g-glutamyltransferase; P/C, paclitaxel and carboplatin.

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 discontinuation. A low incidence of thromboembolic events was AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS observed in both arms. These AEs generally were consistent with OF INTEREST those observed in previous studies of motesanib5,6,21 and other 22-24 angiogenesis inhibitors in advanced NSCLC. Differences in Disclosures provided by the authors are available with this article at patient management versus that in the MONET1 study, such as jco.org. the requirement for early treatment termination for gallbladder toxicities, may have affected the treatment period and led to reduced efficacy with motesanib plus P/C versus that in MONET1. AUTHOR CONTRIBUTIONS The incidence of gallbladder-related AEs (cholecystitis, cholecystitis acute, gallbladder enlargement, gallbladder edema) in Conception and design: Kaoru Kubota, Yukito Ichinose, Keunchil Park, MONET1was8%inthemotesanibplusP/Carmversus, 1% in James Chih-Hsin Yang, Kaori Hara, Takayuki Asato, Kazuhiko Nakagawa the placebo arm, and in the Asian subanalysis of MONET1, Collection and assembly of data: Kaoru Kubota, Hiroshige Yoshioka, this was 9% versus 2%, respectively. This disparity also is re- Fumihiro Oshita, Toyoaki Hida, Kiyotaka Yoh, Hidetoshi Hayashi, flected in the current study, with 19% v 1% of patients reporting Terufumi Kato, Hiroyasu Kaneda, Kazuhiko Yamada, Hiroshi Tanaka, gallbladder-related AEs. Yukito Ichinose, Keunchil Park, Eun Kyung Cho, Kyung-Hee Lee, In summary, this phase III study in East Asian patients with Chih-Bin Lin, James Chih-Hsin Yang, Kazuhiko Nakagawa stage IV/recurrent nonsquamous NSCLC demonstrates that treat- Data analysis and interpretation: Kaoru Kubota, Hiroshige Yoshioka, Kiyotaka Yoh, Hiroyasu Kaneda, Keunchil Park, James Chih-Hsin Yang, ment with motesanib plus P/C shows some hypothesis-generating fi Kaori Hara, Takayuki Asato, Kazuhiko Nakagawa ef cacy signals in terms of ORR and DOR versus placebo plus P/C. Manuscript writing: All authors However, the study did not show a significant improvement in the Final approval of manuscript: All authors primary end point of PFS or the key secondary end point of OS. Accountable for all aspects of the work: All authors

9. Shi Y, Au JS, Thongprasert S, et al: A pro- 17. Mitsudomi T, Yatabe Y: Mutations of the REFERENCES spective, molecular epidemiology study of EGFR epidermal growth factor receptor gene and related mutations in Asian patients with advanced non-small- genes as determinants of epidermal growth factor 1. Polverino A, Coxon A, Starnes C, et al: AMG cell lung cancer of adenocarcinoma histology (PIO- receptor tyrosine kinase inhibitors sensitivity in lung 706, an oral, multikinase inhibitor that selectively NEER). J Thorac Oncol 9:154-162, 2014 cancer. Cancer Sci 98:1817-1824, 2007 targets vascular endothelial growth factor, platelet- 10. Shi Y, Li J, Zhang S, et al: Molecular epide- 18. Ciardiello F, Troiani T, Bianco R, et al: In- derived growth factor, and kit receptors, potently miology of EGFR mutations in Asian patients with teraction between the epidermal growth factor re- inhibits angiogenesis and induces regression in tu- advanced non-small-cell lung cancer of adenocarci- ceptor (EGFR) and the vascular endothelial growth mor xenografts. Cancer Res 66:8715-8721, 2006 noma histology—Mainland China subset analysis of factor (VEGF) pathways: A rational approach for multi- 2. Rosen LS, Kurzrock R, Mulay M, et al: Safety, the PIONEER study. PLoS One 10:e0143515, 2015 target anticancer therapy. Ann Oncol 17:vii109-vii14, pharmacokinetics, and efficacy of AMG 706, an oral 11. Gandara DR, Kawaguchi T, Crowley J, et al: 2006 (suppl 7) multikinase inhibitor, in patients with advanced solid Japanese-US common-arm analysis of paclitaxel plus 19. Zhou W, Christiani DC: East meets West: tumors. J Clin Oncol 25:2369-2376, 2007 carboplatin in advanced non-small-cell lung cancer: A Ethnic differences in epidemiology and clinical be- 3. Schlumberger MJ, Elisei R, Bastholt L, et al: model for assessing population-related pharmaco- haviors of lung cancer between East Asians and Phase II study of safety and efficacy of motesanib in genomics. J Clin Oncol 27:3540-3546, 2009 Caucasians. Chin J Cancer 30:287-292, 2011 patients with progressive or symptomatic, advanced 12. Claret L, Bruno R, Lu JF, et al: Exploratory 20. Lagakos SW: The challenge of subgroup or metastatic medullary thyroid cancer. J Clin Oncol modeling and simulation to support development of analyses—reporting without distorting. N Engl J Med 27:3794-3801, 2009 motesanib in Asian patients with non-small cell lung 354:1667-1669, 2006 4. Sherman SI, Wirth LJ, Droz JP, et al: Mote- cancer based on MONET1 study results. Clin Phar- 21. Blumenschein GR Jr, Reckamp K, Stephenson sanib diphosphate in progressive differentiated thy- macol Ther 95:446-451, 2014 GJ, et al: Phase 1b study of motesanib, an oral an- roid cancer. N Engl J Med 359:31-42, 2008 13. Sandler A, Gray R, Perry MC, et al: Paclitaxel- giogenesis inhibitor, in combination with carboplatin/ 5. Blumenschein GR Jr, Kabbinavar F, Menon H, carboplatin alone or with bevacizumab for non-small- paclitaxel and/or panitumumab for the treatment of et al: A phase II, multicenter, open-label randomized cell lung cancer. N Engl J Med 355:2542-2550, 2006 advanced non-small cell lung cancer. Clin Cancer Res study of motesanib or bevacizumab in combination with [Erratum: N Engl J Med 356:318, 2007] 16:279-290, 2010 paclitaxel and carboplatin for advanced nonsquamous 14. Garon EB, Ciuleanu TE, Arrieta O, et al: 22. Okamoto I, Yoshioka H, Takeda K, et al: Phase non-small-cell lung cancer. Ann Oncol 22:2057-2067, Ramucirumab plus docetaxel versus placebo plus I clinical study of the angiogenesis inhibitor TSU-68 2011 docetaxel for second-line treatment of stage IV non- combined with carboplatin and paclitaxel in 6. Scagliotti GV, Vynnychenko I, Park K, et al: small-cell lung cancer after disease progression on chemotherapy-naive patients with advanced non- International, randomized, placebo-controlled, double- platinum-based therapy (REVEL): A multicentre, small cell lung cancer. J Thorac Oncol 7:427-433, blind phase III study of motesanib plus carboplatin/ double-blind, randomised phase 3 trial. Lancet 384: 2012 paclitaxel in patients with advanced nonsquamous 665-673, 2014 23. Tsai CM, Au JS, Chang GC, et al: Safety and non-small-cell lung cancer: MONET1. J Clin Oncol 30: 15. Reck M, Kaiser R, Mellemgaard A, et al: efficacy of first-line bevacizumab with chemotherapy 2829-2836, 2012 Docetaxel plus nintedanib versus docetaxel plus in Asian patients with advanced nonsquamous 7. Kubota K, Ichinose Y, Scagliotti G, et al: Phase placebo in patients with previously treated non-small- NSCLC: Results from the phase IV MO19390 (SAiL) III study (MONET1) of motesanib plus carboplatin/ cell lung cancer (LUME-Lung 1): A phase 3, double- study. J Thorac Oncol 6:1092-1097, 2011 paclitaxel in patients with advanced nonsquamous blind, randomised controlled trial. Lancet Oncol 15: 24. Zhao X, Mei K, Cai X, et al: A randomized phase nonsmall-cell lung cancer (NSCLC): Asian subgroup 143-155, 2014 II study of recombinant human endostatin plus analysis. Ann Oncol 25:529-536, 2014 16. Hall RD, Le TM, Haggstrom DE, et al: Angio- gemcitabine/cisplatin compared with gemcitabine/ 8. Saijo N, Fukuoka M, Thongprasert S, et al: genesis inhibition as a therapeutic strategy in non- cisplatin alone as first-line therapy in advanced Lung cancer working group report. Jpn J Clin Oncol small cell lung cancer (NSCLC). Transl Lung Cancer non-small-cell lung cancer. Invest New Drugs 30: 40:i7-i12, 2010 (suppl 1) Res 4:515-523, 2015 1144-1149, 2012

Affiliations Kaoru Kubota, Nippon Medical School; Kaori Hara and Takayuki Asato, Takeda Pharmaceutical, Tokyo; Hiroshige Yoshioka, Kurashiki Central Hospital, Kurashiki; Fumihiro Oshita, Kanagawa Prefectural Ashigarakami Hospital, Matsuda; Toyoaki Hida, Aichi Cancer Center Hospital, Nagoya; Kiyotaka Yoh, National Cancer Center Hospital East, Chiba; Hidetoshi Hayashi, Hiroyasu Kaneda, and Kazuhiko Nakagawa, Kindai University Faculty of Medicine; Hidetoshi Hayashi, Kishiwada Municipal Hospital, Osaka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama; Kazuhiko Yamada, Kurume University School of Medicine; Yukito Ichinose, National Kyushu Cancer Center, Fukuoka; Hiroshi Tanaka, Niigata Cancer Center Hospital, Niigata, Japan; Keunchil Park, Samsung Biomedical Research Institute, Seoul; Eun Kyung Cho, Gachon University; Kyung-Hee Lee, Inha University Hospital, Incheon, South Korea; Chih-Bin Lin, Buddhist Tzu-Chi General Hospital, Hualien; James Chih-Hsin Yang, National Taiwan University Hospital; National Taiwan University Cancer Center, Taipei City, Peoples Republic of China. Support Supported by Takeda Pharmaceutical. Prior Presentation Presented at the 15th World Conference on Lung Cancer, Sydney, New South Wales, Australia, October 27-30, 2013. nnn

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST 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 The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Kaoru Kubota Research Funding: Pfizer (Inst) Honoraria: Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Boehringer Ingelheim, Novartis, Hiroshi Tanaka AstraZeneca, Teijin, MSD, Bristol-Myers Squibb, Amgen Honoraria: AstraZeneca, Ono Pharmaceutical, Chugai Pharmaceutical, Research Funding: Boehringer Ingelheim (Inst), Taiho Pharmaceutical Taiho Pharmaceutical, Eli Lilly Japan (Inst), Daiichi Sankyo (Inst) Consulting or Advisory Role: AstraZeneca, MSD, Nippon Boehringer Ingelheim Hiroshige Yoshioka Research Funding: Eli Lilly (Inst), AstraZeneca (Inst), MSD (Inst), Ono Honoraria: Eli Lilly, Chugai Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical (Inst), Takeda Pharmaceutical (Inst), Pfizer (Inst), Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Astellas Pharma (Inst) Fumihiro Oshita Yukito Ichinose No relationship to disclose Honoraria: Chugai Pharmaceutical Toyoaki Hida Keunchil Park Honoraria: Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Consulting or Advisory Role: Astellas Pharma, AstraZeneca, Boehringer Novartis, Taiho Pharmaceutical, AstraZeneca, Nippon Boehringer Ingelheim, Clovis Oncology, Eli Lilly, Hanmi Pharmaceutical, Kyowa Ingelheim, Pfizer, Bristol-Myers Squibb, Clovis Oncology Hakko Kirin, Novartis, Ono Pharmaceutical, Roche Research Funding: Ono Pharmaceutical (Inst), Chugai Pharmaceutical Speakers’ Bureau: Boehringer Ingelheim (Inst), Eli Lilly (Inst), Novartis (Inst), Taiho Pharmaceutical (Inst), Research Funding: AstraZeneca AstraZeneca (Inst), Nippon Boehringer Ingelheim (Inst), Pfizer (Inst), Bristol-Myers Squibb (Inst), Clovis Oncology (Inst), Eisai (Inst), Takeda Eun Kyung Cho Pharmaceutical (Inst), Sumitomo Dainippon Pharma (Inst), AbbVie No relationship to disclose (Inst), Merck Serono (Inst), Kyowa Hakko Kirin (Inst), Daiichi Sankyo Kyung-Hee Lee (Inst), Astellas Pharma (Inst) No relationship to disclose Kiyotaka Yoh Chih-Bin Lin Honoraria: Chugai Pharmaceutical, AstraZeneca, Eli Lilly Japan, No relationship to disclose Boehringer Ingelheim, Taiho Pharmaceutical, Bristol-Myers Squibb Japan, Ono Pharmaceutical James Chih-Hsin Yang Consulting or Advisory Role: Boehringer Ingelheim, AstraZeneca, Eli Honoraria: Boehringer Ingelheim, Roche, Chugai Pharmaceutical, MSD, Lilly Japan AstraZeneca, Novartis Research Funding: Eli Lilly Japan (Inst), Bayer AG (Inst), Novartis (Inst), Consulting or Advisory Role: Boehringer Ingelheim, Novartis, AstraZeneca (Inst), Pfizer (Inst) AstraZeneca, Roche, Genentech, Eli Lilly, MSD Oncology, Merck Serono, Celgene, Astellas Pharma, Bayer AG, Pfizer, Ono Pharmaceutical, Bristol- Hidetoshi Hayashi Myers Squibb, Yuhan, Hansoh Pharmaceutical Honoraria: Ono Pharmaceutical, Bristol-Myers Squibb Japan, Eli Lilly, Taiho Pharmaceutical, Boehringer Ingelheim, AstraZeneca Japan Kaori Hara Consulting or Advisory Role: Eli Lilly, AstraZeneca, Boehringer Ingelheim Employment: Takeda Pharmaceutical Research Funding: Ono Pharmaceutical Takayuki Asato Terufumi Kato Employment: Takeda Pharmaceutical Employment: Eli Lilly (I) Stock or Other Ownership: Chugai Pharmaceutical Honoraria: Chugai Pharmaceutical, Roche, Boehringer Ingelheim, Ono fi Kazuhiko Nakagawa Pharmaceutical, Eli Lilly, AstraZeneca, Taiho Pharmaceutical, P zer, Honoraria: Astellas Pharma, AstraZeneca, EPS Holdings, Ono Kyowa Hakko Kirin Pharmaceutical, Kyowa Hakko Kirin, Showa Yakuhin Kako, SymBio Consulting or Advisory Role: AstraZeneca, Ono Pharmaceutical, Nippon Pharmaceuticals, Daiichi Sankyo, Chugai Pharmaceutical, Nippon Boehringer Ingelheim Boehringer Ingelheim, Eli Lilly, Pfizer, Bristol-Myers Squibb Research Funding: Chugai Pharmaceutical, Merck Sharp & Dohme, Research Funding: Chugai Pharmaceutical (Inst), Merck Sharp & Dohme Takeda Pharmaceutical, Kyowa Hakko Kirin, Daiichi Sankyo, Yakult fi (Inst), Ono Pharmaceutical (Inst), EPS Associates (Inst), Quintiles (Inst), Honsha, Nippon Boehringer Ingelheim, P zer, Taiho Pharmaceutical, Daiichi Sankyo (Inst), Japan Clinical Research Operations (Inst), Eisai Shionogi, AstraZeneca, Eli Lilly, Bristol-Myers Squibb, AbbVie, Astellas (Inst), PPD-SNBL (Inst), Pfizer (Inst), Takeda Pharmaceutical (Inst), Pharma, Quintiles, Parexel International Nippon Boehringer Ingelheim (Inst), Taiho Pharmaceutical (Inst), Bristol- Hiroyasu Kaneda Myers Squibb (Inst), AstraZeneca (Inst), Kyowa Hakko Kirin (Inst), No relationship to disclose OncoTherapy Science (Inst) Kazuhiko Yamada Honoraria: Eli Lilly, AstraZeneca, Bristol-Myers Squibb, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical

Acknowledgment

We thank the patients who participated in this study and their families as well as staff at all investigational sites. We also acknowledge the writing assistance of Hannah Finnigan of FireKite, an Ashﬁeld company, part of UDG Healthcare, during the development of this manuscript, which was funded by Takeda Pharmaceutical and complied with Good Publication Practice 3 ethical guidelines (Battisti WP et al: Ann Intern Med 163:461-464, 2015).