A phase II, multicenter, open-label randomized study of motesanib or bevacizumab in combination with paclitaxel and carboplatin for advanced nonsquamous non-small-cell lung cancer

original article

Annals of Oncology 22: 2057–2067, 2011 doi:10.1093/annonc/mdq731 Published online 14 February 2011

A phase II, multicenter, open-label randomized study of motesanib or bevacizumab in combination with paclitaxel and carboplatin for advanced nonsquamous non-small-cell lung cancer G. R. Blumenschein Jr1* , F. Kabbinavar2,3,4 , H. Menon5, T. S. K. Mok6, J. Stephenson7, J. T. Beck8, K. Lakshmaiah9, K. Reckamp10, Y.-J. Hei11, K. Kracht12, Y.-N. Sun13, R. Sikorski11 & L. Schwartzberg14  on behalf of the Motesanib NSCLC Phase II Study Investigatorsà 1

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston; Department of 2Medicine, University of California Los Angeles Medical Center, Los Angeles; 3Hematology/Oncology, University of California Los Angeles Medical Center, Los Angeles; 4Translational Oncology Research International, Los Angeles, USA; 5Department of Medical Oncology, Tata Memorial Center, Mumbai, India; 6Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China; 7Cancer Center of the Carolinas, Greenville; 8Highlands Oncology Group, Fayetteville, USA; 9Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bangalore, India; 10Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte; 11Department of Oncology; 12Biostatistics and Epidemiology; 13Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks; 14 Department of Hematology and Oncology, The West Clinic, Memphis, USA

Received 10 September 2010; revised 12 November 2010; accepted 17 November 2010

advanced nonsquamous non-small-cell lung cancer (NSCLC) receiving paclitaxel–carboplatin (CP) plus motesanib or bevacizumab. Patients and methods: Chemotherapy-naive patients (N = 186) were randomized 1:1:1 to receive CP plus motesanib 125 mg once daily (qd) (arm A), motesanib 75 mg twice daily (b.i.d.) 5 days on/2 days off (arm B), or bevacizumab 15 mg/kg every 3 weeks (q3w) (arm C). The primary end point was ORR (per RECIST). Other end points included progression-free survival (PFS), overall survival (OS), motesanib pharmacokinetics, and adverse events (AEs). Results: ORRs in the three arms were as follows: arm A, 30% (95% confidence interval 18% to 43%); arm B, 23% (13% to 36%); and arm C, 37% (25% to 50%). Median PFS in arm A was 7.7 months, arm B 5.8 months, and arm C 8.3 months; median OS for arm A was 14.0 months, arm B 12.8 months, and arm C 14.0 months. Incidence of AEs was greater in arms A and B than in arm C. More grade 5 AEs not attributable to disease progression occurred in arm B (n = 10) than in arms A (n = 4) and C (n = 4). Motesanib plasma Cmax and Cmin values were consistent with its pharmacokinetic properties observed in previous studies. Conclusions: The efficacy of 125 mg qd motesanib or bevacizumab plus CP was estimated to be comparable. Toxicity was higher but manageable in both motesanib arms. Efficacy and tolerability of motesanib 125 mg qd plus CP in advanced nonsquamous NSCLC are being further investigated in a phase III study. Key words: bevacizumab, motesanib, nonsquamous non-small-cell lung cancer, objective response rate, pharmacokinetics

introduction The proangiogenic cytokine vascular endothelial growth factor (VEGF) and its receptors are important targets for non-smallcell lung cancer (NSCLC) therapy [1]. In the E4599 study, treatment with the anti-VEGF-A monoclonal antibody *Correspondence to: Prof. G. R. Blumenschein Jr, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel: +1-713-792-6363; Fax: +1-713792-1220; E-mail: [email protected]  

These authors contributed equally to the study.

à

Investigators who participated in the study are listed in the Acknowledgements.

bevacizumab plus carboplatin–paclitaxel (CP) resulted in improved overall survival (OS) compared with CP among patients with stage IIIB or IV NSCLC of nonsquamous histology [2]. Objective response rate (ORR) and progression-free survival (PFS) were also improved as assessed by investigators [2, 3]. Bevacizumab plus CP is the only anti-angiogenic therapy currently approved in the United States for treatment of NSCLC [4]. Addition of bevacizumab to cisplatin–gemcitabine has been shown to improve ORR and PFS (per investigator assessment) in NSCLC but did not have a statistically significant effect on overall survival [5, 6]. Motesanib, an orally administered small-molecule antagonist of VEGF receptors (VEGFRs) 1, 2, and 3, and platelet-derived

ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]

original article

Background: This phase II study estimated the difference in objective response rate (ORR) among patients with

original article growth factor receptor and Kit [7], has shown promising antitumor activity in solid tumors as monotherapy [8–10] and in combination with chemotherapy [11, 12]. In a phase Ib study in NSCLC, treatment with motesanib plus CP was tolerable at doses up to 125 mg once daily (qd), with encouraging preliminary response rates and pharmacokinetics supporting that dosing regimen as combination therapy [13]. In the present study, chemotherapy-naive patients with advanced nonsquamous NSCLC were randomly assigned to receive CP with motesanib at either 125 mg qd or at 75 mg twice daily (b.i.d.) 5 days on/2 days off, or CP with bevacizumab 15 mg/kg every 3 weeks (q3w). The motesanib 75-mg b.i.d. dose schedule was selected to maximize exposure to the drug while minimizing toxicity. The primary objective was to estimate the difference in ORR between each motesanib plus CP treatment arm and the bevacizumab plus CP arm.

methods patients Eligible patients (‡18 years) had histologically or cytologically confirmed advanced nonsquamous NSCLC [unresectable stage IIIB with malignant effusion or stage IV/recurrent; no specific TNM (tumor–node–metastasis) staging was required), Eastern Cooperative Oncology Group (ECOG) performance status of one or less, measurable disease according to RECIST [14], and life expectancy ‡3 months. Key exclusion criteria were central nervous system metastases [as assessed by computed tomography (CT) or magnetic resonance imaging (MRI) of the head within 21 days before randomization]; history of other cancer (unless curatively treated), pulmonary hemorrhage, or gross hemoptysis; bleeding diathesis or nonpulmonary bleeding within 14 days of randomization; uncontrolled hypertension (>150/90 mmHg); peripheral neuropathy grade >1; inadequate cardiac, hepatic, hematologic, or renal function; prior chemotherapy for advanced NSCLC or adjuvant chemotherapy within 52 weeks of randomization; prior targeted therapy; anticoagulant therapy within 7 days of randomization; daily treatment with aspirin (>325 mg/day) or nonsteroidal anti-inflammatory agents; prior chemoradiation for locally advanced stage III disease; central radiation therapy within 28 days of randomization; or other radiation therapy within 14 days of randomization. Study procedures were approved by each site’s institutional ethics committee. All patients provided written informed consent.

Annals of Oncology

accountability records), or (arm C) bevacizumab 15 mg/kg i.v. q3w. Treatment in arm C was similar to that in the bevacizumab arm of the E4599 study [2]. In all three arms, motesanib or bevacizumab monotherapy treatment continued for up to 36 months or until death, disease progression, or unacceptable toxicity occurred. Doses of study drugs could be reduced or withheld, following protocol-specified rules, if patients experienced toxicity. Specific dose reduction/interruption rules applied for the management of hypertension, thrombosis, proteinuria, bleeding, hemoptysis, and gallbladder disorders (supplemental data, available at Annals of Oncology online). Doses of motesanib could be reduced in 25-mg decrements; treatment was stopped in patients requiring two or more dose reductions.

tumor assessments Tumor response was assessed according to RECIST [14] (with modifications; supplemental data, available at Annals of Oncology online) by independent centralized radiological review (Radpharm Inc., Princeton, NJ). CT or MRI was carried out at baseline and every 6 6 1 weeks thereafter. Patients with positive bone scans at screening had additional bone scans every 12 6 1 weeks. Complete or partial responses were confirmed within 4 weeks of the initial response. Patients without confirmation of response were considered nonresponders. Progressive disease determined by bone imaging was confirmed by subsequent radiography.

toxicity All AEs occurring from the beginning of treatment to 30 days after the last dose of study medication were recorded by investigators and graded according to the National Cancer Institute—Common Terminology Criteria for Adverse Events, version 3.0. Blood pressure was measured weekly for the first 6 weeks and at every visit thereafter.

pharmacokinetics Plasma samples in arms A and B were collected at 1 h following dosing on day 1/cycle 1 (peak concentrations, Cmax), at 24 h following dosing on day 2/cycle 1 (trough concentrations, Cmin), and before dosing on day 1 of every third cycle thereafter. Samples were analyzed using a validated liquid chromatography–tandem mass spectrometry method (lower limit of quantification was 0.200 ng/ml; percent coefficient of variation, 15%–20%) and pharmacokinetic analyses carried out as previously described [13]. Pharmacokinetic analyses included all randomly assigned patients who received one or more motesanib doses and had one or more post-treatment assessments of Cmax or Cmin for the protocol-specified dose levels and dosing regimens.

study design and treatment This was a phase II, international, multicenter, open-label randomized study conducted at 64 centers. The primary end point was ORR (per modified RECIST and independent centralized review). Secondary end points included PFS, OS, duration of response, and the pharmacokinetics of motesanib in combination with CP. The safety end point was the incidence of treatment-emergent adverse events (AEs) and changes in laboratory values and vital signs. Patients were randomly assigned in a 1 : 1 : 1 ratio to three treatment arms. Randomization was stratified by disease stage (IIIB or IV) and weight loss (<5% or ‡5%) in the previous 6 months. Treatment cycles were 3 weeks long. All patients received paclitaxel (200 mg/m2 administered i.v. over 3 h) and carboplatin (target area under the curve of 6 mg
ml/min; administered i.v. over 30 min) on day 1 of each 3-week cycle for a maximum of six cycles. Treatment with motesanib or bevacizumab began on day 1 of cycle 1. Patients received (arm A) motesanib 125 mg qd orally, (arm B) motesanib 75 mg b.i.d. orally for 5 days followed by a 2-day treatment-free period every 7 days (compliance was monitored using dose-specific patient diaries and site-specific

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statistical analysis The study was designed as an estimation study assessing the difference [based on two-sided 95% confidence intervals (CIs)] in ORR (and other measures of efficacy) between each of the motesanib arms (arms A and B) versus arm C. No formal statistical hypothesis was tested. Based on an assumption of a 27% ORR (confirmed partial or complete response) in each arm (based on an interim analysis of the E4599 study) [15], a sample size of 60 patients per arm was selected, which was estimated to provide a two-sided 95% CI of 616% from the observed difference in ORR between each of the two motesanib arms (arms A and B) and arm C. The clinical benefit rate was defined as the percentage of patients with an objective response or durable (‡24 weeks) stable disease. PFS was calculated as the time from randomization to the time of disease progression or death. Patients alive without disease progression were censored at the date of the last disease assessment. The OS analysis evaluated time from randomization to death. Patients alive at the date of last contact were censored. The Kaplan–Meier estimate of median PFS and median OS (and their 95% CIs)

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were calculated for each treatment arm [16]. A Cox model stratified by disease stage and weight loss was used to compare PFS between the treatment arms. In an additional analysis, this Cox model was adjusted by ECOG status (0 versus ‡1) and tumor histology (adenocarcinoma versus nonadenocarcinoma). The analyses of ORR, PFS, and OS included the intent-to-treat population. The safety analyses included all patients who received one or more doses of motesanib or bevacizumab.

results patients One hundred eighty-six patients were randomly assigned to the treatment arms (arm A, n = 61; arm B, n = 62; arm C, n = 63) (Figure 1). Five patients (arm A, n = 2; arm C, n = 3) did not receive study treatment. Demographics and baseline characteristics showed some imbalances, specifically in adenocarcinoma histology, Asian ethnicity, ECOG performance status, and cigarette use (Table 1). At the time of this analysis, one patient in arm A continued to receive motesanib and two patients in arm C continued to receive bevacizumab; all other patients had discontinued treatment. The median duration of exposure to motesanib (arm A: 122 days, range 1–546 days; arm B: 102 days, range 3–513 days) or bevacizumab (129 days, range 21–714 days) was similar. Median follow-up times (at time of analysis) in arms A, B, and C were 40 (range 1–126), 45.5 (2–114), and 54 (1–119) weeks, respectively. In arms A, B, and C, 64%, 68%, and 65%, respectively, of patients had died. objective response rate The ORR in the three arms was similar: 30% (95% CI 18% to 43%) for arm A, 23% (95% CI 13% to 36%) for arm B, and 37% (95% CI 25% to 50%) for arm C (Table 2). For the difference in ORR between arms A and C, the 95% CI was 225% to 11%. Similarly, for the difference in ORR between arms B and C, the 95% CI was 230% to 4%. The median

duration of response in arms A, B, and C, was 33, 37, and 33 weeks, respectively. Most patients had measurable disease at baseline (arm A, n = 57; arm B, n = 60; arm C, n = 62). All but five patients (arm B, n = 2; arm C, n = 3) had reductions from baseline in the sum of longest diameters of target lesions (Figure 2).

PFS and OS At the time of this analysis, 73% of patients had disease progression or had died due to any cause (arm A, 70%; arm B, 77%; arm C, 71%; Table 2). The Kaplan–Meier estimate of median PFS was 7.7 months (95% CI 5.6–9.3) for arm A, 5.8 months (95% CI 4.3–7.8) for arm B, and 8.3 months (95% CI 6.8–10.2) for arm C (Figure 3A). The hazard ratio (HR) for PFS in a Cox model adjusted for the stratification factors (i.e. disease stage and weight loss) was 1.14 (95% CI 0.73–1.76) for arm A over arm C and 1.22 (95% CI 0.80–1.85) for arm B over arm C. Estimated median OS was 14.0 months (95% CI 7.7–18.6) for arm A, 12.8 months (95% CI 7.9–17.0) for arm B, and 14.0 months (95% CI 9.3–16.8) for arm C (Figure 3B). The HR for OS in a Cox model stratified by disease stage and weight loss was 1.05 (95% CI 0.67–1.63) for arm A over arm C and 1.18 (95% CI 0.76–1.83) for arm B over arm C. HRs from Cox models for PFS and OS adjusted for ECOG status and tumor histology were similar to those from the model stratified by disease stage and weight loss (data not shown). adverse events Treatment-emergent AEs occurred in 95%, 97%, and 93% of patients in arms A, B, and C, respectively (Table 3). Overall, the patient incidence rate of most any grade, grade ‡3 AEs, and AEs leading to treatment discontinuation was higher in the motesanib treatment arms. Exceptions were peripheral neuropathy and myalgia (arm A, n = 4; arm B, n = 4; arm C, n = 10), which occurred more frequently in the bevacizumab

Figure 1. Patient disposition. qd, once daily; b.i.d., twice daily; q3w, once every 3 weeks.

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Table 1. Demographic and baseline characteristics

Sex Women Men Race White Asian Black Hispanic American Indian or Alaska Native Other Age in years, median (range) ECOG performance status 0 1 2 Weight loss % in the last 6 months <5 ‡5 Missing Cigarette use Never Former Current Missing Histology Adenocarcinoma Large-cell carcinoma Undifferentiated Bronchoalveolar carcinoma Other Missing Disease stage IIIB IV No. of sites of diseasea 1 2 3 4 ‡5 Lines of prior chemotherapyb 0 1 2 Lines of prior radiotherapy 0 1 2

Arm A, motesanib 125 mg qd, n = 61 (%)

Arm B, motesanib 75 mg b.i.d., n = 62 (%)

Arm C, bevacizumab 15 mg/ kg q3w, n = 63 (%)

28 (46) 33 (54)

26 (42) 36 (58)

28 (44) 35 (56)

39 10 6 3 1

34 22 5 1 0

38 22 3 0 0

(64) (16) (10) (5) (2)

(55) (35) (8) (2) (0)

(60) (35) (5) (0) (0)

2 (3) 61 (35–83)

0 (0) 59 (38–82)

0 (0) 64 (32–83)

26 (43) 34 (56) 1 (2)

32 (52) 29 (47) 1 (2)

33 (52) 30 (48) 0 (0)

49 (80) 12 (20) 0 (0)

46 (74) 14 (23) 2 (3)

47 (75) 16 (25) 0 (0)

14 33 13 1

(23) (54) (21) (2)

19 26 17 0

(31) (42) (27) (0)

15 41 7 0

(24) (65) (11) (0)

47 5 3 1

(77) (8) (5) (2)

56 3 0 1

(90) (5) (0) (2)

54 4 2 1

(86) (6) (3) (2)

4 (7) 1 (2)

2 (3) 0 (0)

1 (2) 1 (2)

10 (16) 51 (84)

12 (19) 50 (81)

11 (17) 52 (83)

7 20 20 10 4

6 29 15 8 4

4 25 24 8 2

(11) (33) (33) (16) (7)

(10) (47) (24) (13) (6)

(6) (40) (38) (13) (3)

59 (97) 1 (2) 1 (2)

60 (97) 2 (3) 0 (0)

62 (98) 1 (2) 0 (0)

55 (90) 6 (10) 0 (0)

57 (92) 4 (6) 1 (2)

60 (95) 3 (5) 0 (0)

qd, once daily; b.i.d., twice daily; q3w, once every 3 weeks; ECOG, Eastern Cooperative Oncology Group. As assessed by investigator. b Patients who were enrolled despite having received prior chemotherapy were protocol violations. a

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Table 2. Tumor response

Best tumor response by independent review per RECIST Patients with measurable disease at baseline, n (%) Response assessment, n (%) Confirmed complete response (CR) Confirmed partial response (PR) Stable disease (SD)a Progressive disease Not doneb Confirmed objective response rate, % (95% CI) Difference versus arm C, % (95% CI) Durable SD ‡24 weeks, % (95% CI) Clinical benefit rate (CR + PR + durable SD), % (95% CI) Median duration of response, weeks (95% CI) Survival timec Patients with events, n (%) Disease progression Death (all cause) Kaplan–Meier median progression-free survival time, months (95% CI) Hazard ratio (motesanib/ bevacizumab) (95% CI)d Kaplan–Meier median overall survival time, months (95% CI) Hazard ratio (motesanib/ bevacizumab) (95% CI)d

Arm A, motesanib 125 mg qd, n = 61

Arm B, motesanib 75 mg b.i.d., n = 62

Arm C, bevacizumab 15 mg/kg q3w, n = 63

57 (93)

60 (97)

62 (98)

0 (0)

0 (0)

0 (0)

17 (30)

14 (23)

23 (37)

20 4 16 30

30 4 12 23

26 2 11 37

(35) (7) (28) (18 to 43)

(50) (7) (20) (13 to 36)

(42) (3) (18) (25 to 50)

27 (225 to 11)

214 (230 to 4)

9 (3 to 19)

5 (1 to 14)

5 (1 to 14)

39 (26 to 52)

28 (18 to 41)

42 (30 to 55)

33 (26 to NE)

37 (18 to 60)

33 (25 to 49)

43 37 39 7.7

48 36 42 5.8

45 38 41 8.3

(70) (61) (64) (5.6 to 9.3)

(77) (58) (68) (4.3 to 7.8)

1.14 (0.73 to 1.76)

1.22 (0.80 to 1.85)

14.0 (7.7 to 18.6)

12.8 (7.9 to 17.0)

1.05 (0.67 to 1.63)

1.18 (0.76 to 1.83)

–

(71) (60) (65) (6.8 to 10.2)

–

14.0 (9.3 to 16.8)

–

qd, once daily; b.i.d., twice daily; q3w, once every 3 weeks; CI, confidence interval; NE, not estimable. a Patients with a response assessment of CR or PR that is not subsequently confirmed at least 4 weeks later are included as SD. b Includes patients who had computed tomography (CT)/magnetic resonance imaging (MRI) scans at baseline only. When calculating the objective response rate and SD rate, patients with measurable disease at baseline but without a subsequent CT/MRI assessment were considered nonresponders. c Patients without an assessment of disease progression and/or death at the time of this analysis were censored. d Hazard ratio estimated using a Cox regression model stratified by the randomization factors (i.e. disease stage and weight loss in the previous 6 months).

arm (arm C). Of note, for five patients in arm A and one patient each in arms B and C, NSCLC progression was recorded as a grade 5 AE. Hypertension occurred more frequently in arm A than in arm B or C and was mostly grade <3; no grade ‡4 hypertension was reported. The patient incidence of hemorrhagic events was

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similar across arms. Eight patients had hypothyroidism, elevated blood thyroid-stimulating hormone, or both. Gall-bladder toxicity occurred much more frequently in the motesanib arms than in arm C (Table 3). Specifically, grade 3 cholecystitis occurred in arms A (two patients) and B (three patients), but not in arm C.

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Figure 2. Maximum change from baseline in tumor measurements per RECIST and independent central radiographic assessment for patients receiving (A) motesanib 125 mg qd, (B) motesanib 75 mg b.i.d., or (C) bevacizumab 15 mg/kg q3w. qd, once daily; b.i.d., twice daily; q3w, once every 3 weeks; SLD, sum of longest diameter.

More patients in arms A (n = 31) and B (n = 36) than in arm C (n = 19) had serious treatment-emergent AEs or discontinued treatment because of AEs (n = 23 and n = 22, respectively, versus n = 14). The most frequently occurring serious AEs were dehydration (arms A, B, and C, n = 9, 7, and 3, respectively), pneumonia (n = 4, 6, and 2), and asthenia (n = 3, 2, and 2). One hundred twenty-two deaths occurred on study; 25 were treatment-emergent grade 5 adverse events (arms A, B, and C, n = 9, 11, and 5, respectively). Of these, seven were reported as death due to NSCLC disease progression (arms A, B, and C, n = 5, 1, and 1, respectively). There were more grade 5 AEs not attributable to disease progression or

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NSCLC in arm B (n = 10) than in arms A (n = 4) and C (n = 4; Table 4).

pharmacokinetics Median motesanib Cmax 1 h after coadministration with CP on day 1 was 267 ng/ml in arm A; for arm B, it was 197 ng/ml. Median motesanib Cmin 24 h following dose was 17.9 ng/ml in arm A; for arm B, it was 49.0 ng/ml. In subsequent cycles, the median motesanib Cmin was 5.44 ng/ml (range 0.640–189) after 125 mg qd continuous dosing, whereas the median Cmin in arm B was 0.533 ng/ml (range below quantification limit to 11.5) after the 2-day treatment-free period.

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Figure 3. Median progression-free survival for the full analysis set. The full analysis set includes all patients randomized to motesanib or bevacizumab regardless of whether they received treatment. C, censored observation; qd, once daily; b.i.d., twice daily; q3w, once every 3 weeks.

discussion In this study, the ORR was estimated to be similar between the motesanib and bevacizumab treatment arms based on the respective 95% CIs, which include zero. In the bevacizumab arm, the ORR result is consistent with the investigator-assessed ORRs in the phase II/III E4599 study (35%) [2] and the phase III Avastin in Lung (AVAiL) study (34.6%) [6]. It should be noted that median follow-up time in the present study is shorter than for E4599 (12 versus 19 months). In arm C, median PFS (8.3 months) and OS (14.0 months) were somewhat better than that reported for bevacizumab-treated patients in the E4599 study (6.2 and 12.3 months, respectively) [2] and the AVAiL study (6.5 and 13.4 months, respectively) [5, 6], and were similar to median PFS (7.7 months; HR 1.14, 95% CI 0.73–1.76) and OS (14.0 months; HR 1.05, 95% CI 0.67–1.63) in arm A of the present study. The cross-trial differences between results may be explained by differences in the demographic and clinical characteristics of the patient populations enrolled. Median PFS (5.8 months) and OS (12.8 months) in arm B were shorter than in arms A and C (comparing arms B and C, the HR was 1.22,

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95% CI 0.80–1.85 for PFS; and 1.18, 95% CI 0.76–1.83, for OS). These results confirm and expand upon those from a phase Ib study in NSCLC showing that motesanib 125 mg qd in combination with CP was tolerable and had favorable pharmacokinetics [13]. There are several limitations that must be considered and results should be interpreted with caution. The current study had an open-label design, enrolled only a small number of patients in each treatment arm, and was not statistically powered to detect a statistical difference in response rates between the treatment and control arms. Given these limitations, the study results should be interpreted with caution. Nevertheless, the study achieved its objectives of providing estimates of efficacy and safety of two motesanib doses relative to each other and to bevacizumab in advanced NSCLC, which can inform future studies. Furthermore, this is the only study that allowed for a concurrent evaluation of the two antiangiogenesis agents in the NSCLC setting. The efficacy and tolerability of motesanib 125 mg qd plus CP in patients with stage IIIB/IV nonsquamous NSCLC are currently being investigated more definitively in a large, blinded phase III study (MONET1; http://Clinicaltrials.gov:

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Table 3. Patient incidence of adverse eventsa

Patients with AEs Grade 1 AEs Grade 2 AEs Grade 3 AEs Grade 4 AEs Any grade 3, 4, or 5 AE AEs leading to treatment discontinuation AEs occurring in ‡20% of patients in 1 or more treatment arms Fatigue Diarrhea Hypertension Nausea Vomiting Alopecia Constipation Dehydration Anorexia Weight decreased Neuropathy peripheral Dyspnea Asthenia Anemia Abdominal pain Dizziness Arthralgia Insomnia Neutropenia AEs of interest Hemorrhagic events Gall-bladder toxicity Venous thromboembolic events Arterial thromboembolic events Other thromboembolic eventsd Proteinuria Hypothyroidism, elevated blood thyroid-stimulating hormone, or both Congestive heart failure Impaired wound healing

Arm A, motesanib 125 mg qd, n = 59 (%)

Arm B, motesanib 75 mg b.i.d., n = 62 (%)

Arm C, bevacizumab 15 mg/kg q3w, n = 60 (%)

56 2 12 27 6 42 23

60 2 9 36 2 49 22

56 5 13 30 3 38 14

(95) (3) (20) (46) (10) (71) (39)

(97) (3) (15) (58) (3) (79) (35)

(93) (8) (22) (50) (5) (63) (23)

All grades

Grade 3/4

All grades

Grade 3/4

All Grades

Grade 3/4

37 (63) 30 (51) 28 (47) 28 (47) 28 (47) 24 (41) 20 (34) 19 (32) 19 (32) 18 (31) 16 (27) 15 (25) 14 (24) 13 (22) 12 (20) 12 (20) 11 (19) 9 (15) 5 (8) All grades 13 (22) 10 (17) 4 (7)

10 (17) 11 (19) 3 (5) 5 (8) 3 (5) 0 (0) 2 (3) 10 (17)b 7 (12) 2 (3) 2 (3) 3 (5) 2 (3) 3 (5) 3 (5) 2 (3) 0 (0) 0 (0) 4 (7)b Grade 3/4 2 (3)b 3 (5) 4 (7)b

32 (52) 29 (47) 17 (27) 29 (47) 22 (35) 21 (34) 20 (32) 13 (21) 15 (24) 12 (19) 16 (26) 13 (21) 11 (18) 14 (23) 9 (15) 11 (18) 9 (15) 14 (23) 13 (21) All grades 15 (24) 11 (18) 2 (3)

3 (5) 7 (11) 5 (8) 1 (2) 3 (5) 0 (0) 1 (2) 7 (11) 1 (2) 0 (0) 1 (2) 0 (0) 2 (3) 5 (8) 2 (3) 2 (3) 2 (3) 0 (0) 5 (8)c Grade 3/4 2 (3) 4 (6) 2 (3)

36 (60) 17 (28) 9 (15) 23 (38) 14 (23) 23 (38) 20 (33) 6 (10) 17 (28) 8 (13) 27 (45) 14 (23) 8 (13) 11 (18) 6 (10) 9 (15) 12 (20) 8 (13) 10 (17) All Grades 11 (18) 2 (3) 4 (7)

5 (8) 2 (3) 1 (2) 1 (2) 2 (3) 2 (3) 1 (2) 2 (3) 2 (3) 1 (2) 4 (7) 2 (3) 2 (3) 3 (5) 3 (5)b 0 (0) 2 (3) 0 (0) 8 (13) Grade 3/4 2 (3) 0 (0) 1 (2)

1 (2)

1 (2)b

3 (5)

2 (3)

2 (3)

2 (3)b

1 (2)

1 (2)b

3 (5)

2 (3)b

0 (0)

0 (0)

3 (5) 3 (5)

0 (0) 1 (2)

6 (10) 4 (6)

2 (3) 0 (0)

3 (5) 1 (2)

0 (0) 0 (0)

0 (0) 1 (2)

0 (0) 0 (0)

0 (0) 0 (0)

0 (0) 0 (0)

1 (2) 0 (0)

1 (2) 0 (0)

qd, once daily; b.i.d., twice daily; q3w, once every 3 weeks; AE, adverse event. a Adverse events are reported for patients in the safety analysis set, which included all patients who received one or more doses of motesanib or bevacizumab. Individually listed AEs may occur in more than one patient. b Includes one event of grade 4. c Includes two events of grade 4. d Includes thromboembolic events occurring in unspecified vessel types and mixed arterial and venous thromboembolic events.

NCT00460317). The motesanib phase III study will further inform on the value of small-molecule VEGF(R) pathway inhibitors in NSCLC, given that several phase III studies of such

2064 | Blumenschein Jr et al.

molecules have not demonstrated a survival benefit in either the first-line or the second-line setting. Interim results from the Evaluation of Sorafenib, Carboplatin and Paclitaxel Efficacy in

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Table 4. Patient incidence of grade 5 adverse events

Grade 5 AEs attributed to progression of NSCLC Grade 5 AEs not attributed to progression of NSCLC Cachexia Cardiorespiratory arrest Dyspnea Factor V inhibition Hydropneumothorax Lung neoplasm malignant Metastases to CNS Myocardial infarction Esophagobronchial fistula Pulmonary embolism Respiratory failure Sepsis Adverse event with an uncoded preferred term Sudden death

Arm A, motesanib 125 mg qd, n = 59 (%)

Arm B, motesanib 75 mg b.i.d., n = 62 (%)

Arm C, bevacizumab 15 mg/ kg q3w, n = 60 (%)

5 (8)

1 (2)

1 (2)

4 (7)

10 (16)

4 (7)

0 0 0 0 0 0 0 0 1 1 1 1 0

(0) (0) (0) (0) (0) (0) (0) (0) (2) (2) (2) (2) (0)

0 (0)

1 1 1 1 0 0 0 1 0 0 2 1 1

(2) (2) (2) (2) (0) (0) (0) (2) (0) (0) (3) (2) (2)

1 (2)

0 0 0 0 1 1 1 0 0 0 0 1 0

(0) (0) (0) (0) (2) (2) (2) (0) (0) (0) (0) (2) (0)

0 (0)

qd, once daily; b.i.d., twice daily; q3w, once every 3 weeks; AE, adverse event; NSCLC, non-small-cell lung cancer; CNS, central nervous system.

NSCLC (ESCAPE) study (sorafenib plus CP) [17] as well as final data from the NSCLC research Experience Utilizing Sorafenib (NEXUS) study (sorafenib plus gemcitabine -cisplatin) [18], the ZACTIMA Efficacy with Alimta in Lung cancer (ZEAL) study (vandetanib plus pemetrexed) [19], and the Zactima in combination with Docetaxel In non-small cell lung Cancer (ZODIAC) study (vandetanib plus docetaxel) [20] (all in advanced NSCLC) did not show improvements in OS. The incidence and severity of toxicity was generally consistent with that observed in previous studies of bevacizumab plus CP [2, 21] and of motesanib monotherapy [8, 9] and chemotherapy combination studies [11, 13]. Toxicity associated with motesanib 125 mg qd combined with CP was greater than in the bevacizumab arm but was manageable. Specifically, gastrointestinal toxic effects (including grade 3/4 events), including diarrhea, nausea, and vomiting, occurred more frequently with motesanib treatment. Although motesanib 75-mg b.i.d. given 5 days of every 7 days provided a treatment-free period for the purpose of toxicity management, the dosing schedule was associated with more grade 5 AEs than 125-mg qd continuous dosing (arm A), suggesting that 125-mg qd is the preferred dosing regimen in this patient population. Adverse events considered class effects of VEGF(R) pathway inhibitors, i.e. hypertension, bleeding, or thromboembolic events [22], occurred at incidence rates consistent with those reported in other motesanib studies [8, 9, 11, 13]. Hypertension was more common in arms A and B than in arm C, and is consistent with results from other motesanib studies [8–10, 13]. This may reflect differences in the physiological response to a more complete VEGF pathway inhibition with motesanib as opposed to single VEGF-A blockade. Gall-bladder toxicity, specifically cholecystitis, only occurred with motesanib

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treatment. It has been observed in other motesanib studies, especially with 75-mg b.i.d. dosing [8, 9, 13], and appears to be a motesanib-specific AE, although rare cases have been reported with sorafenib treatment [23]. The underlying mechanism remains uncertain. A separate study is ongoing to investigate the effect of motesanib on the gall-bladder. Similarly, hypothyroidism and/or elevated thyroid-stimulating hormone has been noted earlier with motesanib [8, 10] but has also been described for two other tyrosine kinase inhibitors [24, 25]. Motesanib plasma Cmax and Cmin were similar to those described for motesanib monotherapy [9] or combination treatments with CP [13] or gemcitabine [11]. In arm A, median motesanib Cmin was higher than the concentration that inhibits 50% of proliferation in human umbilical vein endothelial cells (HUVECs; IC50 = 4 ng/ml) [7]. In arm B, motesanib Cmin on day 1 was higher than the concentration that inhibits 90% of proliferation in HUVECs (IC90 = 28 ng/ml) [26]. Following the 2-day treatment-free period, median motesanib concentrations were below 1 ng/ml, suggesting that the washout period was sufficient to attain motesanib plasma concentrations below the IC50 value. However, 75-mg b.i.d 5-days-on/2-days-off dosing did not show better efficacy compared with 125-mg qd dosing despite higher Cmin during the 5-day continuous dosing phase. These results were consistent with population pharmacokinetic simulations based on data obtained from the motesanib first-in-human study [9]. In summary, this is the first study of a small-molecule VEGFR inhibitor and bevacizumab in a single randomized phase II study. Toxicity was greater with motesanib. Efficacy and toxicity of motesanib 75 mg b.i.d. were worse compared with those of motesanib 125 mg qd and bevacizumab treatments. However, the ORR in the motesanib 125-mg qd plus CP treatment arm was estimated to be similar to that of bevacizumab plus CP among chemotherapy-naive patients with

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advanced nonsquamous NSCLC. PFS and OS in both arms were also similar. 4.

acknowledgements The following investigators participated in the study—Hong Kong SAR: A. K. Au, C. K. Cheng, T. S. K. Mok, Y. Tung; India: D. Behera, R. Chacko, K. Lakshmaiah, H. Menon, S. Nirni, A. Pathak, R. Thirumulai; United States: F. Arena, J. T. Beck, N. Belman, G. R. Blumenschein, R. Boccia, D. Chan, B. Clowney, S. Davidson, S. Del Prete, A. Dudek, J. Fain, C. Hagenstad, D. Henry, T. Hoang, C. Holladay, E. Hu, F. Kabbinavar, P. Kaywin, W. MacLaughlin, R. March, T. Marsland, L. Meza, F. Mott, R. Page, E. Paschold, G. Patel, R. Patel, D. Prow, K. Reckamp, P. Rosen, K. Sabbath, B. Samuels, L. Schwartzberg, M. Shah, M. Shtivelband, J. Singh, J. Stephenson, D. Subramaniam, P. Swanson, M. Thomas, and R. Webb. The authors acknowledge Ali Hassan (Complete Healthcare Communications Inc.), whose work was funded by Amgen Inc., and Beate D. Quednau (Amgen Inc.) for their assistance in the preparation of the manuscript; Cindy Wake and Bernd Bruenner (Amgen Inc.) for pharmacokinetic sample analysis; and Rebeca Melara (Amgen Inc.) for pharmacokinetic data analysis. The results of this study were presented in part at the 13th World Conference on Lung Cancer, 31 July to 2 August 2009, San Francisco, CA; at the Joint European Cancer Organization 15–34th European Society of Medical Oncology Multidisciplinary Congress, 20–24 September 2009, Berlin, Germany; and at the 46th Annual Meeting of the American Society of Clinical Oncology, 4–8 June 2010, Chicago, IL. Clinical Trial Registration: http://ClinicalTrials.gov; registration number: NCT00369070.

5.

6.

7.

8. 9.

10.

11.

12.

13.

14.

funding Amgen Inc.; Millenium/Takeda. 15.

disclosure G.R.B. has served as a consultant for and has received research funding from Amgen Inc.; T.S.K.M. has served as a consultant for Roche, AstraZeneca, and Eli Lily and has received honoraria from Roche, AstraZeneca, and Pfizer; J.S. has received funding from Amgen Inc.; J.T.B. has received research funding from Amgen Inc. and Genentech; K.R. has served as a consultant for Amgen Inc.; L.S. has served as a consultant and received honoraria from Amgen Inc.; F.K., K.L., and H.M. have no conflicts to disclose. Y.-J.H., K.K., Y.-N.S., and R.S. are employees of and stockholders in Amgen Inc.

16. 17.

18.

19.

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