Published Ahead of Print on May 26, 2015 as 10.1200/JCO.2014.59.4424 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.59.4424
JOURNAL OF CLINICAL ONCOLOGY
Caicun Zhou, Shanghai Pulmonary Hospital, Tongji University School of Medicine; Shun Lu and Baohui Han, Shanghai Chest Hospital; Guoliang Jiang, Fudan University Shanghai Cancer Center; Wenjuan Zheng and Anny-Yue Yin, Roche (China) Holding Ltd, Shanghai; Yi-Long Wu, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou; Gongyan Chen, Harbin Medical University Cancer Hospital, Harbin; Xiaoqing Liu, Academy of Military Medical Sciences Affiliated Hospital (307 Hospital of People’s Liberation Army); Yunzhong Zhu, Beijing Chest Hospital; Jie Wang, Beijing Cancer Hospital; Gang Cheng, Beijing Hospital of Ministry of Health, Beijing; Jifeng Feng, Jiangsu Cancer Hospital, Nanjing; Chunhong Hu, The Second Xiangya Hospital of Central South University, Changsha; Hao Zhang, Cancer Hospital of Shantou University Medical College, Shantou; Xiangqun Song, Affiliated Cancer Hospital of Guangxi Medical University, Nanning; You Lu, West China Hospital, Sichuan University, Chengdu; and Hongming Pan, Sir Run Run Shaw Hospital Affiliated to Zhejiang University School of Medicine, Hangzhou, China. Published online ahead of print at www.jco.org on May 26, 2015. Support information appears at the end of this article. Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.
O R I G I N A L
R E P O R T
BEYOND: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study of First-Line Carboplatin/Paclitaxel Plus Bevacizumab or Placebo in Chinese Patients With Advanced or Recurrent Nonsquamous Non–Small-Cell Lung Cancer Caicun Zhou, Yi-Long Wu, Gongyan Chen, Xiaoqing Liu, Yunzhong Zhu, Shun Lu, Jifeng Feng, Jianxing He, Baohui Han, Jie Wang, Guoliang Jiang, Chunhong Hu, Hao Zhang, Gang Cheng, Xiangqun Song, You Lu, Hongming Pan, Wenjuan Zheng, and Anny-Yue Yin A
B
S
T
R
A
C
T
Purpose The phase III BEYOND trial was undertaken to confirm in a Chinese patient population the efficacy seen with first-line bevacizumab plus platinum doublet chemotherapy in globally conducted studies. Patients and Methods Patients age ⱖ 18 years with locally advanced, metastatic, or recurrent advanced nonsquamous non–small-cell lung cancer (NSCLC) were randomly assigned to receive carboplatin (area under the curve, 6) intravenously and paclitaxel (175 mg/m2) intravenously (CP) on day 1 of each 3-week cycle, for ⱕ six cycles, plus placebo (Pl⫹CP) or bevacizumab (B⫹CP) 15 mg/kg intravenously, on day 1 of each cycle, until progression, unacceptable toxicity, or death. The primary end point was progression-free survival (PFS); secondary end points were objective response rate, overall survival, exploratory biomarkers, safety. Results A total of 276 patients were randomly assigned, 138 to each arm. PFS was prolonged with B⫹CP versus Pl⫹CP (median, 9.2 v 6.5 months, respectively; hazard ratio [HR], 0.40; 95% CI, 0.29 to 0.54; P ⬍ .001). Objective response rate was improved with B⫹CP compared with Pl⫹CP (54% v 26%, respectively). Overall survival was also prolonged with B⫹CP compared with Pl⫹CP (median, 24.3 v 17.7 months, respectively; HR, 0.68; 95% CI, 0.50 to 0.93; P ⫽ .0154). Median PFS was 12.4 months with B⫹CP and 7.9 months with Pl⫹CP (HR, 0.27; 95% CI, 0.12 to 0.63) in EGFR mutation–positive tumors and 8.3 and 5.6 months, respectively (HR, 0.33; 95% CI, 0.21 to 0.53), in wild-type tumors. Safety was similar to previous studies of B⫹CP in NSCLC; no new safety signals were observed. Conclusion The addition to bevacizumab to carboplatin/paclitaxel was well tolerated and resulted in a clinically meaningful treatment benefit in Chinese patients with advanced nonsquamous NSCLC. J Clin Oncol 33. © 2015 by American Society of Clinical Oncology
Clinical trial information: NCT01364012. Corresponding author: Caicun Zhou, MD, PhD, Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433 China; e-mail: [email protected]. © 2015 by American Society of Clinical Oncology 0732-183X/15/3399-1/$20.00 DOI: 10.1200/JCO.2014.59.4424
INTRODUCTION
Platinum-based chemotherapy remains the standard of care for patients with unresectable, advanced, non– small-celllungcancer(NSCLC).1 Platinum-basedchemotherapy plus third-generation agents (including gemcitabine, paclitaxel, and pemetrexed) have produced significant incremental survival benefits.2 Existingliteraturesupportsbothcisplatinandcarboplatinas valid first-line treatment for advanced NSCLC.1,3,4 In China, first-line platinum-based doublets are widely
used, and gemcitabine and paclitaxel are two of the most common companion agents in clinical practice.5 The discovery of activating mutations of the epidermal growth factor receptor (EGFR) and the echinoderm microtubule-associated protein like 4 –anaplastic lymphoma kinase (EML4-ALK) fusion has led to changing treatment for patients with NSCLC who harbor these drivers. Agents that inhibit the tyrosine kinase binding sites of these molecules have demonstrated improved progression-free survival (PFS) versus chemotherapy.6-8 © 2015 by American Society of Clinical Oncology
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Copyright 2015 by American Society of Clinical Oncology
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The incidence of patients with NSCLC testing positive for EGFR mutations is approximately 30% in East Asia and 10% outside of Asia.9,10 The reported incidence of EML4-ALK is closer to 5%, with no known variation in incidence according to ethnicity.8,11 However, in most patients with NSCLC in whom no known targetable molecular aberrations are identified, platinum-based treatment remains standard first-line therapy and represents the most appropriate comparator for new treatments. For patients with nonsquamous NSCLC without identified oncogenic drivers, bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), in combination with platinum-based chemotherapy remains a valid first-line treatment option. Bevacizumab has proven efficacy in extending overall survival (OS) and PFS when added to platinum-based chemotherapy as first-line treatment for advanced nonsquamous NSCLC in a number of pivotal studies.12-15 These studies included mainly white patients; however, subgroup analyses of the Avastin in Lung (AVAiL) and phase IV Safety of Avastin in Lung (SAiL) studies suggested that bevacizumab was also efficacious in Asian populations.14,15 The BEYOND study (YO25404; NCT01364012) was initiated to confirm the efficacy of bevacizumab-based first-line treatment in a Chinese population by showing consistency with the PFS results seen in the predominantly white population in the global E4599 study. PATIENTS AND METHODS BEYOND was a randomized, double-blind, multicenter, placebo-controlled, phase III study of first-line bevacizumab plus carboplatin/paclitaxel versus placebo plus carboplatin/paclitaxel in Chinese patients with advanced/recurrent nonsquamous NSCLC. The study was conducted in 16 hospitals across
China in accordance with the Declaration of Helsinki and International Conference on Harmonization (ICH) Good Clinical Practice guidelines. The protocol was approved by the relevant ethics committees, and all patients provided written informed consent to participate in the study. Patients age ⱖ 18 years with histologically or cytologically confirmed, locally advanced, metastatic, or recurrent nonsquamous NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1 were eligible. Exclusion criteria included mixed non–small-cell and small-cell histology or mixed adenocarcinoma with predominant squamous histology, history of hemoptysis (ⱖ onehalf teaspoon of bright red blood in the 3 months before enrolment), tumors invading major blood vessels, CNS metastases, and uncontrolled hypertension. Current or recent (within 10 days of first bevacizumab dose) use of full-dose anticoagulants or a thrombolytic agent for therapeutic purposes was not permitted, but prophylactic use of anticoagulants was allowed. Patients were randomly assigned 1:1 by an interactive voice/Web response system to receive carboplatin (area under the curve, 6) intravenously (IV) and paclitaxel (175 mg/m2) IV (CP) on day 1 of each 3-week cycle for up to six cycles plus either placebo (Pl⫹CP) or bevacizumab (B⫹CP) 15 mg/kg IV on day 1 of each cycle until disease progression, unacceptable toxicity, withdrawal of patient consent, or death. Bevacizumab, placebo, and chemotherapy agents were provided by Roche (Shanghai, China). Random assignment was stratified by sex (male v female), smoking status (smokers [including former heavy smokers] v nonsmokers/former light smokers), and age (⬍ v ⱖ 65 years). The dose of paclitaxel was 175 mg/m2 to reflect the approved dose in China. Patients randomly assigned to the bevacizumab arm were allowed to enter an optional open-label, postprogression phase of the protocol, provided the investigator believed it was in their best interest. Postprogression treatment continued until the investigator believed that the patient no longer derived any benefit or until the patient experienced a third disease progression event. The primary end point was PFS as assessed by investigators. Secondary end points included objective response rate (ORR), duration of response, OS, analysis of VEGF-A and VEGFR-2 biomarkers, and safety. Exploratory analyses of tumor tissue for EGFR mutation status were performed. Detailed results from the biomarker analysis will be presented in a separate publication.
Screened (N = 302)
Screening failures* (n = 26)
Randomly assigned (n = 276)
Randomly assigned to B+CP (n = 138)
2
Randomly assigned to Pl+CP (n = 138)
Treated Completed first six cycles Discontinued any component in first six cycles Received single-agent B Discontinued single-agent B
(n = 137) (n = 96) (n = 41) (n = 107) (n = 101)
Treated Completed first six cycles Discontinued any component in first six cycles Received single-agent PI Discontinued single-agent PI
Reason for discontinuing B Discontinued Disease progression Deaths Adverse events Other reasons†
(n = 131) (n = 93) (n = 2 ) (n = 15) (n = 21)
Reason for discontinuing PI Discontinued Disease progression Deaths Adverse events Other reasons†
© 2015 by American Society of Clinical Oncology
(n = 137) (n = 80) (n = 57) (n = 78) (n = 77)
Fig 1. CONSORT diagram. (*) Twentysix patients did not pass screening; the most common reasons (ⱖ two patients) were CNS metastases (n ⫽ 6), withdrawal of informed consent (n ⫽ 5), inability to comply with the protocol (n ⫽ 3), inadequate hematologic or organ function (n ⫽ 3), and evidence of tumor invading major blood vessels on imaging (n ⫽ 2). (†) Other reasons for discontinuing B included noncompliance (n ⫽ 8), withdrawal (n ⫽ 7), loss to follow-up (n ⫽ 1), protocol violation (n ⫽ 1), and other (n ⫽ 1). Other reasons for discontinuing Pl included noncompliance (n ⫽ 5), withdrawal (n ⫽ 7), and physician decision (n ⫽ 1). B, bevacizumab; B⫹CP, bevacizumab, carboplatin, and paclitaxel; Pl, placebo; Pl⫹CP, placebo, carboplatin, and paclitaxel.
(n = 136) (n = 107) (n = 1) ( n = 13 ) ( n = 15 )
JOURNAL OF CLINICAL ONCOLOGY
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First-Line Bevacizumab Plus Platinum Chemotherapy in Chinese Patients
Tumor response and progression were assessed by investigators according to RECIST version 1.0. After random assignment, assessments were performed at the end of every second treatment cycle until first progression. One final tumor scan was performed 4 to 6 weeks after the first progression. Safety was evaluated through the reporting of adverse events (AEs), relevant laboratory assessments, and vital signs. Safety reporting was carried out according to relevant ICH Good Clinical Practice guidance. AEs were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Statistical Analysis The intent-to-treat (ITT) population included all randomly assigned patients. The safety analysis population comprised all randomly assigned patients who received at least one dose of any component of study medication. Patients were analyzed according to the treatment they received if this differed from their allocated treatment. The Kaplan-Meier method was used to assess median PFS and OS with 95% CIs. A stratified Cox regression analysis with the three stratification variables for random assignment was used to estimate hazard ratios (HRs) for PFS and OS with 95% CIs; a log-rank test was used to calculate the P value. PFS was calculated after censoring for nonprotocol therapy (see Appendix, online only, for further details). ORRs were compared using the Mantel-Haenszel 2 test. To demonstrate that the benefit of adding bevacizumab to CP in the Chinese population is consistent with the benefit observed in the global E4599 study with 80% probability, a total sample size of 270 patients was required. This sample size estimation was based on assumptions of a median PFS of 8.0 months for the bevacizumab arm and 5.9 months for the placebo arm. The primary analysis was to be performed when approximately 194 PFS events (disease progression or death) had occurred. Consistency was defined as maintaining 50% of the risk reduction of disease progression from E4599, resulting in a threshold for the HR of ⱕ 0.83.16 Statistical analyses were conducted by Roche in Shanghai according to internal standard operating procedures and ICH guidelines.
Table 1. Baseline Characteristics in the Intent-to-Treat Population No. of Patients (%) Characteristic Age, years Median Range Sex Male Female ECOG PS 0 1 Smoking status Nonsmoker/former smoker Smoker Histology Adenocarcinoma Large-cell carcinoma Mixed cell carcinoma Disease stage Recurrent IIIB IV Unknown EGFR mutation status assessmentⴱ EGFR mutation positive EGFR wild type
B⫹CP (n ⫽ 138)
Pl⫹CP (n ⫽ 138)
57.0 30-75
56.0 23-74
75 (54) 63 (46)
77 (56) 61 (44)
34 (25) 104 (75)
27 (20) 111 (80)
69 (50) 69 (50)
77 (56) 61 (44)
137 (99) 1 (1) 0 (0.0)
136 (98) 1 (1) 1 (1)
4 (3) 8 (6) 126 (91) 0 (0.0) 85 23 (27) 62 (73)
3 (2) 9 (7) 125 (91) 1 (1) 66 17 (26) 49 (74)
Abbreviations: B⫹CP, bevacizumab, carboplatin, and paclitaxel; ECOG PS, Eastern Cooperative Oncology Group performance status; Pl⫹CP, placebo, carboplatin, and paclitaxel. ⴱ Provision of a tissue sample for EGFR mutation testing was optional.
RESULTS
Patient Population A total of 276 patients were recruited between May 23, 2011, and May 3, 2012, and randomly assigned to study treatment, with 138 patients in each arm (Fig 1). The primary PFS analysis clinical cutoff (January 27, 2013) was triggered by the 194th PFS event; OS analysis was triggered after 171 OS events with a clinical cutoff date of April 30, 2014. At the cutoff of April 30, 2014, six patients were still receiving bevacizumab treatment and one patient was still receiving placebo. Median follow-up time was 28.1 months for B⫹CP and 26.9 months for Pl⫹CP. Baseline characteristics were balanced between arms. The median age was 57 years in the B⫹CP arm and 56 years in the Pl⫹CP arm (range, 23 to 75 years across both arms), with the majority of patients in both arms having Eastern Cooperative Oncology Group performance status 1, stage IV disease, and adenocarcinoma histology (Table 1). A total of 50% of the B⫹CP arm and 44% of the Pl⫹CP arm were current smokers. The proportion of patients (data cutoff April 30, 2014) who completed the first six cycles of all components of study treatment was 70% (n ⫽ 96) in the B⫹CP arm and 58% (n ⫽ 80) in the Pl⫹CP arm. A total of 78% of patients continued with blinded single-agent bevacizumab after discontinuing or completing CP in the B⫹CP arm compared with 57% of the Pl⫹CP arm. The median number of cycles received was 11 (range, one to 25 cycles) for B⫹CP and eight (range, one to 20 cycles) for Pl⫹CP (median, six cycles of CP in both arms). www.jco.org
Median dose-intensity was 100% (range, 74% to 100%) for bevacizumab and 100% (range, 64% to 114%) for placebo. Median doseintensity for the chemotherapy component was 98% versus 99% for carboplatin and 99% versus 99% for paclitaxel in the B⫹CP and Pl⫹CP arms, respectively. Efficacy The primary end point of PFS (data cutoff January 27, 2013) was prolonged for B⫹CP versus Pl⫹CP (HR, 0.40; 95% CI, 0.29 to 0.54; P ⬍ .001); median PFS was 9.2 months (95% CI, 8.4 to 10.7 months) versus 6.5 months (95% CI, 5.8 to 7.1 months) for B⫹CP and Pl⫹CP, respectively (Fig 2A). All subgroups analyzed derived PFS benefit in favor of bevacizumab, as seen in the overall study population (Fig 2B). The median OS (data cutoff April 30, 2014) was 24.3 months for B⫹CP and 17.7 months for Pl⫹CP (HR, 0.68; 95% CI, 0.50 to 0.93; P ⫽ .0154; Fig 3A). Subgroup analysis is shown in Figure 3B. ORR was also improved with the addition of bevacizumab to chemotherapy (data cutoff January 27, 2013), with an ORR of 54% (95% CI, 46% to 63%) in the B⫹CP arm versus 26% (95% CI, 19% to 35%) in the Pl⫹CP arm (P ⬍ .001; Table 2). Disease control rate (defined as patients with confirmed complete response, partial response, or stable disease as best overall response) was 94% (95% CI, 89% to 98%) versus 89% (95% CI, 82% to 93%) in the B⫹CP and Pl⫹CP arms, respectively. Median duration of response was 8.0 months (95% CI, 6.9 to 9.4 months) with B⫹CP versus 5.3 months (95% CI, 4.4 to 6.0 months) with Pl⫹CP. © 2015 by American Society of Clinical Oncology
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A Progression-Free Survival (proportion)
1.0
Randomly assigned treatment PI + CP B + CP
0.8
Median PFS 6.5 v 9.2 months HR, 0.40; 95% CI, 0.29 to 0.54 P < .001
0.6
0.4
0.2
6
0
12
18
24
0 0
0 0
Time of Study (month) No. at risk PI + CP B + CP
138 138
63 95
2 22
B
Lower Upper CI Estimate CI
Category
No.
All
276
0.29
0.40
0.54
Age, years < 65 ≥ 65
223 53
0.26 0.24
0.36 0.47
0.51 0.89
Gender Female Male
124 152
0.25 0.26
0.39 0.39
0.61 0.58
ECOG performance status 0 1
61 215
0.20 0.25
0.36 0.36
0.66 0.52
130 146
0.28 0.22
0.44 0.34
0.69 0.52
Disease stage Recurrent Stage IIIB Stage IV
7 17 251
0.03 0.15 0.27
0.30 0.52 0.37
2.98 1.78 0.51
Prior curative intent cancer therapy Yes No
16 260
0.09 0.29
0.35 0.39
1.30 0.53
Smoking status Smokers Nonsmokers/former light smokers
0.2
0.4 0.6 1.0
2
Fig 2. (A) Kaplan-Meier curve of progression-free survival (PFS) in the intent-totreat population. (B) Forest plot of PFS by subgroup. B⫹CP, bevacizumab, carboplatin, and paclitaxel; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; Pl⫹CP, placebo, carboplatin, and paclitaxel.
3
Hazard Ratio
Subsequent Lines of Anticancer Therapies A total of 70% of B⫹CP patients and 71% of Pl⫹CP patients received subsequent anticancer therapies. The proportion of subsequent lines of therapy was balanced overall between the two arms, other than the open-label bevacizumab treatment (36% B⫹CP arm only). The most common subsequent therapy other than the open-label bevacizumab was pemetrexed (31% of B⫹CP patients and 34% of Pl⫹CP patients). EGFR tyrosine kinase inhibitors were also common and balanced between the arms (erlotinib, gefitinib, icotinib, afatinib, or epitinib in 36% of B⫹CP patients and 38% of Pl⫹CP patients). Asensitivityanalysiswasperformedassessingthepotentialimpactof the open-label bevacizumab phase on the OS benefit conferred by the B⫹CP combination. When patients who received open-label bevacizumab were censored, the results were consistent with those from the ITT analysis, with approximately a 10-month difference in median OS in the 4
© 2015 by American Society of Clinical Oncology
sensitivity analysis (median OS, 28.5 months for B⫹CP and 17.7 months for Pl⫹CP; HR, 0.58; 95% CI, 0.41 to 0.82; P ⫽ .002). Biomarkers A total of 151 patients (85 patients in the B⫹CP arm and 66 patients in the Pl⫹CP arm) contributed tissue to the optional tumor biomarker analysis to assess EGFR mutation status using the cobas EGFR FFPET test (Roche Molecular Systems, Pleasanton, CA). The observed EGFR mutation–positive rates were 27% and 26% for B⫹CP and Pl⫹CP, respectively. PFS was prolonged for patients receiving B⫹CP regardless of EGFR mutation status. Median PFS in patients with EGFR mutation–positive disease was 12.4 months in the B⫹CP arm and 7.9 months in the Pl⫹CP arm (HR, 0.27; 95% CI, 0.12 to 0.63). Median PFS in patients with EGFR wild-type disease was 8.3 months in the B⫹CP arm and 5.6 months in the Pl⫹CP arm (HR, JOURNAL OF CLINICAL ONCOLOGY
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First-Line Bevacizumab Plus Platinum Chemotherapy in Chinese Patients
A Overall Survival (proportion)
1.0
Randomly assigned treatment PI + CP B + CP
0.8
Median OS 17.7 v 24.3 months HR, 0.68; 95% CI, 0.50 to 0.93 P = .0154
0.6
0.4
0.2
6
0
12
18
24
30
36
9 18
0 0
Time of Study (month) No. at risk PI + CP B + CP
138 138
122 128
89 102
64 83
50 64
B
Lower Upper CI Estimate CI
Category
No.
All
276
0.50
0.68
0.93
Age, years < 65 ≥ 65
223 53
0.42 0.50
0.60 0.96
0.84 1.85
Gender Female Male
124 152
0.38 0.47
0.62 0.68
1.02 1.00
ECOG performance status 0 1
61 215
0.71 0.37
1.43 0.52
2.91 0.74
130 146
0.50 0.36
0.76 0.56
1.16 0.87
Disease stage Recurrent Stage IIIB Stage IV
7 17 251
NA 0.29 0.48
NA 0.92 0.66
NA 2.91 0.91
Prior curative intent cancer therapy Yes No
16 260
0.10 0.49
0.34 0.66
1.15 0.91
Smoking status Smokers Nonsmokers/former light smokers
0.2
0.4 0.6 1.0
2
Fig 3. (A) Kaplan-Meier curve of overall survival (OS) in the intent-to-treat population (data cutoff April 30, 2014). (B) Forest plot of OS by subgroup (data cutoff April 30, 2014). B⫹CP, bevacizumab, carboplatin, and paclitaxel; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; Pl⫹CP, placebo, carboplatin, and paclitaxel.
3
Hazard Ratio
0.33; 95% CI, 0.21 to 0.53). Median OS for the subgroup with EGFR mutation–positive disease was 24.3 months for B⫹CP and 27.5 months for Pl⫹CP (HR, 0.90; 95% CI, 0.40 to 2.02), and in the wild-type subgroup, median OS was 20.3 months for B⫹CP and 13.8 months for Pl⫹CP (HR, 0.57; 95% CI, 0.36 to 0.89). Safety Two patients did not receive trial treatment (one Pl⫹CP patient because the patient’s condition deteriorated and one B⫹CP patient because of treatment refusal). Three patients randomly assigned to the Pl⫹CP arm received bevacizumab in error and are, therefore, included in the B⫹CP arm. The safety analysis population comprised 134 patients in the Pl⫹CP arm and 140 patients in the B⫹CP arm. The safety profile at the April 30, 2014, data cutoff was similar to that at the PFS data cutoff and was consistent with the established www.jco.org
safety profile of the study treatments (Table 3). The most common AEs (incidence ⱖ 30%, any grade) were hematologic, GI-related disorders, and alopecia (Appendix Table A1, online only). The incidence of grade ⱖ 3 AEs was comparable in both arms (67% of the B⫹CP arm and 62% of the Pl⫹CP arm). Grade ⱖ 3 AEs with a difference in incidence of ⱖ 2% between arms are listed in Table 4. Grade 5 treatment-related AEs were low in both arms (B⫹CP, n ⫽ 3 [2%], multiorgan failure, cerebral hemorrhage with thrombocytopenia, and possible pulmonary infarction, embolism, or cardiac insufficiency; and Pl⫹CP, n ⫽ 1 [1%], multiorgan failure). The incidence of grade ⱖ 3 AEs of special interest was generally low (Table 3), but they occurred with a higher frequency in the B⫹CP arm (11%) compared with the Pl⫹CP arm (2%). This increase was largely a result of hypertension (n ⫽ 7 [5%] in B⫹CP arm v n ⫽ 1 [1%] in Pl⫹CP arm) and proteinuria (n ⫽ 6 [4%] in B⫹CP arm v © 2015 by American Society of Clinical Oncology
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Table 4. Overview of AEs and Grade ⱖ 3 AEs With a Difference in Incidence of ⱖ 2% Between Treatment Arms (data cutoff of April 30, 2014)
Table 2. ORR and Response in the ITT Population No. of Patients (%) Response
B⫹CP (n ⫽ 138)
Pl⫹CP (n ⫽ 138)
ORR Complete response Partial response Stable disease Progressive disease Missing
74 (54) 0 (0) 74 (54) 55 (40) 2 (2) 5 (4)
35 (26) 0 (0) 35 (26) 83 (62) 10 (8) 5 (4)
Abbreviations: B⫹CP, bevacizumab, carboplatin, and paclitaxel; ITT, intent to treat; ORR, objective response rate; Pl⫹CP, placebo, carboplatin, and paclitaxel.
n ⫽ 0 [0%] in Pl⫹CP arm). Grade ⱖ 3 pulmonary bleeding–type events were not observed. DISCUSSION
The BEYOND study met its primary end point because the HR of 0.40 for PFS was less than the predefined consistency threshold of 0.83. OS was also prolonged with B⫹CP versus Pl⫹CP. The study was well balanced in terms of patient characteristics; the trial population included a higher proportion of female patients and never-smokers compared with the Western population, which is typical for an East Asian, advanced NSCLC population. The compliance with trial study medication was high in all treatment arms, as shown by high treatment exposures. These data show that the addition of bevacizumab to CP provided a clinically meaningful benefit in Chinese patients, consistent with that seen in globally conducted trials.12,13,17 The positive OS benefit seen in the E4599 trial and PFS benefits shown in E4599 and AVAiL, alongside the acceptable safety profile demonstrated by the E4599 and AVAiL studies, have formed the basis of regulatory approval of bevacizumab for the treatment of advanced NSCLC in many countries.12,13 The PFS in BEYOND (median, 9.2 months; HR, 0.40) was comparable to that seen in previous Asian subpopulation analyses, including the AVAiL East Asian subgroup (median PFS, 8.2 months; HR,
Table 3. Overview of AEs of Special Interest in the Safety Population (data cutoff of April 30, 2014) No. of Patients (%) AE
B⫹CP (n ⫽ 140)
Pl⫹CP (n ⫽ 134)
AEs of special interest Grade ⱖ 3 AEs of special interest Hypertension Proteinuria GI perforations Bleedingⴱ Cerebral hemorrhage Hematuria Upper GI hemorrhage Congestive heart failure Thromboembolic events
68 (49) 16 (11) 7 (5) 6 (4) 1 (1) 2 (1) 1 (⬍ 1) 0 (0) 2 (⬍ 1) 1 (1) 0 (0)
31 (23) 3 (2) 1 (1) 0 (0) 0 (0) 1 (1) 0 (0) 1 (⬎ 1) 0 (0) 0 (0) 1 (1)
Abbreviations: AE, adverse event; B⫹CP, bevacizumab, carboplatin, and paclitaxel; Pl⫹CP, placebo, carboplatin, and paclitaxel. ⴱ No grade ⱖ 3 pulmonary bleeding events (pulmonary hemorrhage or hemoptysis) were described by the investigators.
6
© 2015 by American Society of Clinical Oncology
No. of Patients (%) AE Overview of AEs Grade ⱖ 3 Serious AEs AEs leading to death AEs leading to study withdrawal Grade ⱖ 3 AEs with a difference in incidence of ⱖ 2% between treatment arms Neutropenia Anemia Thrombocytopenia Bone marrow failure Febrile neutropenia WBC count decreased Hypertension Diarrhea Proteinuria Back pain
B⫹CP (n ⫽ 140)
Pl⫹CP (n ⫽ 134)
94 (67) 19 (14) 3 (2) 27 (19)
83 (62) 16 (12) 1 (1) 20 (15)
32 (23) 10 (7) 10 (7) 15 (11) 4 (3) 15 (11) 7 (5) 1 (1) 6 (4) 0 (0)
37 (28) 15 (11) 12 (9) 4 (3) 7 (5) 7 (5) 1 (1) 4 (3) 0 (0) 3 (2)
Abbreviations: AE, adverse event; B⫹CP, bevacizumab, carboplatin, and paclitaxel; Pl⫹CP, placebo, carboplatin, and paclitaxel.
0.60; 95% CI, 0.32 to 1.13).14 In East Asian patients in the SAiL trial (n ⫽ 314), median time to progression was 8.3 months,15 with further subgroup analysis of Chinese patients (n ⫽ 198) demonstrating a median time to progression of 8.8 months.18 In addition, a first-line study of CP with or without bevacizumab in Japanese patients with NSCLC showed a median PFS of 6.9 months with the bevacizumabbased combination versus 5.9 months for chemotherapy alone (HR, 0.61; 95% CI, 0.42 to 0.89; P ⫽ .0090).19 Secondary end points in BEYOND, including ORR and disease control rate, also showed improvement with the addition of bevacizumab, which further corroborates the benefit of bevacizumab-based treatment compared with chemotherapy alone in the Chinese population. Median OS reported in the BEYOND study for the bevacizumab arm (24.3 months) was longer than previously reported OS results for bevacizumab-based regimens in Chinese populations. In the noncomparative, single-arm SAiL trial, the Chinese subgroup reported a median OS of 18.5 months.18 The enrollment of B⫹CP patients onto the postprogression bevacizumab phase may have impacted the OS findings; however, sensitivity analyses censoring those on the postprogression phase reported a median OS of 28.5 months for B⫹CP treatment, which was in line with the overall ITT results. Exposure was higher in the B⫹CP arm for all three study drugs; the median duration of placebo or bevacizumab treatment was longer (5.1 months for Pl⫹CP v 7.4 months for B⫹CP) and more patients received six cycles of carboplatin (58% in Pl⫹CP arm v 72% in B⫹CP arm) and paclitaxel (59% in Pl⫹CP arm v 71% in B⫹CP arm) in the B⫹CP arm compared with the Pl⫹CP arm. The enrollment of only Chinese patients in this study may be viewed as a potential limitation; however, the objective was to confirm the efficacy of this regimen previously demonstrated in global populations in the Chinese population; therefore, this specific enrollment was warranted. Although PFS was not assessed by an independent JOURNAL OF CLINICAL ONCOLOGY
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First-Line Bevacizumab Plus Platinum Chemotherapy in Chinese Patients
review board, the study design was a double-blind randomized controlled trial, and there was a high degree of investigator compliance with protocol-defined tumor assessment schedules. There was no (switch) maintenance included in the control arm, which is now a treatment option for some patients after first-line chemotherapy for NSCLC. However, BEYOND was designed to demonstrate consistency of treatment effect with E4599, which had a similar study design. The introduction of switch maintenance to the control arm of the BEYOND study would not have permitted the comparison that composed BEYOND’s primary end point. The incidence of patients with confirmed EGFR mutation– positive disease was lower than anticipated, at approximately 25%. Because the collection of tumor tissue specimens for biomarker analysis was not mandatory, this may have contributed to the lower than anticipated observed incidence. In the EGFR mutation–positive group, high EGFR tyrosine kinase inhibitor use in both arms was seen after progression, but overall postprogression treatments were balanced. EGFR mutation–positive tumor status seemed to be prognostic for a better outcome regardless of treatment. Favorable survival outcomes for Asian populations with advanced NSCLC compared with a mainly white population receiving chemotherapy have been observed in a meta-analysis.20 However, this meta-analysis was based on summary data rather than individual patient data, and multivariable analysis for confounding factors such as histologic subtypes, sex, weight loss, and smoking status was not conducted. The incidence of AEs in BEYOND was generally comparable to that seen in Asian subpopulations in previous bevacizumab studies, and no new safety signals were observed.14,15 These data have confirmed that REFERENCES 1. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98, 2002 2. Bareschino MA, Schettino C, Rossi A, et al: Treatment of advanced non small cell lung cancer. J Thorac Dis 3:122-133, 2011 3. Hotta K, Matsuo K, Ueoka H, et al: Addition of platinum-doublet compounds to a new agent in patients with advanced non-small-cell lung cancer: A literature-based meta-analysis of randomized trials. Ann Oncol 15:1782-1789, 2004 4. Klastersky J, Awada A: Milestones in the use of chemotherapy for the management of non-small cell lung cancer (NSCLC). Crit Rev Oncol Hematol 81:49-57, 2012 5. Xue C, Hu Z, Jiang W, et al: National survey of medical treatment status for non-small cell lung cancer (NSCLC) in China. Lung Cancer 77:371375, 2012 6. Rosell R, Carcereny E, Gervais R, et al: Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13:239-246, 2012
bevacizumab has clinically meaningful efficacy and an acceptable safety profile in Asian populations, as well as in global populations.12,13 The addition of bevacizumab to CP chemotherapy resulted in a clinically meaningful prolongation of PFS and OS in Chinese patients with nonsquamous NSCLC, consistent with the previously reported E4599 and AVAiL results. No new safety concerns were reported. The efficacy and safety profile in the bevacizumab clinical trial program support the use of first-line bevacizumab plus platinum-based chemotherapy in ethnically diverse nonsquamous NSCLC patient populations compared with platinum-based chemotherapy alone. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at www.jco.org.
AUTHOR CONTRIBUTIONS Conception and design: Caicun Zhou, Yi-Long Wu, Shun Lu, Hongming Pan, Wenjuan Zheng, Anny-Yue Yin Financial support: Caicun Zhou Administrative support: Caicun Zhou, Hongming Pan Provision of study materials or patients: Caicun Zhou, Baohui Han, Hongming Pan Collection and assembly of data: All authors Data analysis and interpretation: Caicun Zhou, Yi-Long Wu, Shun Lu, Hongming Pan, Wenjuan Zheng, Anny-Yue Yin Manuscript writing: All authors Final approval of manuscript: All authors
7. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-957, 2009 8. Casaluce F, Sgambato A, Maione P, et al: ALK inhibitors: A new targeted therapy in the treatment of advanced NSCLC. Target Oncol 8:55-67, 2013 9. Thomas RK, Weir B, Meyerson M: Genomic approach to lung cancer. Clin Cancer Res 12:4384s4391s, 2006 10. Paz-Ares L, Soulières D, Melezínek I, et al: Clinical outcomes in the non-small cell lung cancer patients with EGFR mutations: Pooled analysis. J Cell Mol Med 14:51-69, 2010 11. Shaw AT, Yeap BY, Mino-Kenudson M, et al: Clinical features and outcome of patients with nonsmall-cell lung cancer who harbor EML4-ALK. J Clin Oncol 27:4247-4253, 2009 12. Sandler A, Gray R, Perry MC, et al: Paclitaxelcarboplatin alone or with bevacizumab for non-smallcell lung cancer. N Engl J Med 355:2542-2550, 2006 13. Reck M, von Pawel J, Zatloukal P, et al: Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAiL. J Clin Oncol 27:1227-1234, 2009 14. Mok T, Hsia T, Tsai CM, et al: Efficacy of bevacizumab with cisplatin and gemcitabine in Asian patients with advanced or recurrent non-squamous non-small-cell lung cancer who have not received
prior chemotherapy: A substudy of the Avastin in Lung trial. Asia Pac J Clin Oncol 7:4-12, 2011 15. Tsai CM, Au JS, Chang GC, et al: Safety and efficacy of first-line bevacizumab with chemotherapy in Asian patients with advanced nonsquamous NSCLC: Results from the phase IV MO19390 (SAiL) study. J Thorac Oncol 6:1092-1097, 2011 16. Pharmaceuticals and Medical Devices Agency: Basic principles on Global Clinical Trials 2007. http:// www.pmda.go.jp/kijunsakusei/file/guideline/new_drug/ GlobalClinicalTrials_en.pdf 17. Crinò L, Dansin E, Garrido P, et al: Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): A phase 4 study. Lancet Oncol 11:733-740, 2010 18. Zhou C, Bai C, Guan Z, et al: Safety and efficacy of first-line bevacizumab combination therapy in Chinese population with advanced non-squamous NSCLC: Data of subgroup analyses from MO19390 (SAiL) study. Clin Transl Oncol 16:463-468, 2014 19. Niho S, Kunitoh H, Nokihara H, et al: Randomized phase II study of first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-small-cell lung cancer. Lung Cancer 76:362-367, 2012 20. Soo RA, Loh M, Mok TS, et al: Ethnic differences in survival outcomes in patients with advanced stage non-small cell lung cancer. J Thorac Oncol 6:1030-1038, 2011
Support Supported by F. Hoffmann-La Roche. Third-party medical writing was funded by F. Hoffmann-La Roche. ■ ■ ■
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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
BEYOND: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study of First-Line Carboplatin/Paclitaxel Plus Bevacizumab or Placebo in Chinese Patients With Advanced or Recurrent 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 jco.ascopubs.org/site/ifc. Caicun Zhou Honoraria: F. Hoffmann-La Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca Yi-Long Wu Honoraria: F. Hoffmann-La Roche, Eli Lilly, AstraZeneca, Pfizer Gongyan Chen No relationship to disclose Xiaoqing Liu No relationship to disclose Yunzhong Zhu No relationship to disclose Shun Lu No relationship to disclose
Guoliang Jiang No relationship to disclose Chunhong Hu No relationship to disclose Hao Zhang No relationship to disclose Gang Cheng No relationship to disclose Xiangqun Song No relationship to disclose You Lu No relationship to disclose
Jifeng Feng Honoraria: F. Hoffmann-La Roche
Hongming Pan No relationship to disclose
Jianxing He No relationship to disclose
Wenjuan Zheng Employment: Roche (China) Holding
Baohui Han No relationship to disclose
Anny-Yue Yin Employment: Roche (China) Holding
Jie Wang Honoraria: F. Hoffmann-La Roche, Eli Lilly, AstraZeneca, Pfizer, Sanofi
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First-Line Bevacizumab Plus Platinum Chemotherapy in Chinese Patients
Acknowledgment Presented in part at the 15th World Congress on Lung Cancer, Sydney, Australia, October 27-31, 2013. Appendix Cox Regression Analysis
Consistent with the primary stratified analysis of progression-free survival (PFS), the results of the nonstratified analysis on the intent-to-treat (ITT) population showed a reduction in the risk of progression or death of 62% in the bevacizumab, carboplatin, and paclitaxel arm compared with the placebo, carboplatin, and paclitaxel arm (hazard ratio [HR], 0.38; 95% CI, 0.28 to 0.52; P ⬍ .001). Results of the nonstratified overall survival analysis for the ITT population (HR, 0.68; 95% CI, 0.48 to 0.88; P ⫽ .0049) were also consistent with those of the primary stratified analysis for the ITT population. In the primary analysis of PFS, patients who received nonprotocol therapy before disease progression were censored at the last tumor assessment before they initiated nonprotocol therapy. A total of 10 patients (7%) in the placebo, carboplatin, and paclitaxel arm and 12 patients (9%) in the bevacizumab, carboplatin, and paclitaxel arm had nonprotocol therapy before disease progression and were therefore subject to this censoring rule. The results of the stratified PFS analysis without censoring for nonprotocol therapy were consistent with those of the primary PFS analysis (HR, 0.40; 95% CI, 0.30 to 0.54; P ⬍ .001). No adjustment for other baseline characteristics was included in the Cox regression models.
Table A1. AEs (any grade) With an Incidence of ⬎10% in Either Treatment Arm No. (%) AE
B⫹CP (n ⫽ 141)
Pl⫹CP (n ⫽ 133)
Leukopenia Neutropenia Anemia Thrombocytopenia Bone marrow failure Platelet count decreased WBC count decreased Neutrophil count decreased ALT increased AST increased Nausea Vomiting Constipation Diarrhea Alopecia Rash Myalgia Arthralgia Pain in extremity Fatigue Pyrexia Hypoesthesia Paraesthesia Decreased appetite Epistaxis Cough Proteinuria Hypertension
56 (40) 49 (35) 48 (34) 27 (19) 26 (18) 42 (30) 36 (26) 31 (22) 21 (15) 19 (13) 25 (18) 24 (17) 15 (11) 17 (12) 50 (35) 18 (13) 33 (23) 21 (15) 18 (13) 34 (24) 15 (11) 37 (26) 16 (11) 39 (28) 28 (20) 20 (14) 20 (14) 20 (14)
49 (37) 47 (35) 47 (35) 25 (19) 14 (11) 38 (29) 30 (23) 32 (24) 31 (23) 19 (14) 44 (33) 35 (26) 17 (13) 11 (8) 56 (42) 10 (8) 23 (17) 16 (12) 15 (11) 37 (28) 19 (14) 32 (24) 15 (11) 40 (30) 6 (5) 11 (8) 9 (7) 6 (5)
Abbreviation: AE, adverse event.
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Caicun Zhou, Shanghai Pulmonary Hospital, Tongji University School of Medicine; Shun Lu and Baohui Han, Shanghai Chest Hospital; Guoliang Jiang, Fudan University Shanghai Cancer Center; Wenjuan Zheng and Anny-Yue Yin, Roche (China) Holding Ltd, Shanghai; Yi-Long Wu, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Jianxing He, The First Affiliated Hospital of Guangzhou Medical University, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou; Gongyan Chen, Harbin Medical University Cancer Hospital, Harbin; Xiaoqing Liu, Academy of Military Medical Sciences Affiliated Hospital (307 Hospital of People’s Liberation Army); Yunzhong Zhu, Beijing Chest Hospital; Jie Wang, Beijing Cancer Hospital; Gang Cheng, Beijing Hospital of Ministry of Health, Beijing; Jifeng Feng, Jiangsu Cancer Hospital, Nanjing; Chunhong Hu, The Second Xiangya Hospital of Central South University, Changsha; Hao Zhang, Cancer Hospital of Shantou University Medical College, Shantou; Xiangqun Song, Affiliated Cancer Hospital of Guangxi Medical University, Nanning; You Lu, West China Hospital, Sichuan University, Chengdu; and Hongming Pan, Sir Run Run Shaw Hospital Affiliated to Zhejiang University School of Medicine, Hangzhou, China. Published online ahead of print at www.jco.org on May 26, 2015. Support information appears at the end of this article. Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.
O R I G I N A L
R E P O R T
BEYOND: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study of First-Line Carboplatin/Paclitaxel Plus Bevacizumab or Placebo in Chinese Patients With Advanced or Recurrent Nonsquamous Non–Small-Cell Lung Cancer Caicun Zhou, Yi-Long Wu, Gongyan Chen, Xiaoqing Liu, Yunzhong Zhu, Shun Lu, Jifeng Feng, Jianxing He, Baohui Han, Jie Wang, Guoliang Jiang, Chunhong Hu, Hao Zhang, Gang Cheng, Xiangqun Song, You Lu, Hongming Pan, Wenjuan Zheng, and Anny-Yue Yin A
B
S
T
R
A
C
T
Purpose The phase III BEYOND trial was undertaken to confirm in a Chinese patient population the efficacy seen with first-line bevacizumab plus platinum doublet chemotherapy in globally conducted studies. Patients and Methods Patients age ⱖ 18 years with locally advanced, metastatic, or recurrent advanced nonsquamous non–small-cell lung cancer (NSCLC) were randomly assigned to receive carboplatin (area under the curve, 6) intravenously and paclitaxel (175 mg/m2) intravenously (CP) on day 1 of each 3-week cycle, for ⱕ six cycles, plus placebo (Pl⫹CP) or bevacizumab (B⫹CP) 15 mg/kg intravenously, on day 1 of each cycle, until progression, unacceptable toxicity, or death. The primary end point was progression-free survival (PFS); secondary end points were objective response rate, overall survival, exploratory biomarkers, safety. Results A total of 276 patients were randomly assigned, 138 to each arm. PFS was prolonged with B⫹CP versus Pl⫹CP (median, 9.2 v 6.5 months, respectively; hazard ratio [HR], 0.40; 95% CI, 0.29 to 0.54; P ⬍ .001). Objective response rate was improved with B⫹CP compared with Pl⫹CP (54% v 26%, respectively). Overall survival was also prolonged with B⫹CP compared with Pl⫹CP (median, 24.3 v 17.7 months, respectively; HR, 0.68; 95% CI, 0.50 to 0.93; P ⫽ .0154). Median PFS was 12.4 months with B⫹CP and 7.9 months with Pl⫹CP (HR, 0.27; 95% CI, 0.12 to 0.63) in EGFR mutation–positive tumors and 8.3 and 5.6 months, respectively (HR, 0.33; 95% CI, 0.21 to 0.53), in wild-type tumors. Safety was similar to previous studies of B⫹CP in NSCLC; no new safety signals were observed. Conclusion The addition to bevacizumab to carboplatin/paclitaxel was well tolerated and resulted in a clinically meaningful treatment benefit in Chinese patients with advanced nonsquamous NSCLC. J Clin Oncol 33. © 2015 by American Society of Clinical Oncology
Clinical trial information: NCT01364012. Corresponding author: Caicun Zhou, MD, PhD, Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433 China; e-mail: [email protected]. © 2015 by American Society of Clinical Oncology 0732-183X/15/3399-1/$20.00 DOI: 10.1200/JCO.2014.59.4424
INTRODUCTION
Platinum-based chemotherapy remains the standard of care for patients with unresectable, advanced, non– small-celllungcancer(NSCLC).1 Platinum-basedchemotherapy plus third-generation agents (including gemcitabine, paclitaxel, and pemetrexed) have produced significant incremental survival benefits.2 Existingliteraturesupportsbothcisplatinandcarboplatinas valid first-line treatment for advanced NSCLC.1,3,4 In China, first-line platinum-based doublets are widely
used, and gemcitabine and paclitaxel are two of the most common companion agents in clinical practice.5 The discovery of activating mutations of the epidermal growth factor receptor (EGFR) and the echinoderm microtubule-associated protein like 4 –anaplastic lymphoma kinase (EML4-ALK) fusion has led to changing treatment for patients with NSCLC who harbor these drivers. Agents that inhibit the tyrosine kinase binding sites of these molecules have demonstrated improved progression-free survival (PFS) versus chemotherapy.6-8 © 2015 by American Society of Clinical Oncology
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Zhou et al
The incidence of patients with NSCLC testing positive for EGFR mutations is approximately 30% in East Asia and 10% outside of Asia.9,10 The reported incidence of EML4-ALK is closer to 5%, with no known variation in incidence according to ethnicity.8,11 However, in most patients with NSCLC in whom no known targetable molecular aberrations are identified, platinum-based treatment remains standard first-line therapy and represents the most appropriate comparator for new treatments. For patients with nonsquamous NSCLC without identified oncogenic drivers, bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), in combination with platinum-based chemotherapy remains a valid first-line treatment option. Bevacizumab has proven efficacy in extending overall survival (OS) and PFS when added to platinum-based chemotherapy as first-line treatment for advanced nonsquamous NSCLC in a number of pivotal studies.12-15 These studies included mainly white patients; however, subgroup analyses of the Avastin in Lung (AVAiL) and phase IV Safety of Avastin in Lung (SAiL) studies suggested that bevacizumab was also efficacious in Asian populations.14,15 The BEYOND study (YO25404; NCT01364012) was initiated to confirm the efficacy of bevacizumab-based first-line treatment in a Chinese population by showing consistency with the PFS results seen in the predominantly white population in the global E4599 study. PATIENTS AND METHODS BEYOND was a randomized, double-blind, multicenter, placebo-controlled, phase III study of first-line bevacizumab plus carboplatin/paclitaxel versus placebo plus carboplatin/paclitaxel in Chinese patients with advanced/recurrent nonsquamous NSCLC. The study was conducted in 16 hospitals across
China in accordance with the Declaration of Helsinki and International Conference on Harmonization (ICH) Good Clinical Practice guidelines. The protocol was approved by the relevant ethics committees, and all patients provided written informed consent to participate in the study. Patients age ⱖ 18 years with histologically or cytologically confirmed, locally advanced, metastatic, or recurrent nonsquamous NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1 were eligible. Exclusion criteria included mixed non–small-cell and small-cell histology or mixed adenocarcinoma with predominant squamous histology, history of hemoptysis (ⱖ onehalf teaspoon of bright red blood in the 3 months before enrolment), tumors invading major blood vessels, CNS metastases, and uncontrolled hypertension. Current or recent (within 10 days of first bevacizumab dose) use of full-dose anticoagulants or a thrombolytic agent for therapeutic purposes was not permitted, but prophylactic use of anticoagulants was allowed. Patients were randomly assigned 1:1 by an interactive voice/Web response system to receive carboplatin (area under the curve, 6) intravenously (IV) and paclitaxel (175 mg/m2) IV (CP) on day 1 of each 3-week cycle for up to six cycles plus either placebo (Pl⫹CP) or bevacizumab (B⫹CP) 15 mg/kg IV on day 1 of each cycle until disease progression, unacceptable toxicity, withdrawal of patient consent, or death. Bevacizumab, placebo, and chemotherapy agents were provided by Roche (Shanghai, China). Random assignment was stratified by sex (male v female), smoking status (smokers [including former heavy smokers] v nonsmokers/former light smokers), and age (⬍ v ⱖ 65 years). The dose of paclitaxel was 175 mg/m2 to reflect the approved dose in China. Patients randomly assigned to the bevacizumab arm were allowed to enter an optional open-label, postprogression phase of the protocol, provided the investigator believed it was in their best interest. Postprogression treatment continued until the investigator believed that the patient no longer derived any benefit or until the patient experienced a third disease progression event. The primary end point was PFS as assessed by investigators. Secondary end points included objective response rate (ORR), duration of response, OS, analysis of VEGF-A and VEGFR-2 biomarkers, and safety. Exploratory analyses of tumor tissue for EGFR mutation status were performed. Detailed results from the biomarker analysis will be presented in a separate publication.
Screened (N = 302)
Screening failures* (n = 26)
Randomly assigned (n = 276)
Randomly assigned to B+CP (n = 138)
2
Randomly assigned to Pl+CP (n = 138)
Treated Completed first six cycles Discontinued any component in first six cycles Received single-agent B Discontinued single-agent B
(n = 137) (n = 96) (n = 41) (n = 107) (n = 101)
Treated Completed first six cycles Discontinued any component in first six cycles Received single-agent PI Discontinued single-agent PI
Reason for discontinuing B Discontinued Disease progression Deaths Adverse events Other reasons†
(n = 131) (n = 93) (n = 2 ) (n = 15) (n = 21)
Reason for discontinuing PI Discontinued Disease progression Deaths Adverse events Other reasons†
© 2015 by American Society of Clinical Oncology
(n = 137) (n = 80) (n = 57) (n = 78) (n = 77)
Fig 1. CONSORT diagram. (*) Twentysix patients did not pass screening; the most common reasons (ⱖ two patients) were CNS metastases (n ⫽ 6), withdrawal of informed consent (n ⫽ 5), inability to comply with the protocol (n ⫽ 3), inadequate hematologic or organ function (n ⫽ 3), and evidence of tumor invading major blood vessels on imaging (n ⫽ 2). (†) Other reasons for discontinuing B included noncompliance (n ⫽ 8), withdrawal (n ⫽ 7), loss to follow-up (n ⫽ 1), protocol violation (n ⫽ 1), and other (n ⫽ 1). Other reasons for discontinuing Pl included noncompliance (n ⫽ 5), withdrawal (n ⫽ 7), and physician decision (n ⫽ 1). B, bevacizumab; B⫹CP, bevacizumab, carboplatin, and paclitaxel; Pl, placebo; Pl⫹CP, placebo, carboplatin, and paclitaxel.
(n = 136) (n = 107) (n = 1) ( n = 13 ) ( n = 15 )
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First-Line Bevacizumab Plus Platinum Chemotherapy in Chinese Patients
Tumor response and progression were assessed by investigators according to RECIST version 1.0. After random assignment, assessments were performed at the end of every second treatment cycle until first progression. One final tumor scan was performed 4 to 6 weeks after the first progression. Safety was evaluated through the reporting of adverse events (AEs), relevant laboratory assessments, and vital signs. Safety reporting was carried out according to relevant ICH Good Clinical Practice guidance. AEs were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Statistical Analysis The intent-to-treat (ITT) population included all randomly assigned patients. The safety analysis population comprised all randomly assigned patients who received at least one dose of any component of study medication. Patients were analyzed according to the treatment they received if this differed from their allocated treatment. The Kaplan-Meier method was used to assess median PFS and OS with 95% CIs. A stratified Cox regression analysis with the three stratification variables for random assignment was used to estimate hazard ratios (HRs) for PFS and OS with 95% CIs; a log-rank test was used to calculate the P value. PFS was calculated after censoring for nonprotocol therapy (see Appendix, online only, for further details). ORRs were compared using the Mantel-Haenszel 2 test. To demonstrate that the benefit of adding bevacizumab to CP in the Chinese population is consistent with the benefit observed in the global E4599 study with 80% probability, a total sample size of 270 patients was required. This sample size estimation was based on assumptions of a median PFS of 8.0 months for the bevacizumab arm and 5.9 months for the placebo arm. The primary analysis was to be performed when approximately 194 PFS events (disease progression or death) had occurred. Consistency was defined as maintaining 50% of the risk reduction of disease progression from E4599, resulting in a threshold for the HR of ⱕ 0.83.16 Statistical analyses were conducted by Roche in Shanghai according to internal standard operating procedures and ICH guidelines.
Table 1. Baseline Characteristics in the Intent-to-Treat Population No. of Patients (%) Characteristic Age, years Median Range Sex Male Female ECOG PS 0 1 Smoking status Nonsmoker/former smoker Smoker Histology Adenocarcinoma Large-cell carcinoma Mixed cell carcinoma Disease stage Recurrent IIIB IV Unknown EGFR mutation status assessmentⴱ EGFR mutation positive EGFR wild type
B⫹CP (n ⫽ 138)
Pl⫹CP (n ⫽ 138)
57.0 30-75
56.0 23-74
75 (54) 63 (46)
77 (56) 61 (44)
34 (25) 104 (75)
27 (20) 111 (80)
69 (50) 69 (50)
77 (56) 61 (44)
137 (99) 1 (1) 0 (0.0)
136 (98) 1 (1) 1 (1)
4 (3) 8 (6) 126 (91) 0 (0.0) 85 23 (27) 62 (73)
3 (2) 9 (7) 125 (91) 1 (1) 66 17 (26) 49 (74)
Abbreviations: B⫹CP, bevacizumab, carboplatin, and paclitaxel; ECOG PS, Eastern Cooperative Oncology Group performance status; Pl⫹CP, placebo, carboplatin, and paclitaxel. ⴱ Provision of a tissue sample for EGFR mutation testing was optional.
RESULTS
Patient Population A total of 276 patients were recruited between May 23, 2011, and May 3, 2012, and randomly assigned to study treatment, with 138 patients in each arm (Fig 1). The primary PFS analysis clinical cutoff (January 27, 2013) was triggered by the 194th PFS event; OS analysis was triggered after 171 OS events with a clinical cutoff date of April 30, 2014. At the cutoff of April 30, 2014, six patients were still receiving bevacizumab treatment and one patient was still receiving placebo. Median follow-up time was 28.1 months for B⫹CP and 26.9 months for Pl⫹CP. Baseline characteristics were balanced between arms. The median age was 57 years in the B⫹CP arm and 56 years in the Pl⫹CP arm (range, 23 to 75 years across both arms), with the majority of patients in both arms having Eastern Cooperative Oncology Group performance status 1, stage IV disease, and adenocarcinoma histology (Table 1). A total of 50% of the B⫹CP arm and 44% of the Pl⫹CP arm were current smokers. The proportion of patients (data cutoff April 30, 2014) who completed the first six cycles of all components of study treatment was 70% (n ⫽ 96) in the B⫹CP arm and 58% (n ⫽ 80) in the Pl⫹CP arm. A total of 78% of patients continued with blinded single-agent bevacizumab after discontinuing or completing CP in the B⫹CP arm compared with 57% of the Pl⫹CP arm. The median number of cycles received was 11 (range, one to 25 cycles) for B⫹CP and eight (range, one to 20 cycles) for Pl⫹CP (median, six cycles of CP in both arms). www.jco.org
Median dose-intensity was 100% (range, 74% to 100%) for bevacizumab and 100% (range, 64% to 114%) for placebo. Median doseintensity for the chemotherapy component was 98% versus 99% for carboplatin and 99% versus 99% for paclitaxel in the B⫹CP and Pl⫹CP arms, respectively. Efficacy The primary end point of PFS (data cutoff January 27, 2013) was prolonged for B⫹CP versus Pl⫹CP (HR, 0.40; 95% CI, 0.29 to 0.54; P ⬍ .001); median PFS was 9.2 months (95% CI, 8.4 to 10.7 months) versus 6.5 months (95% CI, 5.8 to 7.1 months) for B⫹CP and Pl⫹CP, respectively (Fig 2A). All subgroups analyzed derived PFS benefit in favor of bevacizumab, as seen in the overall study population (Fig 2B). The median OS (data cutoff April 30, 2014) was 24.3 months for B⫹CP and 17.7 months for Pl⫹CP (HR, 0.68; 95% CI, 0.50 to 0.93; P ⫽ .0154; Fig 3A). Subgroup analysis is shown in Figure 3B. ORR was also improved with the addition of bevacizumab to chemotherapy (data cutoff January 27, 2013), with an ORR of 54% (95% CI, 46% to 63%) in the B⫹CP arm versus 26% (95% CI, 19% to 35%) in the Pl⫹CP arm (P ⬍ .001; Table 2). Disease control rate (defined as patients with confirmed complete response, partial response, or stable disease as best overall response) was 94% (95% CI, 89% to 98%) versus 89% (95% CI, 82% to 93%) in the B⫹CP and Pl⫹CP arms, respectively. Median duration of response was 8.0 months (95% CI, 6.9 to 9.4 months) with B⫹CP versus 5.3 months (95% CI, 4.4 to 6.0 months) with Pl⫹CP. © 2015 by American Society of Clinical Oncology
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Zhou et al
A Progression-Free Survival (proportion)
1.0
Randomly assigned treatment PI + CP B + CP
0.8
Median PFS 6.5 v 9.2 months HR, 0.40; 95% CI, 0.29 to 0.54 P < .001
0.6
0.4
0.2
6
0
12
18
24
0 0
0 0
Time of Study (month) No. at risk PI + CP B + CP
138 138
63 95
2 22
B
Lower Upper CI Estimate CI
Category
No.
All
276
0.29
0.40
0.54
Age, years < 65 ≥ 65
223 53
0.26 0.24
0.36 0.47
0.51 0.89
Gender Female Male
124 152
0.25 0.26
0.39 0.39
0.61 0.58
ECOG performance status 0 1
61 215
0.20 0.25
0.36 0.36
0.66 0.52
130 146
0.28 0.22
0.44 0.34
0.69 0.52
Disease stage Recurrent Stage IIIB Stage IV
7 17 251
0.03 0.15 0.27
0.30 0.52 0.37
2.98 1.78 0.51
Prior curative intent cancer therapy Yes No
16 260
0.09 0.29
0.35 0.39
1.30 0.53
Smoking status Smokers Nonsmokers/former light smokers
0.2
0.4 0.6 1.0
2
Fig 2. (A) Kaplan-Meier curve of progression-free survival (PFS) in the intent-totreat population. (B) Forest plot of PFS by subgroup. B⫹CP, bevacizumab, carboplatin, and paclitaxel; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; Pl⫹CP, placebo, carboplatin, and paclitaxel.
3
Hazard Ratio
Subsequent Lines of Anticancer Therapies A total of 70% of B⫹CP patients and 71% of Pl⫹CP patients received subsequent anticancer therapies. The proportion of subsequent lines of therapy was balanced overall between the two arms, other than the open-label bevacizumab treatment (36% B⫹CP arm only). The most common subsequent therapy other than the open-label bevacizumab was pemetrexed (31% of B⫹CP patients and 34% of Pl⫹CP patients). EGFR tyrosine kinase inhibitors were also common and balanced between the arms (erlotinib, gefitinib, icotinib, afatinib, or epitinib in 36% of B⫹CP patients and 38% of Pl⫹CP patients). Asensitivityanalysiswasperformedassessingthepotentialimpactof the open-label bevacizumab phase on the OS benefit conferred by the B⫹CP combination. When patients who received open-label bevacizumab were censored, the results were consistent with those from the ITT analysis, with approximately a 10-month difference in median OS in the 4
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sensitivity analysis (median OS, 28.5 months for B⫹CP and 17.7 months for Pl⫹CP; HR, 0.58; 95% CI, 0.41 to 0.82; P ⫽ .002). Biomarkers A total of 151 patients (85 patients in the B⫹CP arm and 66 patients in the Pl⫹CP arm) contributed tissue to the optional tumor biomarker analysis to assess EGFR mutation status using the cobas EGFR FFPET test (Roche Molecular Systems, Pleasanton, CA). The observed EGFR mutation–positive rates were 27% and 26% for B⫹CP and Pl⫹CP, respectively. PFS was prolonged for patients receiving B⫹CP regardless of EGFR mutation status. Median PFS in patients with EGFR mutation–positive disease was 12.4 months in the B⫹CP arm and 7.9 months in the Pl⫹CP arm (HR, 0.27; 95% CI, 0.12 to 0.63). Median PFS in patients with EGFR wild-type disease was 8.3 months in the B⫹CP arm and 5.6 months in the Pl⫹CP arm (HR, JOURNAL OF CLINICAL ONCOLOGY
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First-Line Bevacizumab Plus Platinum Chemotherapy in Chinese Patients
A Overall Survival (proportion)
1.0
Randomly assigned treatment PI + CP B + CP
0.8
Median OS 17.7 v 24.3 months HR, 0.68; 95% CI, 0.50 to 0.93 P = .0154
0.6
0.4
0.2
6
0
12
18
24
30
36
9 18
0 0
Time of Study (month) No. at risk PI + CP B + CP
138 138
122 128
89 102
64 83
50 64
B
Lower Upper CI Estimate CI
Category
No.
All
276
0.50
0.68
0.93
Age, years < 65 ≥ 65
223 53
0.42 0.50
0.60 0.96
0.84 1.85
Gender Female Male
124 152
0.38 0.47
0.62 0.68
1.02 1.00
ECOG performance status 0 1
61 215
0.71 0.37
1.43 0.52
2.91 0.74
130 146
0.50 0.36
0.76 0.56
1.16 0.87
Disease stage Recurrent Stage IIIB Stage IV
7 17 251
NA 0.29 0.48
NA 0.92 0.66
NA 2.91 0.91
Prior curative intent cancer therapy Yes No
16 260
0.10 0.49
0.34 0.66
1.15 0.91
Smoking status Smokers Nonsmokers/former light smokers
0.2
0.4 0.6 1.0
2
Fig 3. (A) Kaplan-Meier curve of overall survival (OS) in the intent-to-treat population (data cutoff April 30, 2014). (B) Forest plot of OS by subgroup (data cutoff April 30, 2014). B⫹CP, bevacizumab, carboplatin, and paclitaxel; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; Pl⫹CP, placebo, carboplatin, and paclitaxel.
3
Hazard Ratio
0.33; 95% CI, 0.21 to 0.53). Median OS for the subgroup with EGFR mutation–positive disease was 24.3 months for B⫹CP and 27.5 months for Pl⫹CP (HR, 0.90; 95% CI, 0.40 to 2.02), and in the wild-type subgroup, median OS was 20.3 months for B⫹CP and 13.8 months for Pl⫹CP (HR, 0.57; 95% CI, 0.36 to 0.89). Safety Two patients did not receive trial treatment (one Pl⫹CP patient because the patient’s condition deteriorated and one B⫹CP patient because of treatment refusal). Three patients randomly assigned to the Pl⫹CP arm received bevacizumab in error and are, therefore, included in the B⫹CP arm. The safety analysis population comprised 134 patients in the Pl⫹CP arm and 140 patients in the B⫹CP arm. The safety profile at the April 30, 2014, data cutoff was similar to that at the PFS data cutoff and was consistent with the established www.jco.org
safety profile of the study treatments (Table 3). The most common AEs (incidence ⱖ 30%, any grade) were hematologic, GI-related disorders, and alopecia (Appendix Table A1, online only). The incidence of grade ⱖ 3 AEs was comparable in both arms (67% of the B⫹CP arm and 62% of the Pl⫹CP arm). Grade ⱖ 3 AEs with a difference in incidence of ⱖ 2% between arms are listed in Table 4. Grade 5 treatment-related AEs were low in both arms (B⫹CP, n ⫽ 3 [2%], multiorgan failure, cerebral hemorrhage with thrombocytopenia, and possible pulmonary infarction, embolism, or cardiac insufficiency; and Pl⫹CP, n ⫽ 1 [1%], multiorgan failure). The incidence of grade ⱖ 3 AEs of special interest was generally low (Table 3), but they occurred with a higher frequency in the B⫹CP arm (11%) compared with the Pl⫹CP arm (2%). This increase was largely a result of hypertension (n ⫽ 7 [5%] in B⫹CP arm v n ⫽ 1 [1%] in Pl⫹CP arm) and proteinuria (n ⫽ 6 [4%] in B⫹CP arm v © 2015 by American Society of Clinical Oncology
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Table 4. Overview of AEs and Grade ⱖ 3 AEs With a Difference in Incidence of ⱖ 2% Between Treatment Arms (data cutoff of April 30, 2014)
Table 2. ORR and Response in the ITT Population No. of Patients (%) Response
B⫹CP (n ⫽ 138)
Pl⫹CP (n ⫽ 138)
ORR Complete response Partial response Stable disease Progressive disease Missing
74 (54) 0 (0) 74 (54) 55 (40) 2 (2) 5 (4)
35 (26) 0 (0) 35 (26) 83 (62) 10 (8) 5 (4)
Abbreviations: B⫹CP, bevacizumab, carboplatin, and paclitaxel; ITT, intent to treat; ORR, objective response rate; Pl⫹CP, placebo, carboplatin, and paclitaxel.
n ⫽ 0 [0%] in Pl⫹CP arm). Grade ⱖ 3 pulmonary bleeding–type events were not observed. DISCUSSION
The BEYOND study met its primary end point because the HR of 0.40 for PFS was less than the predefined consistency threshold of 0.83. OS was also prolonged with B⫹CP versus Pl⫹CP. The study was well balanced in terms of patient characteristics; the trial population included a higher proportion of female patients and never-smokers compared with the Western population, which is typical for an East Asian, advanced NSCLC population. The compliance with trial study medication was high in all treatment arms, as shown by high treatment exposures. These data show that the addition of bevacizumab to CP provided a clinically meaningful benefit in Chinese patients, consistent with that seen in globally conducted trials.12,13,17 The positive OS benefit seen in the E4599 trial and PFS benefits shown in E4599 and AVAiL, alongside the acceptable safety profile demonstrated by the E4599 and AVAiL studies, have formed the basis of regulatory approval of bevacizumab for the treatment of advanced NSCLC in many countries.12,13 The PFS in BEYOND (median, 9.2 months; HR, 0.40) was comparable to that seen in previous Asian subpopulation analyses, including the AVAiL East Asian subgroup (median PFS, 8.2 months; HR,
Table 3. Overview of AEs of Special Interest in the Safety Population (data cutoff of April 30, 2014) No. of Patients (%) AE
B⫹CP (n ⫽ 140)
Pl⫹CP (n ⫽ 134)
AEs of special interest Grade ⱖ 3 AEs of special interest Hypertension Proteinuria GI perforations Bleedingⴱ Cerebral hemorrhage Hematuria Upper GI hemorrhage Congestive heart failure Thromboembolic events
68 (49) 16 (11) 7 (5) 6 (4) 1 (1) 2 (1) 1 (⬍ 1) 0 (0) 2 (⬍ 1) 1 (1) 0 (0)
31 (23) 3 (2) 1 (1) 0 (0) 0 (0) 1 (1) 0 (0) 1 (⬎ 1) 0 (0) 0 (0) 1 (1)
Abbreviations: AE, adverse event; B⫹CP, bevacizumab, carboplatin, and paclitaxel; Pl⫹CP, placebo, carboplatin, and paclitaxel. ⴱ No grade ⱖ 3 pulmonary bleeding events (pulmonary hemorrhage or hemoptysis) were described by the investigators.
6
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No. of Patients (%) AE Overview of AEs Grade ⱖ 3 Serious AEs AEs leading to death AEs leading to study withdrawal Grade ⱖ 3 AEs with a difference in incidence of ⱖ 2% between treatment arms Neutropenia Anemia Thrombocytopenia Bone marrow failure Febrile neutropenia WBC count decreased Hypertension Diarrhea Proteinuria Back pain
B⫹CP (n ⫽ 140)
Pl⫹CP (n ⫽ 134)
94 (67) 19 (14) 3 (2) 27 (19)
83 (62) 16 (12) 1 (1) 20 (15)
32 (23) 10 (7) 10 (7) 15 (11) 4 (3) 15 (11) 7 (5) 1 (1) 6 (4) 0 (0)
37 (28) 15 (11) 12 (9) 4 (3) 7 (5) 7 (5) 1 (1) 4 (3) 0 (0) 3 (2)
Abbreviations: AE, adverse event; B⫹CP, bevacizumab, carboplatin, and paclitaxel; Pl⫹CP, placebo, carboplatin, and paclitaxel.
0.60; 95% CI, 0.32 to 1.13).14 In East Asian patients in the SAiL trial (n ⫽ 314), median time to progression was 8.3 months,15 with further subgroup analysis of Chinese patients (n ⫽ 198) demonstrating a median time to progression of 8.8 months.18 In addition, a first-line study of CP with or without bevacizumab in Japanese patients with NSCLC showed a median PFS of 6.9 months with the bevacizumabbased combination versus 5.9 months for chemotherapy alone (HR, 0.61; 95% CI, 0.42 to 0.89; P ⫽ .0090).19 Secondary end points in BEYOND, including ORR and disease control rate, also showed improvement with the addition of bevacizumab, which further corroborates the benefit of bevacizumab-based treatment compared with chemotherapy alone in the Chinese population. Median OS reported in the BEYOND study for the bevacizumab arm (24.3 months) was longer than previously reported OS results for bevacizumab-based regimens in Chinese populations. In the noncomparative, single-arm SAiL trial, the Chinese subgroup reported a median OS of 18.5 months.18 The enrollment of B⫹CP patients onto the postprogression bevacizumab phase may have impacted the OS findings; however, sensitivity analyses censoring those on the postprogression phase reported a median OS of 28.5 months for B⫹CP treatment, which was in line with the overall ITT results. Exposure was higher in the B⫹CP arm for all three study drugs; the median duration of placebo or bevacizumab treatment was longer (5.1 months for Pl⫹CP v 7.4 months for B⫹CP) and more patients received six cycles of carboplatin (58% in Pl⫹CP arm v 72% in B⫹CP arm) and paclitaxel (59% in Pl⫹CP arm v 71% in B⫹CP arm) in the B⫹CP arm compared with the Pl⫹CP arm. The enrollment of only Chinese patients in this study may be viewed as a potential limitation; however, the objective was to confirm the efficacy of this regimen previously demonstrated in global populations in the Chinese population; therefore, this specific enrollment was warranted. Although PFS was not assessed by an independent JOURNAL OF CLINICAL ONCOLOGY
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First-Line Bevacizumab Plus Platinum Chemotherapy in Chinese Patients
review board, the study design was a double-blind randomized controlled trial, and there was a high degree of investigator compliance with protocol-defined tumor assessment schedules. There was no (switch) maintenance included in the control arm, which is now a treatment option for some patients after first-line chemotherapy for NSCLC. However, BEYOND was designed to demonstrate consistency of treatment effect with E4599, which had a similar study design. The introduction of switch maintenance to the control arm of the BEYOND study would not have permitted the comparison that composed BEYOND’s primary end point. The incidence of patients with confirmed EGFR mutation– positive disease was lower than anticipated, at approximately 25%. Because the collection of tumor tissue specimens for biomarker analysis was not mandatory, this may have contributed to the lower than anticipated observed incidence. In the EGFR mutation–positive group, high EGFR tyrosine kinase inhibitor use in both arms was seen after progression, but overall postprogression treatments were balanced. EGFR mutation–positive tumor status seemed to be prognostic for a better outcome regardless of treatment. Favorable survival outcomes for Asian populations with advanced NSCLC compared with a mainly white population receiving chemotherapy have been observed in a meta-analysis.20 However, this meta-analysis was based on summary data rather than individual patient data, and multivariable analysis for confounding factors such as histologic subtypes, sex, weight loss, and smoking status was not conducted. The incidence of AEs in BEYOND was generally comparable to that seen in Asian subpopulations in previous bevacizumab studies, and no new safety signals were observed.14,15 These data have confirmed that REFERENCES 1. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98, 2002 2. Bareschino MA, Schettino C, Rossi A, et al: Treatment of advanced non small cell lung cancer. J Thorac Dis 3:122-133, 2011 3. Hotta K, Matsuo K, Ueoka H, et al: Addition of platinum-doublet compounds to a new agent in patients with advanced non-small-cell lung cancer: A literature-based meta-analysis of randomized trials. Ann Oncol 15:1782-1789, 2004 4. Klastersky J, Awada A: Milestones in the use of chemotherapy for the management of non-small cell lung cancer (NSCLC). Crit Rev Oncol Hematol 81:49-57, 2012 5. Xue C, Hu Z, Jiang W, et al: National survey of medical treatment status for non-small cell lung cancer (NSCLC) in China. Lung Cancer 77:371375, 2012 6. Rosell R, Carcereny E, Gervais R, et al: Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13:239-246, 2012
bevacizumab has clinically meaningful efficacy and an acceptable safety profile in Asian populations, as well as in global populations.12,13 The addition of bevacizumab to CP chemotherapy resulted in a clinically meaningful prolongation of PFS and OS in Chinese patients with nonsquamous NSCLC, consistent with the previously reported E4599 and AVAiL results. No new safety concerns were reported. The efficacy and safety profile in the bevacizumab clinical trial program support the use of first-line bevacizumab plus platinum-based chemotherapy in ethnically diverse nonsquamous NSCLC patient populations compared with platinum-based chemotherapy alone. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at www.jco.org.
AUTHOR CONTRIBUTIONS Conception and design: Caicun Zhou, Yi-Long Wu, Shun Lu, Hongming Pan, Wenjuan Zheng, Anny-Yue Yin Financial support: Caicun Zhou Administrative support: Caicun Zhou, Hongming Pan Provision of study materials or patients: Caicun Zhou, Baohui Han, Hongming Pan Collection and assembly of data: All authors Data analysis and interpretation: Caicun Zhou, Yi-Long Wu, Shun Lu, Hongming Pan, Wenjuan Zheng, Anny-Yue Yin Manuscript writing: All authors Final approval of manuscript: All authors
7. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-957, 2009 8. Casaluce F, Sgambato A, Maione P, et al: ALK inhibitors: A new targeted therapy in the treatment of advanced NSCLC. Target Oncol 8:55-67, 2013 9. Thomas RK, Weir B, Meyerson M: Genomic approach to lung cancer. Clin Cancer Res 12:4384s4391s, 2006 10. Paz-Ares L, Soulières D, Melezínek I, et al: Clinical outcomes in the non-small cell lung cancer patients with EGFR mutations: Pooled analysis. J Cell Mol Med 14:51-69, 2010 11. Shaw AT, Yeap BY, Mino-Kenudson M, et al: Clinical features and outcome of patients with nonsmall-cell lung cancer who harbor EML4-ALK. J Clin Oncol 27:4247-4253, 2009 12. Sandler A, Gray R, Perry MC, et al: Paclitaxelcarboplatin alone or with bevacizumab for non-smallcell lung cancer. N Engl J Med 355:2542-2550, 2006 13. Reck M, von Pawel J, Zatloukal P, et al: Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAiL. J Clin Oncol 27:1227-1234, 2009 14. Mok T, Hsia T, Tsai CM, et al: Efficacy of bevacizumab with cisplatin and gemcitabine in Asian patients with advanced or recurrent non-squamous non-small-cell lung cancer who have not received
prior chemotherapy: A substudy of the Avastin in Lung trial. Asia Pac J Clin Oncol 7:4-12, 2011 15. Tsai CM, Au JS, Chang GC, et al: Safety and efficacy of first-line bevacizumab with chemotherapy in Asian patients with advanced nonsquamous NSCLC: Results from the phase IV MO19390 (SAiL) study. J Thorac Oncol 6:1092-1097, 2011 16. Pharmaceuticals and Medical Devices Agency: Basic principles on Global Clinical Trials 2007. http:// www.pmda.go.jp/kijunsakusei/file/guideline/new_drug/ GlobalClinicalTrials_en.pdf 17. Crinò L, Dansin E, Garrido P, et al: Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): A phase 4 study. Lancet Oncol 11:733-740, 2010 18. Zhou C, Bai C, Guan Z, et al: Safety and efficacy of first-line bevacizumab combination therapy in Chinese population with advanced non-squamous NSCLC: Data of subgroup analyses from MO19390 (SAiL) study. Clin Transl Oncol 16:463-468, 2014 19. Niho S, Kunitoh H, Nokihara H, et al: Randomized phase II study of first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-small-cell lung cancer. Lung Cancer 76:362-367, 2012 20. Soo RA, Loh M, Mok TS, et al: Ethnic differences in survival outcomes in patients with advanced stage non-small cell lung cancer. J Thorac Oncol 6:1030-1038, 2011
Support Supported by F. Hoffmann-La Roche. Third-party medical writing was funded by F. Hoffmann-La Roche. ■ ■ ■
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AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
BEYOND: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study of First-Line Carboplatin/Paclitaxel Plus Bevacizumab or Placebo in Chinese Patients With Advanced or Recurrent 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 jco.ascopubs.org/site/ifc. Caicun Zhou Honoraria: F. Hoffmann-La Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca Yi-Long Wu Honoraria: F. Hoffmann-La Roche, Eli Lilly, AstraZeneca, Pfizer Gongyan Chen No relationship to disclose Xiaoqing Liu No relationship to disclose Yunzhong Zhu No relationship to disclose Shun Lu No relationship to disclose
Guoliang Jiang No relationship to disclose Chunhong Hu No relationship to disclose Hao Zhang No relationship to disclose Gang Cheng No relationship to disclose Xiangqun Song No relationship to disclose You Lu No relationship to disclose
Jifeng Feng Honoraria: F. Hoffmann-La Roche
Hongming Pan No relationship to disclose
Jianxing He No relationship to disclose
Wenjuan Zheng Employment: Roche (China) Holding
Baohui Han No relationship to disclose
Anny-Yue Yin Employment: Roche (China) Holding
Jie Wang Honoraria: F. Hoffmann-La Roche, Eli Lilly, AstraZeneca, Pfizer, Sanofi
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First-Line Bevacizumab Plus Platinum Chemotherapy in Chinese Patients
Acknowledgment Presented in part at the 15th World Congress on Lung Cancer, Sydney, Australia, October 27-31, 2013. Appendix Cox Regression Analysis
Consistent with the primary stratified analysis of progression-free survival (PFS), the results of the nonstratified analysis on the intent-to-treat (ITT) population showed a reduction in the risk of progression or death of 62% in the bevacizumab, carboplatin, and paclitaxel arm compared with the placebo, carboplatin, and paclitaxel arm (hazard ratio [HR], 0.38; 95% CI, 0.28 to 0.52; P ⬍ .001). Results of the nonstratified overall survival analysis for the ITT population (HR, 0.68; 95% CI, 0.48 to 0.88; P ⫽ .0049) were also consistent with those of the primary stratified analysis for the ITT population. In the primary analysis of PFS, patients who received nonprotocol therapy before disease progression were censored at the last tumor assessment before they initiated nonprotocol therapy. A total of 10 patients (7%) in the placebo, carboplatin, and paclitaxel arm and 12 patients (9%) in the bevacizumab, carboplatin, and paclitaxel arm had nonprotocol therapy before disease progression and were therefore subject to this censoring rule. The results of the stratified PFS analysis without censoring for nonprotocol therapy were consistent with those of the primary PFS analysis (HR, 0.40; 95% CI, 0.30 to 0.54; P ⬍ .001). No adjustment for other baseline characteristics was included in the Cox regression models.
Table A1. AEs (any grade) With an Incidence of ⬎10% in Either Treatment Arm No. (%) AE
B⫹CP (n ⫽ 141)
Pl⫹CP (n ⫽ 133)
Leukopenia Neutropenia Anemia Thrombocytopenia Bone marrow failure Platelet count decreased WBC count decreased Neutrophil count decreased ALT increased AST increased Nausea Vomiting Constipation Diarrhea Alopecia Rash Myalgia Arthralgia Pain in extremity Fatigue Pyrexia Hypoesthesia Paraesthesia Decreased appetite Epistaxis Cough Proteinuria Hypertension
56 (40) 49 (35) 48 (34) 27 (19) 26 (18) 42 (30) 36 (26) 31 (22) 21 (15) 19 (13) 25 (18) 24 (17) 15 (11) 17 (12) 50 (35) 18 (13) 33 (23) 21 (15) 18 (13) 34 (24) 15 (11) 37 (26) 16 (11) 39 (28) 28 (20) 20 (14) 20 (14) 20 (14)
49 (37) 47 (35) 47 (35) 25 (19) 14 (11) 38 (29) 30 (23) 32 (24) 31 (23) 19 (14) 44 (33) 35 (26) 17 (13) 11 (8) 56 (42) 10 (8) 23 (17) 16 (12) 15 (11) 37 (28) 19 (14) 32 (24) 15 (11) 40 (30) 6 (5) 11 (8) 9 (7) 6 (5)
Abbreviation: AE, adverse event.
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