original articles
Annals of Oncology Annals of Oncology 25: 132–138, 2014 doi:10.1093/annonc/mdt489
Randomised phase II study of axitinib or bevacizumab combined with paclitaxel/carboplatin as first-line therapy for patients with advanced non-small-cell lung cancer C. Twelves1*, E. Chmielowska2, L. Havel3, S. Popat4, A. Swieboda-Sadlej5, P. Sawrycki6, P. Bycott7, A. Ingrosso8, S. Kim7, †, J. A. Williams7, C. Chen9, A. J. Olszanski10, P. de Besi8 & J. H. Schiller11
Received 25 March 2013; revised 26 September 2013; accepted 2 October 2013
Background: Efficacy and safety of first-line axitinib/paclitaxel/carboplatin versus bevacizumab/paclitaxel/carboplatin in advanced non-squamous non-small-cell lung cancer (NSCLC) was evaluated.
Patients and methods: Patients with stage IIIB/IV disease stratified by adjuvant therapy and gender were randomised 1 : 1 to axitinib (5 mg twice daily) or bevacizumab [15 mg/kg every 3 weeks (Q3W)], both with paclitaxel (200 mg/m2 Q3W)/carboplatin (AUC 6 mg min/ml Q3W). Results: The trial was discontinued after preliminary analysis. Median progression-free survival ( primary end point) for axitinib (N = 58) and bevacizumab (N = 60), respectively, was 5.7 and 6.1 months [hazard ratio (HR) 1.09, 95% confidence interval (CI) 0.68–1.76; one-sided stratified P = 0.64]; median overall survival was 10.6 and 13.3 months (HR 1.12, 95% CI 0.74–1.69; one-sided stratified P = 0.70). Objective response rates (95% CI) were 29.3% (18.1–42.7) and 43.3% (30.6–56.8), respectively; risk ratio 0.676 (95% CI 0.41–1.11; one-sided stratified P = 0.94). The most common grade 3/4 adverse events included neutropenia (28% versus 20%), fatigue (14% versus 7%), and hypertension (14% versus 5%). Patient-reported outcomes based on the EORTC QLQ-C30 were similar between arms. Conclusions: In patients with advanced non-squamous NSCLC, axitinib/paclitaxel/carboplatin did not improve efficacy versus bevacizumab/paclitaxel/carboplatin, and was less well tolerated. Key words: axitinib; bevacizumab; chemotherapy; non-squamous, non-small-cell lung cancer
introduction The majority of patients with non-small-cell lung cancer (NSCLC) present with inoperable disease for which no curative therapy exists. Platinum-based doublet chemotherapy is the standard of care; however, the 1-year survival rate is ∼33% [1]. Singleagent bevacizumab showed little clinical benefit in advanced solid tumours [2], but the E4599 study [3] demonstrated its addition to first-line paclitaxel/carboplatin chemotherapy in NSCLC
*Correspondence to: Prof. Chris Twelves, Clinical Cancer Research Groups, Leeds Institute of Molecular Medicine and St James’s Institute of Oncology, Level 4, Bexley Wing, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK; Tel: +44-11320-68186; Fax: +44-113-206-8474; E-mail: [email protected] †
Employed at Pfizer Inc. at the time of the study described here and development of this manuscript.
significantly improved median overall survival (OS) by 2 months. In the AVAiL study [4], addition of bevacizumab to first-line gemcitabine/cisplatin significantly improved median progression-free survival (PFS), but no significant OS improvement was observed [5]. Bevacizumab plus chemotherapy is an approved first-line treatment of NSCLC [6]. Tyrosine kinase inhibitors (TKIs) were initially considered to hold promise of increased efficacy compared with bevacizumab. Single-agent studies in patients with previously treated advanced NSCLC demonstrated some efficacy and acceptable tolerability of sorafenib [7], sunitinib [8, 9], and axitinib [10]. Preclinical studies supported combination with chemotherapy [11]. Axitinib, a potent, selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors (VEGFRs), is approved in many countries as second-line treatment of advanced renal cell carcinoma. A single-agent phase I study
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at University of Guelph on December 9, 2014
1 Cancer Research UK Clinical Centre, St James’s University Hospital, Leeds, UK; 2Department of Clinical Oncology, Bydgoszcz Cancer Center, Nicolaus Copernicus University, Torun, Poland; 3Department of Pneumology and Thoracic Surgery, University Hospital Bulovka, Praha, Czech Republic; 4Medical Oncology, Royal Marsden Hospital, London, UK; 5Department of Internal Medicine Hematology and Oncology, Independent Public Central Clinical Hospital, Warsaw; 6Department of Oncology and Chemotherapy, L. Rydygiera District Hospital, Torun, Poland; 7Pfizer Oncology, Pfizer Inc., San Diego, USA; 8Pfizer Oncology, Pfizer Italia Srl, Milan, Italy; 9Pfizer Oncology, Pfizer Inc., New York; 10Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia; 11Division of Hematology-Oncology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, USA
original articles
Annals of Oncology
demonstrated promising activity and acceptable safety at the starting dose of 5 mg twice daily (b.i.d.) in patients with advanced solid tumours [12]. A phase II study demonstrated encouraging single-agent activity in advanced NSCLC [10]. Based on a phase I study of chemotherapy combinations, the recommended axitinib starting dose in combination with paclitaxel/ carboplatin was 5 mg b.i.d. [13]. This study compared efficacy and safety of axitinib/paclitaxel/ carboplatin versus bevacizumab/paclitaxel/carboplatin as firstline treatment of advanced NSCLC.
methods study design
treatments Patients received axitinib (5 mg b.i.d. starting dose, orally with food) or bevacizumab [15 mg/kg every 3 weeks (Q3W) on day 1 of each cycle] plus paclitaxel (200 mg/m2) and carboplatin Q3W (area under curve 6 mg min/ml; calculated by Calvert formula [14] on day 1 of each cycle). Patients tolerating axitinib with no grade >2 treatment-related adverse events (AEs) per Common Terminology Criteria for AEs version 3 for consecutive 2-week periods, had a one-dose-level increase (to 7 mg b.i.d.; maximum 10 mg b.i.d.) unless BP was >150/90 mmHg or patient was on antihypertensive medication. Standard antiemetic/antihypersensitivity medication was administered before chemotherapy. Chemotherapy was continued for a maximum of six cycles, after which patients could receive maintenance therapy with single-agent axitinib or bevacizumab until disease progression, unmanageable AEs, or withdrawal of consent.
study objectives The primary objective was to compare PFS. Secondary objectives included OS, objective response rate (ORR), duration of response (DR), safety and
Volume 25 | No. 1 | January 2014
assessments Radiologic tumour assessments were carried out at screening, 6-weekly on-study, and on-suspected disease progression. Baseline assessments were carried out as close to and ≤28 days before randomisation. Responses were evaluated per RECIST, and partial or complete response confirmed ≥4 weeks after the initial scan. Tumour cavitation was assessed using chest X-ray at baseline and at the start of each treatment cycle unless computed tomography scan was completed ≤7 days before day 1 of that cycle. Axitinib/bevacizumab was immediately discontinued for tumour cavitation or haemoptysis (≥2.5 ml blood in 24 h). Safety was assessed through AE monitoring, physical examinations, laboratory tests, and daily self-monitored BP. Plasma samples for measurement of soluble protein concentrations were collected before dosing and analysed at ALTA Analytical Laboratory (San Diego, CA).
statistical analysis Assuming a 50% improvement in median PFS (bevacizumab 6.5 months; axitinib 9.75 months), 70 events were required for a log-rank test (stratified) with an overall one-sided significance level of 0.20 to have power of 0.80. With planned accrual of ∼11 month and ∼7 month follow-up, 108 patients
Table 1. Patient demographic and baseline characteristics
Gender, male, n (%) Mean age, years (SD) Race, n (%) White Black Asian Other ECOG PS score,a n (%) 0 1 Not reported Smoking status, n (%) Never smoked Ex-smoker Current smoker Histological classification, n (%) Adenocarcinoma Large cell Not otherwise specified Other Stage of disease, n (%) IIIB IV Mean time since metastatic diagnosis, years (SD)
Axitinib (N = 58)
Bevacizumab (N = 60)
36 (62.1) 61.7 (8.6)
37 (61.7) 59.9 (8.4)
54 (93.1) 1 (1.7) 1 (1.7) 2 (3.4)
56 (93.3) 3 (5.0) 0 1 (1.7)
16 (27.6) 42 (72.4) 0
16 (26.7) 43 (71.7) 1 (1.7)
6 (10.3) 34 (58.6) 18 (31.0)
8 (13.3) 34 (56.7) 18 (30.0)
47 (81.0) 3 (5.2) 6 (10.3) 2 (3.4)
48 (80.0) 3 (5.0) 4 (6.7) 5 (8.3)
6 (10.3) 52 (89.7) 0.1 (0.2)
5 (8.3) 55 (91.7) 0.1 (0.1)
a
ECOG PS was not reported for one patient in the bevacizumab arm. SD, standard deviation; ECOG PS, Eastern Cooperative Oncology Group performance status.
doi:10.1093/annonc/mdt489 |
Downloaded from http://annonc.oxfordjournals.org/ at University of Guelph on December 9, 2014
In this phase II, multicentre, randomised, open-label study, patients aged ≥18 years with histologically or cytologically confirmed non-squamous-cell advanced NSCLC [stage IIIB with malignant pleural effusion, stage IV (American Joint Committee on Cancer, version 6) or recurrent disease] were randomised 1 : 1 to axitinib or bevacizumab, each in combination with paclitaxel/carboplatin. Patients were stratified by prior adjuvant therapy and gender. Eligibility included one or more sites of measurable disease [ per Response Evaluation Criteria in Solid Tumours (RECIST) version 1], Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1, and no prior systemic therapy (except adjuvant therapy >12 months before enrolment). Prior surgery or radiation was allowed if completed ≥21 or ≥28 days, respectively, before starting study treatment. Patients were excluded if they had predominantly squamous-cell NSCLC, prior treatment with a VEGF/VEGFR inhibitor, uncontrolled hypertension [two baseline blood pressure (BP) readings >140/90 mmHg taken ≥1 h apart], central nervous system metastasis, use of thrombolytic or anticoagulation agents, haematologic diathesis within 6 months of study entry, haemoptysis within 4 weeks of enrolment, myocardial infarction, severe/unstable angina, coronary/ peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischaemic attack, deep vein thrombosis or pulmonary embolism within 12 months before study treatment, gastrointestinal abnormalities, active invasive malignancies other than NSCLC, or current/ anticipated use of potent cytochrome P450 3A4 inhibitors/inducers. The study (ClinicalTrials.gov, NCT00600821) complied with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice Guidelines. All patients provided written consent.
tolerability of axitinib/paclitaxel/carboplatin, and patient-reported outcomes (supplementary material, available at Annals of Oncology online). Assessment of plasma soluble protein concentrations was exploratory.
original articles
Annals of Oncology
(21.1%) had the dose reduced 0 are included. a Assuming proportional hazards, a HR >1 indicates a reduction in hazard rate in favour of
Annals of Oncology Annals of Oncology 25: 132–138, 2014 doi:10.1093/annonc/mdt489
Randomised phase II study of axitinib or bevacizumab combined with paclitaxel/carboplatin as first-line therapy for patients with advanced non-small-cell lung cancer C. Twelves1*, E. Chmielowska2, L. Havel3, S. Popat4, A. Swieboda-Sadlej5, P. Sawrycki6, P. Bycott7, A. Ingrosso8, S. Kim7, †, J. A. Williams7, C. Chen9, A. J. Olszanski10, P. de Besi8 & J. H. Schiller11
Received 25 March 2013; revised 26 September 2013; accepted 2 October 2013
Background: Efficacy and safety of first-line axitinib/paclitaxel/carboplatin versus bevacizumab/paclitaxel/carboplatin in advanced non-squamous non-small-cell lung cancer (NSCLC) was evaluated.
Patients and methods: Patients with stage IIIB/IV disease stratified by adjuvant therapy and gender were randomised 1 : 1 to axitinib (5 mg twice daily) or bevacizumab [15 mg/kg every 3 weeks (Q3W)], both with paclitaxel (200 mg/m2 Q3W)/carboplatin (AUC 6 mg min/ml Q3W). Results: The trial was discontinued after preliminary analysis. Median progression-free survival ( primary end point) for axitinib (N = 58) and bevacizumab (N = 60), respectively, was 5.7 and 6.1 months [hazard ratio (HR) 1.09, 95% confidence interval (CI) 0.68–1.76; one-sided stratified P = 0.64]; median overall survival was 10.6 and 13.3 months (HR 1.12, 95% CI 0.74–1.69; one-sided stratified P = 0.70). Objective response rates (95% CI) were 29.3% (18.1–42.7) and 43.3% (30.6–56.8), respectively; risk ratio 0.676 (95% CI 0.41–1.11; one-sided stratified P = 0.94). The most common grade 3/4 adverse events included neutropenia (28% versus 20%), fatigue (14% versus 7%), and hypertension (14% versus 5%). Patient-reported outcomes based on the EORTC QLQ-C30 were similar between arms. Conclusions: In patients with advanced non-squamous NSCLC, axitinib/paclitaxel/carboplatin did not improve efficacy versus bevacizumab/paclitaxel/carboplatin, and was less well tolerated. Key words: axitinib; bevacizumab; chemotherapy; non-squamous, non-small-cell lung cancer
introduction The majority of patients with non-small-cell lung cancer (NSCLC) present with inoperable disease for which no curative therapy exists. Platinum-based doublet chemotherapy is the standard of care; however, the 1-year survival rate is ∼33% [1]. Singleagent bevacizumab showed little clinical benefit in advanced solid tumours [2], but the E4599 study [3] demonstrated its addition to first-line paclitaxel/carboplatin chemotherapy in NSCLC
*Correspondence to: Prof. Chris Twelves, Clinical Cancer Research Groups, Leeds Institute of Molecular Medicine and St James’s Institute of Oncology, Level 4, Bexley Wing, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK; Tel: +44-11320-68186; Fax: +44-113-206-8474; E-mail: [email protected] †
Employed at Pfizer Inc. at the time of the study described here and development of this manuscript.
significantly improved median overall survival (OS) by 2 months. In the AVAiL study [4], addition of bevacizumab to first-line gemcitabine/cisplatin significantly improved median progression-free survival (PFS), but no significant OS improvement was observed [5]. Bevacizumab plus chemotherapy is an approved first-line treatment of NSCLC [6]. Tyrosine kinase inhibitors (TKIs) were initially considered to hold promise of increased efficacy compared with bevacizumab. Single-agent studies in patients with previously treated advanced NSCLC demonstrated some efficacy and acceptable tolerability of sorafenib [7], sunitinib [8, 9], and axitinib [10]. Preclinical studies supported combination with chemotherapy [11]. Axitinib, a potent, selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors (VEGFRs), is approved in many countries as second-line treatment of advanced renal cell carcinoma. A single-agent phase I study
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at University of Guelph on December 9, 2014
1 Cancer Research UK Clinical Centre, St James’s University Hospital, Leeds, UK; 2Department of Clinical Oncology, Bydgoszcz Cancer Center, Nicolaus Copernicus University, Torun, Poland; 3Department of Pneumology and Thoracic Surgery, University Hospital Bulovka, Praha, Czech Republic; 4Medical Oncology, Royal Marsden Hospital, London, UK; 5Department of Internal Medicine Hematology and Oncology, Independent Public Central Clinical Hospital, Warsaw; 6Department of Oncology and Chemotherapy, L. Rydygiera District Hospital, Torun, Poland; 7Pfizer Oncology, Pfizer Inc., San Diego, USA; 8Pfizer Oncology, Pfizer Italia Srl, Milan, Italy; 9Pfizer Oncology, Pfizer Inc., New York; 10Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia; 11Division of Hematology-Oncology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, USA
original articles
Annals of Oncology
demonstrated promising activity and acceptable safety at the starting dose of 5 mg twice daily (b.i.d.) in patients with advanced solid tumours [12]. A phase II study demonstrated encouraging single-agent activity in advanced NSCLC [10]. Based on a phase I study of chemotherapy combinations, the recommended axitinib starting dose in combination with paclitaxel/ carboplatin was 5 mg b.i.d. [13]. This study compared efficacy and safety of axitinib/paclitaxel/ carboplatin versus bevacizumab/paclitaxel/carboplatin as firstline treatment of advanced NSCLC.
methods study design
treatments Patients received axitinib (5 mg b.i.d. starting dose, orally with food) or bevacizumab [15 mg/kg every 3 weeks (Q3W) on day 1 of each cycle] plus paclitaxel (200 mg/m2) and carboplatin Q3W (area under curve 6 mg min/ml; calculated by Calvert formula [14] on day 1 of each cycle). Patients tolerating axitinib with no grade >2 treatment-related adverse events (AEs) per Common Terminology Criteria for AEs version 3 for consecutive 2-week periods, had a one-dose-level increase (to 7 mg b.i.d.; maximum 10 mg b.i.d.) unless BP was >150/90 mmHg or patient was on antihypertensive medication. Standard antiemetic/antihypersensitivity medication was administered before chemotherapy. Chemotherapy was continued for a maximum of six cycles, after which patients could receive maintenance therapy with single-agent axitinib or bevacizumab until disease progression, unmanageable AEs, or withdrawal of consent.
study objectives The primary objective was to compare PFS. Secondary objectives included OS, objective response rate (ORR), duration of response (DR), safety and
Volume 25 | No. 1 | January 2014
assessments Radiologic tumour assessments were carried out at screening, 6-weekly on-study, and on-suspected disease progression. Baseline assessments were carried out as close to and ≤28 days before randomisation. Responses were evaluated per RECIST, and partial or complete response confirmed ≥4 weeks after the initial scan. Tumour cavitation was assessed using chest X-ray at baseline and at the start of each treatment cycle unless computed tomography scan was completed ≤7 days before day 1 of that cycle. Axitinib/bevacizumab was immediately discontinued for tumour cavitation or haemoptysis (≥2.5 ml blood in 24 h). Safety was assessed through AE monitoring, physical examinations, laboratory tests, and daily self-monitored BP. Plasma samples for measurement of soluble protein concentrations were collected before dosing and analysed at ALTA Analytical Laboratory (San Diego, CA).
statistical analysis Assuming a 50% improvement in median PFS (bevacizumab 6.5 months; axitinib 9.75 months), 70 events were required for a log-rank test (stratified) with an overall one-sided significance level of 0.20 to have power of 0.80. With planned accrual of ∼11 month and ∼7 month follow-up, 108 patients
Table 1. Patient demographic and baseline characteristics
Gender, male, n (%) Mean age, years (SD) Race, n (%) White Black Asian Other ECOG PS score,a n (%) 0 1 Not reported Smoking status, n (%) Never smoked Ex-smoker Current smoker Histological classification, n (%) Adenocarcinoma Large cell Not otherwise specified Other Stage of disease, n (%) IIIB IV Mean time since metastatic diagnosis, years (SD)
Axitinib (N = 58)
Bevacizumab (N = 60)
36 (62.1) 61.7 (8.6)
37 (61.7) 59.9 (8.4)
54 (93.1) 1 (1.7) 1 (1.7) 2 (3.4)
56 (93.3) 3 (5.0) 0 1 (1.7)
16 (27.6) 42 (72.4) 0
16 (26.7) 43 (71.7) 1 (1.7)
6 (10.3) 34 (58.6) 18 (31.0)
8 (13.3) 34 (56.7) 18 (30.0)
47 (81.0) 3 (5.2) 6 (10.3) 2 (3.4)
48 (80.0) 3 (5.0) 4 (6.7) 5 (8.3)
6 (10.3) 52 (89.7) 0.1 (0.2)
5 (8.3) 55 (91.7) 0.1 (0.1)
a
ECOG PS was not reported for one patient in the bevacizumab arm. SD, standard deviation; ECOG PS, Eastern Cooperative Oncology Group performance status.
doi:10.1093/annonc/mdt489 |
Downloaded from http://annonc.oxfordjournals.org/ at University of Guelph on December 9, 2014
In this phase II, multicentre, randomised, open-label study, patients aged ≥18 years with histologically or cytologically confirmed non-squamous-cell advanced NSCLC [stage IIIB with malignant pleural effusion, stage IV (American Joint Committee on Cancer, version 6) or recurrent disease] were randomised 1 : 1 to axitinib or bevacizumab, each in combination with paclitaxel/carboplatin. Patients were stratified by prior adjuvant therapy and gender. Eligibility included one or more sites of measurable disease [ per Response Evaluation Criteria in Solid Tumours (RECIST) version 1], Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1, and no prior systemic therapy (except adjuvant therapy >12 months before enrolment). Prior surgery or radiation was allowed if completed ≥21 or ≥28 days, respectively, before starting study treatment. Patients were excluded if they had predominantly squamous-cell NSCLC, prior treatment with a VEGF/VEGFR inhibitor, uncontrolled hypertension [two baseline blood pressure (BP) readings >140/90 mmHg taken ≥1 h apart], central nervous system metastasis, use of thrombolytic or anticoagulation agents, haematologic diathesis within 6 months of study entry, haemoptysis within 4 weeks of enrolment, myocardial infarction, severe/unstable angina, coronary/ peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischaemic attack, deep vein thrombosis or pulmonary embolism within 12 months before study treatment, gastrointestinal abnormalities, active invasive malignancies other than NSCLC, or current/ anticipated use of potent cytochrome P450 3A4 inhibitors/inducers. The study (ClinicalTrials.gov, NCT00600821) complied with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice Guidelines. All patients provided written consent.
tolerability of axitinib/paclitaxel/carboplatin, and patient-reported outcomes (supplementary material, available at Annals of Oncology online). Assessment of plasma soluble protein concentrations was exploratory.
original articles
Annals of Oncology
(21.1%) had the dose reduced 0 are included. a Assuming proportional hazards, a HR >1 indicates a reduction in hazard rate in favour of
