Efficacy and Safety of Axitinib in Patients With ...

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Aug 10, 2009 - Efficacy and Safety of Axitinib in Patients With Advanced. Non–Small-Cell Lung Cancer: Results From a. Phase II Study. Joan H. Schiller ...
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Efficacy and Safety of Axitinib in Patients With Advanced Non–Small-Cell Lung Cancer: Results From a Phase II Study Joan H. Schiller, Timothy Larson, S.-H. Ignatius Ou, Steven Limentani, Alan Sandler, Everett Vokes, Sinil Kim, Katherine Liau, Paul Bycott, Anthony J. Olszanski, and Joachim von Pawel From the University of Texas Southwestern Medical Center, Simmons Comprehensive Cancer Center, Dallas, TX; Hubert H. Humphrey Cancer Center-North Memorial Health Care, Robbinsdale, MN; University of California Irvine, Orange; Pfizer Global Research and Development, San Diego, CA; Carolinas Hematology Oncology Associates, Charlotte, NC; Vanderbilt University Medical Center, Nashville, TN; University of Chicago, Chicago, IL; Pfizer Global Research and Development, New London, CT; and AsklepiosFachkliniken Munich-Gauting, Gauting, Germany. Submitted November 19, 2008; accepted February 24, 2009; published online ahead of print at www.jco.org on July 13, 2009. Supported by Pfizer, La Jolla Laboratories, Clinical Development Department, San Diego, CA. Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

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Purpose This phase II study evaluated efficacy and safety of single-agent axitinib, an oral, potent, selective inhibitor of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3, in patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods This was an open-label, single-arm, multicenter, phase II study with a Simon two-stage minimax design. Patients received a starting dose of axitinib 5 mg orally BID. The primary end point was Response Evaluation Criteria in Solid Tumors (RECIST) – defined objective response rate. Secondary end points included safety and tolerability, overall survival (OS), and progression-free survival (PFS). Results Thirty-two patients were enrolled, with a median age of 66.5 years. The majority of patients (75%) had adenocarcinoma. Nine patients (28%) had received no prior chemotherapy for metastatic disease, and 23 (72%) had received ⱖ one regimen. Three patients (9%) had a RECIST investigator-assessed, confirmed partial response (PR); disease control rate (PR ⫹ stable disease) was 41%. Median PFS was 4.9 months overall (95% CI, 3.6 to 7.0 months). Median OS was 14.8 months (95% CI, 10.7 months to not estimable) overall and 14.8 months (95% CI, 12.5 months to not estimable) in patients receiving first-line axitinib. One-year survival rates for patients with or without prior therapy for metastatic disease were 57% and 78%, respectively. Grade 3 treatment-related adverse events in ⱖ 5% of patients comprised fatigue (22%), hypertension (9%), and hyponatremia (9%).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Conclusion Axitinib demonstrated single-agent activity in patients with advanced NSCLC. Therapy was well tolerated with manageable toxicities. Further investigation of this VEGFR inhibitor in NSCLC is of interest.

Clinical Trials repository link available on JCO.org.

J Clin Oncol 27:3836-3841. © 2009 by American Society of Clinical Oncology

Corresponding author: Joan H. Schiller, MD, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8852; e-mail: [email protected]. The Acknowledgment is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF version (via Adobe® Reader®). © 2009 by American Society of Clinical Oncology 0732-183X/09/2723-3836/$20.00 DOI: 10.1200/JCO.2008.20.8355

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INTRODUCTION

Lung cancer is a major cause of morbidity and mortality. In the United States, it is the leading cause of cancer deaths, accounting for an estimated 161,840 lost lives in 2008.1 Once diagnosed, the disease is associated with poor prognosis; the 5-year survival rate for lung cancer is only 15%, among the lowest relative to other cancers. Unfortunately, the majority of patients are diagnosed at an advanced stage, and only 3% of patients with advanced lung disease survive 5 years.1 Non–small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer diagnoses. Despite continued efforts to refine and optimize

management of NSCLC, the introduction of newer chemotherapeutic agents, nonplatinum doublets, or triplet regimens has resulted in little added survival benefit to patients. Among recent notable advances, the combination of bevacizumab (a monoclonal antibody that binds to vascular endothelial growth factor [VEGF]) with carboplatin and paclitaxel was shown to prolong overall survival (OS) compared with chemotherapy alone (median OS, 12.3 v 10.3 months, respectively) in patients with nonsquamous advanced NSCLC.2 Bevacizumab has also been combined with gemcitabine and cisplatin, with a modest benefit observed in progression-free survival (PFS) but no differences seen in OS.3 In addition, a recent phase III study conducted in Europe

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Axitinib in Advanced Non–Small-Cell Lung Cancer

showed that pemetrexed plus cisplatin was superior to gemcitabine plus cisplatin (median OS, 12.6 v 10.9 months, respectively) in a preplanned subset analysis of patients with adenocarcinoma NSCLC4; the median OS of 12.6 months is numerically similar to that obtained with bevacizumab in combination with carboplatin and paclitaxel in patients with nonsquamous NSCLC. Continued evaluation of newer agents and novel combinations for the treatment of advanced NSCLC are needed to extend the median OS beyond the current 12 to 13 months. Further therapeutic advances may be realized via broad inhibition of the VEGF pathway using receptor tyrosine kinase inhibitors (TKIs) that target all three VEGF receptors (VEGFRs). Axitinib (AG013736; Pfizer, New York, NY) is an oral, potent, selective inhibitor of VEGFR-1, -2, and -3, and relative to most other VEGFR-TKIs, axitinib has a high potency for VEGFR-2. Single-agent axitinib reduced microvessel density and induced tumor necrosis in a murine Lewis lung carcinoma model and has also shown dose-dependent inhibition of tumor growth in this model.5 In a phase I trial in 36 patients with advanced solid tumors, single-agent axitinib demonstrated tumor response in multiple cancers, with evidence of antitumor activity in two patients with NSCLC. The safety profile was acceptable and typical of VEGFR TKIs.6 Here, we present the findings from an open-label, multicenter, phase II study assessing the safety and efficacy of singleagent axitinib in patients with advanced NSCLC.

were observed, axitinib treatment was interrupted temporarily until resolution to grade ⱕ 1 and restarted at a reduced dose. Axitinib was discontinued in the event of grade ⱖ 2 hemoptysis or grade 1 hemoptysis that did not resolve within 1 week. Therapy could continue if hemoptysis resolved within a week. Urine protein was assessed by dipstick and if ⱖ 2⫹, resulted in a 24-hour urine assessment. The axitinib dose was reduced if proteinuria was 2.0 to 3.5 g/24 hours; axitinib was discontinued if proteinuria was more than 3.5 g/24 hours. Patients continued treatment until tumor progression or unacceptable toxicity occurred. Assessments Tumor response was assessed using RECIST.7 All baseline and on-study assessments were conducted every 8 weeks. Responses (complete response [CR] or partial response [PR]) were confirmed 4 weeks after first noted. Adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 3.0.8 Physical examinations and laboratory tests were performed at baseline and repeated every 4 weeks. Patients measured their blood pressure daily throughout the study and notified their physician if blood pressure was more than 150/90 mmHg. A follow-up safety assessment was carried out no fewer than 28 days after the final axitinib dose. Statistical Analyses The sample size was based on a Simon two-stage minimax design9 to evaluate the null hypothesis that the true objective response rate (ORR) was 5% and the alternative hypothesis that the ORR was ⱖ 20%, with a type I error (␣) level ⫽ .10 and type II error (␤) level ⫽ .10. Given these criteria, there was a target accrual of 18 patients in stage 1 and an additional 14 patients in stage 2 if ⱖ one confirmed response (CR or PR) was observed. The primary end point was RECIST-defined ORR (CR ⫹ PR); secondary end points included safety and tolerability, duration of response, PFS, and OS.

PATIENTS AND METHODS Patients Patients age ⱖ 18 years with histologically confirmed NSCLC (any histology) that was metastatic (stage IV or recurrent) or locally advanced (stage IIIB) with malignant pleural effusion were eligible, irrespective of prior adjuvant therapy for localized disease, if they met the following criteria: up to one prior systemic therapy for metastatic disease (however, after a protocol amendment, patients were required to have had at least one prior therapy for metastatic disease); at least one Response Evaluation Criteria in Solid Tumors (RECIST) – defined target lesion that had not been irradiated; an Eastern Cooperative Oncology Group performance status of 0 or 1; adequate bone marrow, hepatic, and renal function; and urinary protein less than 2⫹ by urine dipstick. Patients were excluded if they had received prior treatment with antiangiogenic agents; had current or anticipated use of drugs known to be potent CYP3A4 inhibitors or inducers; had major surgery or radiation therapy within 4 weeks of treatment; or had central lung lesions involving major blood vessels, history of grade ⱖ 2 hemoptysis, GI abnormalities including inability to take oral medication or malabsorption syndrome, history of malignancy other than NSCLC, uncontrolled brain metastases, or evidence of pre-existing or uncontrolled hypertension (defined as ⬎ 140/90 mmHg despite adequate medical therapy). The study was approved by the institutional review board or ethics committee at each participating center and was performed in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. Written informed consent was obtained from all patients before study entry. This trial is registered on the clinical trials site of the US National Cancer Institute Web site (http://www.clinicaltrials.gov/ct/show/NCT00094094). Treatment Axitinib was administered as a single agent at a starting dose of 5 mg orally twice daily. The dose could be escalated in 2-mg increments up to a maximum of 10 mg twice daily if no treatment-related adverse events of grade ⱖ 3 occurred for 2 weeks. Intrapatient dose escalations were not permitted if blood pressure was more than 150/90 mmHg or the patient was receiving antihypertensive medication. If grade ⱖ 3 treatment-related adverse events www.jco.org

RESULTS

Patient Demographics A patient flowchart is shown in Figure 1. Demographics and baseline characteristics of the 32 enrolled patients are listed in Table 1. Median age was 66.5 years (range, 39 to 80 years). The majority of patients had adenocarcinoma (75%). Most patients (n ⫽ 27; 84%) had received prior chemotherapy; 23 patients (72%) had received one or more chemotherapy regimen(s) for metastatic disease, including eight patients (25%) who had also received adjuvant chemotherapy. Four patients (13%) had received chemotherapy only in the adjuvant setting (Table 1).

61 patients assessed for eligibility

Enrollment (N = 32)

29 patients were excluded • 18 patients did not meet inclusion criteria • 7 patients refused to participate • 4 patients did not enroll for other reasons

32 patients received axitinib starting at 5 mg twice daily • 7 patients remained on 5 mg twice daily • 13 patients titrated to < 5 mg twice daily • 12 patients titrated to > 5 mg twice daily

32 patients were evaluable for safety and efficacy 32 patients discontinued treatment by study end • 23 because of disease progression • 7 because of nonfatal adverse events • 2 because of death

Fig 1. Trial profile.

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nonfatal adverse events in seven patients (22%), and death in two patients (6%; Fig 1).

Table 1. Patient Baseline Demographics and Clinical Characteristics No. of Patients (N ⫽ 32)

Characteristic Age, years Median Range Sex Male Female Smoking status Current smoker Ex-smoker Never smoker Disease stage IIIB IV ECOG PS 0 1 Unknown Tumor histology Adenocarcinoma Squamous cell carcinoma Other Prior surgery Prior radiotherapy Prior chemotherapy None Adjuvant chemotherapy only Chemotherapy for metastatic disease 1 regimen (without adjuvant) 1 regimen (with adjuvant) ⱖ 2 regimens (without adjuvant) ⱖ 2 regimens (with adjuvant)

%

Efficacy The ORR by investigator assessment was 9%, with three patients having a PR (Table 2). One of these patients was previously untreated, one had received one prior therapy, and one had received ⱖ two prior therapies for metastatic disease. Median duration of response was 8.3 months (95% CI, 5.9 to 10.6 months). Stable disease (ⱖ 16 weeks) was reported in 31% of patients, and 28% of patients had progressive disease. An additional 19% of patients had stable disease lasting less than 16 weeks. Four patients (13%) did not have a postbaseline tumor assessment. The maximum percentage change in tumor size for all assessable patients is shown in Figure 2. At a median follow-up time of 19.9 months, median OS was 14.8 months (95% CI, 10.7 months to not estimable), as shown in Figure 3A. The encouraging OS was observed in the subset of patients who had received prior treatment for metastatic disease, with a median OS of 15.5 months (95% CI, 7.8 months to not estimable), and also in those patients who had not received prior therapy for metastatic disease (14.8 months; 95% CI, 12.5 months to not estimable). The 1-year survival rates for patients with and without prior therapy for metastatic disease were 56.5% and 77.8%, respectively. Overall median PFS was 4.9 months (95% CI, 3.6 to 7.0 months; Fig 3B). In patients who had not received prior therapy for metastatic disease, median PFS was 9.2 months (95% CI, 5.8 to 16.3 months) compared with 3.8 months (95% CI, 3.1 to 5.4 months) in patients who had received at least one prior treatment (Figs 3C and 3D).

66.5 39-80 19 13

59 41

2 23 7

6 72 22

2 30

6 94

13 16 3

41 50 9

24 4 4 8 17

75 13 13 25 53

5 4

16 13

8 5 7 3

25 16 22 9

Abbreviations: ECOG, Eastern Cooperative Oncology Group; PS, performance status.

Treatment Median duration of treatment was 3.5 months (range, 0.5 to 22.5 months). The median axitinib dose was 10 mg/d (range, 5 to 16.6 mg/d). Dose reductions were required in 44% of patients, whereas 25% of patients were dose escalated to 6 to 8 mg twice daily and 13% received 9 to 10 mg twice daily. All 32 patients discontinued treatment for the following reasons: disease progression in 23 patients (72%),

Safety The most common (ⱖ 15%) treatment-related adverse events are listed in Table 3. Hoarseness occurred in nine patients (28%), although like most of the other most common adverse events, it did not exceed grade 1 or 2 in severity. Epistaxis occurred in two patients (6%) and was grade 1 in both patients (one patient with squamous cell histology). Treatment-related grade 3 or 4 adverse events comprised fatigue, diarrhea, hypertension, vomiting (Table 3); grade 3 hyponatremia (n ⫽ 3), aggravated hypertension, glossodynia, headache, obstructed inferior vena cava, pain, and peripheral neuropathy (all n ⫽ 1); and grade 4 acute renal failure, cerebrovascular accident, and hyperkalemia (all n ⫽ 1). In total, seven patients had a total of eight treatment-related adverse events and discontinued axitinib treatment;

Table 2. Investigator-Assessed Response Rates by Number of Prior Regimens for Metastatic Disease No. of Prior Regimens for Metastatic Disease 0

ⱖ2

1

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Response

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%

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%

No. of Patients

%

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%

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1 5 1 2 9

11 56 11 22 28

1 3 5 4 13

10 30 16 40 41

1 2 3 4 10

8ⴱ 15 9 31 31

3 10 9 10 32

9 31 28 31 100

NOTE. Four patients (13%) had missing data (no baseline assessments available). Abbreviations: PR, partial response; SD, stable disease; PD, progressive disease. ⴱ Patient had received seven prior regimens for metastatic disease.

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Axitinib in Advanced Non–Small-Cell Lung Cancer

Change From Baseline (%)

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Table 3. Treatment-Related, Nonhematologic, and Laboratory-Confirmed Hematologic Adverse Events Occurring in ⱖ 15% of Patients

Progressive disease/ stable disease

40

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Partial response

20

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0 Adverse Event

-20

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%

16 16 13 11 9 7 7 6 6 5 5 5

50 50 41 34 28 22 22 19 19 16 16 16

7 0 1 0 0 3 0 1 0 0 0 0

22 0 3 0 0 9 0 3 0 0 0 0

10

31

0

0

Nonhematologic Fatigue Anorexia Diarrhea Nausea Hoarseness Hypertension Arthralgia Vomiting Dyspepsia Weight decrease Mucosal inflammation Rash Hematologic Anemia

-40 -60 -80

Fig 2. Maximum percentage change in target lesion size by Response Evaluation Criteria in Solid Tumors (best response as assessed by investigators). Target lesion size was the sum of the longest diameter of target lesions (ⱕ five lesions per organ and ⱕ 10 lesions in total, representative of all involved organs) selected based on size (longest diameter) and suitability for accurate repeated measurements by imaging or clinical assessment, compared with baseline.

these adverse events included acute coronary syndrome, pulmonary embolism, inferior vena cava obstruction, anorexia, and diarrhea not otherwise specified (n ⫽ 1 each) and fatigue (n ⫽ 3).

Grade 3

No. of Patients

DISCUSSION

Several other VEGFR TKIs are currently being studied in advanced NSCLC, either as single agents or in combination with chemotherapy. These include cediranib (AZD2171)10 and vatalanib (PTK787),11 as well as multitargeted TKIs such as sunitinib,12 sorafenib,13 motesanib diphosphate (AMG706; http://www.clinicaltrials.gov/ct2/ show/NCT00369070), vandetanib,14 and BIBF1120.15 Structural similarities between the different receptor tyrosine kinases are such that the latter agents inhibit multiple receptors in addition to VEGFR. However, a survey of published preclinical data, including half maximal inhibitory concentration values, indicates that axitinib is among those agents having the highest potency for VEGFR-2, which is thought to be the major angiogenesis-associated receptor tyrosine kinase in NSCLC and other tumor types.16 VEGFRs are associated

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Axitinib is an oral, potent, selective inhibitor of VEGFR-1, -2, and -3. Unlike monoclonal antibodies such as bevacizumab or VEGF trap, which block a single VEGF ligand, inhibition of downstream signaling at all three known VEGFRs may lead to more complete inhibition of the VEGF pathway and potentially greater antitumor activity. This phase II study demonstrates that single-agent axitinib is active in patients with advanced NSCLC, as evidenced by an ORR of 9% and a median OS time of 14.8 months. Treatment follow-up data are available for 10 patients, eight of whom received subsequent therapy. None of these patients received bevacizumab as a later line of therapy. On the basis of these findings, further study of axitinib in patients with NSCLC is of interest.

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Fig 3. Kaplan-Meier curve of (A) overall survival and (B) progression-free survival for the overall trial population and (C) overall survival and (D) progression-free survival by prior number of chemotherapy regimens for metastatic disease.

0.6 0.4 0.2 0

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with a variety of other cellular functions, and potent inhibition seems to result in numerous antitumor effects. Recently reported preclinical data show that axitinib has the potential to control tumors and metastases by inhibiting angiogenesis and lymphangiogenesis, as well as via effects on tumor cells (apoptosis).5 In this study of single-agent axitinib as first-line or later treatment, the ORR of 9% and a median OS of 14.8 months are encouraging, comparing favorably with recent phase II reports evaluating monotherapy with other TKIs in similar patient populations. In a study of first-line sorafenib monotherapy in 25 patients, a confirmed ORR of 5% and a median OS of 8.8 months were reported13; in patients with relapsed or refractory advanced NSCLC, patients (n ⫽ 51) had an ORR of 0% and a median OS of 6.7 months17; in patients with previously treated advanced disease (n ⫽ 63), sunitinib monotherapy resulted in an ORR of 11% and a median OS of 5.4 months.12 A further, ongoing study of sorafenib in previously treated patients with NSCLC (n ⫽ 15) has reported a preliminary ORR of 13% and a median time to progression of 5 months.18 Responses to the multitargeted TKI vandetanib have been reported in Japanese patients,19 although a double-blind randomized phase II trial of this agent as maintenance therapy in North American patients failed to show a survival benefit.20 Comparable data for the efficacy of bevacizumab and VEGF trap as single agents are scant because phase I studies contained few patients with NSCLC and phase II studies have evaluated them in combination with chemotherapy.21,22 Our findings indicated that, in general, treatment with axitinib was well tolerated. The most common treatment-related adverse events were fatigue, anorexia, diarrhea, and nausea. Toxicities were manageable using dose modification and/or supportive treatment. Fatigue, the most common adverse event seen in this study, has been associated with hypothyroidism as a class effect of VEGFR-targeted therapy,23 and levothyroxine has been successfully used in affected patients receiving axitinib or other agents.24-26 In this study, thyroid function tests were not required, and hypothyroidism was reported in only one patient (3%). Currently, thyroid function tests are regularly performed in all axitinib studies. Grade 1 or 2 hoarseness, seen in 28% of patients, has also been reported in 37% of axitinib-treated patients with advanced renal cell carcinoma27 and has also been observed with the VEGFR-TKI cediranib.10 Hypertension is commonly observed with antiangiogenic agents28-32 and was managed with standard antihypertensive agents as necessary. Indeed, a recent retrospective analysis across multiple tumor types found that the occurrence of diastolic blood pressure more than 90 mmHg after treatment with axitinib seemed to be associated with longer OS,28 suggesting that the development of high blood pressure may be a predictive biomarker for good clinical outcome, a hypothesis that requires prospective validation in future trials. In conclusion, axitinib was generally well tolerated and demonstrated encouraging antitumor activity in patients with advanced NSCLC. Although this was a small, single-arm study with a heterogeneous population of patients with NSCLC, the activity observed in REFERENCES 1. Jemal A, Siegel R, Ward E, et al: Cancer statistics, 2008. CA Cancer J Clin 58:71-96, 2008 2. Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab 3840

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both previously treated and untreated patients is encouraging. Further testing of single-agent axitinib may also be warranted in patients not considered to be appropriate candidates for chemotherapy. In addition, ongoing phase II studies are investigating the use of axitinib in combination with chemotherapy in patients with advanced NSCLC (http://www.clinicaltrials.gov/ct2/show/NCT00600821; http://www.clinicaltrials.gov/ct2/show/NCT00768755; http://www .clinicaltrials.gov/ct2/show/NCT00735904). Axitinib, an oral, potent, selective inhibitor of VEGFR-1, -2, and -3, offers potential benefits to patients with NSCLC based on its tolerability and encouraging antitumor activity demonstrated to date. Further studies of axitinib, both as a single agent and in combination with other anticancer agents, in patients with advanced NSCLC are ongoing. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Sinil Kim, Pfizer (C); Katherine Liau, Pfizer (C); Paul Bycott, Pfizer (C); Anthony J. Olszanski, Pfizer (C) Consultant or Advisory Role: Joan H. Schiller, Pfizer (C); Alan Sandler, Pfizer (C); Everett Vokes, Pfizer (C) Stock Ownership: Sinil Kim, Pfizer; Katherine Liau, Pfizer; Paul Bycott, Pfizer; Anthony J. Olszanski, Pfizer Honoraria: Everett Vokes, Pfizer Research Funding: Joan H. Schiller, Pfizer; Steven Limentani, Pfizer; Alan Sandler, Pfizer; Everett Vokes, Pfizer Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS Conception and design: Joan H. Schiller, Sinil Kim, Katherine Liau, Paul Bycott, Anthony J. Olszanski Provision of study materials or patients: Joan H. Schiller, Timothy Larson, S.-H. Ignatius Ou, Steven Limentani, Alan Sandler, Everett Vokes, Sinil Kim, Katherine Liau, Paul Bycott, Anthony J. Olszanski, Joachim von Pawel Collection and assembly of data: S.-H. Ignatius Ou, Steven Limentani, Everett Vokes, Joachim von Pawel Data analysis and interpretation: Joan H. Schiller, S.-H. Ignatius Ou, Steven Limentani, Everett Vokes, Sinil Kim, Katherine Liau, Paul Bycott, Anthony J. Olszanski, Joachim von Pawel Manuscript writing: Joan H. Schiller, Steven Limentani, Alan Sandler, Everett Vokes, Sinil Kim, Anthony J. Olszanski Final approval of manuscript: Joan H. Schiller, Timothy Larson, S.-H. Ignatius Ou, Steven Limentani, Alan Sandler, Everett Vokes, Sinil Kim, Katherine Liau, Paul Bycott, Anthony J. Olszanski, Joachim von Pawel

for non-small-cell lung cancer. N Engl J Med 355:2542-2550, 2006 3. Manegold C, von Pawel J, Zatloukal P, et al: BO17704 (AVAIL): A phase III randomized study of first-line bevacizumab combined with cisplatin/gemcitabine (CB) in patients (pts) with advanced or recurrent non-squamous, non-snall cell lung cancer

(NSCLC). Ann Oncol 19:viii1, 2008 (suppl; abstr LBA1) 4. Scagliotti GV, Parikh P, von Pawel J, et al: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapynaive patients with advanced-stage non–small-cell lung cancer. J Clin Oncol 26:3543-3551, 2008 JOURNAL OF CLINICAL ONCOLOGY

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Axitinib in Advanced Non–Small-Cell Lung Cancer

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