Originally published as JCO Early Release 10.1200/JCO.2008.17.3138 on October 20 2008

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Randomized Phase II Study of Vandetanib Alone or With Paclitaxel and Carboplatin as First-Line Treatment for Advanced Non–Small-Cell Lung Cancer

John V. Heymach, Luis Paz-Ares, Filippo De Braud, Martin Sebastian, David J. Stewart, Wilfried E.E. Eberhardt, Anantbhushan A. Ranade, Graham Cohen, Jose Manuel Trigo, Alan B. Sandler, Philip D. Bonomi, Roy S. Herbst, Annetta D. Krebs, James Vasselli, Bruce E. Johnson

From the Dana-Farber Cancer Institute, Boston, MA; Doce de Octubre University Hospital, Madrid; Hospital Clínico Virgen de la Victoria, Málaga, Spain; European Institute of Oncology, Milan, Italy; Universität Mainz III Med. Klinik, Mainz, Germany; University of Texas M.D. Anderson Cancer Center, Houston, TX; Universitatsklinikum of the University of Duisburg-Essen, Essen, Germany; Deenanath Mangeshkar Hospital and Research Center, Pune, India; Mary Potter Oncology Centre, Pretoria, South Africa; Vanderbilt University Medical Center, Nashville, TN; Rush University Medical Center, Chicago, IL; and AstraZeneca, Wilmington, DE

Corresponding author: Bruce E. Johnson, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: bruce_johnson{at}dfci.harvard.edu

	ABSTRACT

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Purpose Vandetanib is a once-daily, oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling. The antitumor activity of vandetanib monotherapy or vandetanib with paclitaxel and carboplatin (VPC) was compared with paclitaxel and carboplatin (PC) in previously untreated patients with non–small-cell lung cancer (NSCLC).

Patients and Methods All NSCLC histologies and previously treated CNS metastases were permitted in this partially blinded, placebo-controlled, randomized phase II study. Patients were randomly assigned 2:1:1 to receive vandetanib, VPC, or PC. Progression-free survival (PFS) was the primary end point, and the study was powered to detect a reduced risk of progression with VPC versus PC (hazard ratio = 0.70; one-sided P < .2) and to demonstrate noninferiority for vandetanib versus PC. Overall survival was a secondary assessment.

Results The risk of progression was reduced for patients receiving VPC (n = 56) versus PC (n = 52; hazard ratio = 0.76, one-sided P = .098); median PFS was 24 weeks (VPC) and 23 weeks (PC). The vandetanib monotherapy arm (n = 73) was discontinued after a planned interim PFS analysis met the criterion for discontinuation (hazard ratio > 1.33 v PC). Overall survival was not significantly different between patients receiving VPC or PC. Rash, diarrhea, and hypertension were common adverse events; no pulmonary or CNS hemorrhage events required intervention.

Conclusion VPC could be safely administered to patients with NSCLC, including those with squamous cell histology and treated brain metastases. Compared with the PC control arm, patients receiving VPC had longer PFS, meeting the prespecified study end point, whereas those receiving vandetanib monotherapy had shorter PFS.

	INTRODUCTION

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Non–small-cell lung cancer (NSCLC) is the most common cause of cancer-related deaths,^1,2 and conventional chemotherapy offers only modest survival benefits. The vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling pathways are established therapeutic targets in NSCLC. Bevacizumab, an anti-VEGF antibody, prolonged survival when added to paclitaxel and carboplatin (PC) in patients with previously untreated nonsquamous NSCLC.³ However, its use is limited by the risk of life-threatening hemoptysis and is not indicated in patients with squamous cell histology or brain metastases. EGFR tyrosine kinase inhibitors have demonstrated clinical benefit in previously treated NSCLC^4-7 but did not improve outcome when added to front-line chemotherapy.^8-11 The rationale for targeting both VEGF and EGFR in advanced NSCLC is supported by recent promising phase II data with bevacizumab and erlotinib.¹²

Vandetanib (Zactima; ZD6474; AstraZeneca, Macclesfield, United Kingdom) is an oral TKI that selectively targets VEGFR-, EGFR-, and RET-dependent signaling.^13,14 Vandetanib inhibits tumor growth and angiogenesis, even in human NSCLC xenograft tumors that are resistant to EGFR inhibitors.^13,15-17 Phase I evaluation showed vandetanib monotherapy was generally well tolerated at doses of 300 mg/d, and its half-life of approximately 120 hours supports a once-daily dosing.^18,19 In patients with previously treated NSCLC, including those with squamous histology and stable brain metastases, progression-free survival (PFS) prolongation was observed with vandetanib 100 mg/d plus docetaxel versus docetaxel alone.²⁰

This two-part phase II study (6474IL/0007) in previously untreated advanced NSCLC assessed whether vandetanib monotherapy was noninferior to PC and whether vandetanib in combination with PC prolonged PFS versus PC alone.

	PATIENTS AND METHODS

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Patients
Eligible patients had previously untreated locally advanced (stage IIIB with malignant pleural effusion) or metastatic (stage IV) NSCLC, age 18 years, WHO performance status 0 to 1, and life expectancy 12 weeks. All NSCLC histologies, including squamous cell carcinoma, were eligible. Brain metastases were permitted if treated at least 4 weeks before entry and clinically stable without corticosteroid treatment for 1 week. Patients with clinically significant hemoptysis in the previous 3 months were excluded. The trial was approved by all relevant institutional ethical committees or review bodies, and was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and the AstraZeneca policy on bioethics. Each patient provided written informed consent.

Study Design and Treatment
Both study parts consisted of continuous 21-day treatment periods in which patients received once-daily oral vandetanib and/or P (200 mg/m²) plus C (area under the concentration-time curve at steady-state, 6 mg/mL · min) once every 3 weeks for a maximum of six cycles (Fig 1). Patients continued vandetanib until progressive disease, unacceptable toxicity, or withdrawal of consent.

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Study design. NSCLC, non–small-cell lung cancer; P, paclitaxel (200 mg/m2). C, carboplatin (area under the concentration-time curve at steady-state, 6 mg/mL · min); (*) The vandetanib 300 mg arm commenced after six patients in the 200 mg cohort had received 6 weeks’ treatment with no safety concerns. () Patients were randomly assigned 2:1:1 to receive vandetanib, vandetanib + PC or placebo + PC.

Assessments
Objective tumor assessments were conducted using Response Evaluation Criteria in Solid Tumors,²¹ with evaluations at baseline and every 6 weeks until progression or withdrawal of consent. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.²² Unless otherwise clinically indicated, 12-lead ECGs were performed during screening; pretreatment (day 1); once a week (cycles 1 through 3); once during subsequent cycles; and at the end of the study. The QTc interval was evaluated centrally, and prolongation was defined as described previously.²⁰ Tumor biopsy samples obtained from consenting patients were formalin-fixed and embedded in paraffin. The investigators prospectively determined that EGFR and KRAS mutations were to be analyzed by DNA sequencing and/or by using the amplification refractory mutation system assay.²³

Statistical Considerations
Using a noninferiority margin derived from meta-analysis of cisplatin versus best supportive care (hazard ratio [HR] = 0.73),²⁴ this trial was designed to have 75% power to demonstrate noninferiority for vandetanib versus PC (one-sided significance level of 0.20) and 75% power to demonstrate a reduction in the risk of progression for VPC versus PC (HR = 0.70; one-sided significance level of .20). A one-sided significance level of .20 was regarded as adequate to assess whether vandetanib showed sufficient promise to consider further investigation in this disease setting.²⁵ PFS and overall survival were analyzed on an intention-to-treat basis using a Cox proportional hazards regression model that allowed for the effect of treatment and included terms for TNM stage²⁶ and number of organs involved (Appendix, online only). The same model was used to perform separate exploratory analyses of PFS and overall survival for subgroups defined by sex, histology (squamous/nonsquamous), and smoking status (smoker/nonsmoker; defined in Appendix). Patients who had not experienced disease progression or died at the time of analysis were censored at the time of their last tumor assessment. This included patients who were lost to follow-up or withdrew consent. One-sided P values are reported for PFS and overall survival in accordance with the trial design; two-sided P values are reported for completeness. One-sided and two-sided P values should be interpreted against the one-sided 20% significance level and two-sided 5% significance level, respectively.

When 60 patients had completed 12 weeks of treatment in the randomized phase, a preplanned interim analysis of PFS (vandetanib monotherapy v PC) was performed by the data safety monitoring committee; because the observed PFS hazard ratio was more than 1.33, recruitment to the vandetanib arm was stopped and treatment was discontinued, unless the patient was deemed by the treating physician to be receiving clinical benefit. PFS analysis was planned when approximately 75% of the patients had experienced disease progression; survival analysis was planned at approximately 75% of deaths. Duration of follow-up was the time from randomization to date of last contact.

	RESULTS

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Run-In Phase
Patients received vandetanib 200 mg (n = 15) or 300 mg (n = 10) plus PC. In both cohorts, treatment was tolerable (Appendix Table A1, online only) and there were no detectable changes in pharmacokinetic exposure to vandetanib with the addition of PC.²⁷ Overall, the incidence of grade 3 or worse adverse events was similar between the two cohorts. One patient (300-mg cohort) experienced a serious adverse event leading to death (pulmonary embolism); this was not considered to be related to study treatment. These results established vandetanib 300 mg as an appropriate dose to be administered with PC in the randomized phase.

Randomized Phase
Between November 2004 and October 2005, 181 patients entered the randomized phase of the study (Fig 2; Table 1). Baseline demographics and patient characteristics were generally similar across all three treatment arms, including the proportions of patients with squamous histology (20% to 29%) or stable brain metastases (approximately 12%).

View larger version (33K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Randomized phase enrollment and follow-up. (*) Median follow-up from randomization to last contact for patients still alive on June 30, 2007. () The progression-free survival (PFS) primary analysis did not include the vandetanib monotherapy arm, which was stopped early after the preplanned interim analysis met the criterion for discontinuation. An exploratory analysis compared patients randomly assigned to vandetanib (n = 73) with those patients randomly assigned during the same period to paclitaxel and carboplatin (PC; n = 40).

Efficacy
For VPC versus PC alone, the estimated hazard ratio for PFS was 0.76 (one-sided P = .098; Fig 3A). The study therefore achieved its primary objective of demonstrating a prolongation in PFS for VPC at the predefined one-sided significance level of P < .20. Median PFS was 24 weeks (VPC) and 23 weeks (PC).

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. (A) Kaplan-Meier plot for progression-free survival: vandetanib + paclitaxel and carboplatin (PC) versus placebo + PC (randomized phase intent-to-treat population; data cutoff June 30, 2007). (B) Kaplan-Meier plot for overall survival: vandetanib + PC versus placebo + PC (randomized phase intent-to-treat population; data cutoff June 30, 2007). (C) Kaplan-Meier plot for PFS: vandetanib versus placebo + PC (randomized phase up until the date the last monotherapy patient was enrolled [August 17, 2005]; data cutoff June 30, 2007). (D) Kaplan-Meier plot for overall survival: vandetanib versus placebo + PC (randomized phase up until the date the last monotherapy patient was enrolled [August 17, 2005]; data cutoff June 30, 2007).

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Exploratory subgroup analysis of (A) progression-free survival (PFS) and (B) overall survival by sex (male v female), smoking status (current or previous smokers v nonsmokers) and histology (squamous v nonsquamous). Nonsquamous cell histology included adenocarcinoma, adenocarcinoma bronchioloalveolar, large-cell carcinoma, adenosquamous carcinoma, and other. A hazard ratio less than 1 favors vandetanib + paclitaxel and carboplatin (PC; randomized phase intent-to-treat population; data cutoff June 30, 2007).

Tumor Biomarkers
KRAS and EGFR mutations were analyzed in 32 tumor samples available for analysis (Table 2). One of 27 assessable tumors had a KRAS mutation. Three of 29 patients had activating EGFR mutations: one receiving vandetanib monotherapy had a partial response, whereas one receiving VPC had a PFS of 692 days.

	DISCUSSION

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This study evaluated vandetanib alone or in combination with PC for patients with previously untreated advanced NSCLC. The run-in phase established that vandetanib 300 mg with PC was tolerable, and the randomized phase achieved the primary end point of demonstrating PFS prolongation with vandetanib plus PC compared with PC alone at the prespecified one-sided significance level of .20 (HR = 0.76; one-sided P = .098). The vandetanib monotherapy arm of the randomized phase was stopped early after the planned interim analysis of PFS met the criterion for discontinuation (HR > 1.33 v PC).

The PFS prolongation with VPC suggests that vandetanib may provide some benefit when added to platinum-based doublet chemotherapy as a first-line treatment for NSCLC. The PFS benefit was mainly observed among patients treated for more than 4 months (Fig 3A), suggesting that postchemotherapy maintenance therapy with vandetanib may have contributed to this benefit, a phenomenon potentially similar to that proposed for adenocarcinoma patients receiving gefitinib after PC plus gefitinib in the Iressa NSCLC Trial Assessing Combination Treatment (INTACT)-2 study.¹⁰ In contrast to INTACT-2, the objective response rate was modestly improved with VPC compared with PC (32% v 25%), suggesting that vandetanib may also augment the antitumor effects of chemotherapy as previously observed.²⁰

This PFS outcome is similar to that observed with vandetanib plus docetaxel in previously treated NSCLC.²⁰ Perhaps unexpectedly, vandetanib 100 mg plus docetaxel showed greater antitumor activity than vandetanib 300 mg plus docetaxel in prolonging PFS. The potential for greater efficacy with vandetanib 100 mg with chemotherapy was not known when the present study was initiated (selection of 300 mg vandetanib in this study was based on the run-in phase results).

The PFS outcome did not, however, translate into a detectable survival advantage for VPC versus PC. Patients receiving PC had a median survival of 12.6 months, which was longer than the 10 months previously observed in large randomized studies.^3,10 Therefore, overall survival (a secondary end point) may be confounded by the substantial numbers of patients who received postprogression anticancer treatments (43%, VPC arm; 56%, PC arm; Appendix Table A2, online only). Other possible explanations include statistical chance or potential imbalances in baseline prognostic factors. In this respect, a correlative analysis of blood-based prognostic/predictive markers and clinical outcome from the randomized phase is ongoing.²⁸ It is also conceivable that treatment with vandetanib adversely impacted postprogression survival, either through effects on tumor growth or toxicities, but there was no evidence of postprogression deaths related to drug toxicity.

The PFS results suggest that vandetanib 300 mg/d is inferior to PC in unselected patients. Shorter PFS was also reported with erlotinib monotherapy versus PC in patients with previously untreated, advanced NSCLC with performance status of 2.²⁹ However, overall survival was not different in patients initially randomly assigned to vandetanib monotherapy or PC, and most patients who discontinued vandetanib monotherapy received subsequent anticancer therapy with the anticipated survival benefit. Moreover, the eight patients who continued to receive vandetanib monotherapy for more than 6 months may have derived long-term benefit, including one patient with an activating EGFR mutation who had a partial response (PFS of 192 days). There were no other obvious predictive factors for efficacy, including those (female, adenocarcinoma, nonsmoker, and former smoker) previously associated with response to gefitinib/erlotinib.³⁰

Although patient numbers are small and there was also considerable overlap between the female and nonsmoker subpopulations, exploratory subgroup analyses showed a trend toward improved PFS for females and for nonsmokers in the VPC arm versus PC. The potential PFS benefit in females is consistent with exploratory findings observed with vandetanib plus docetaxel in second-line NSCLC,²⁰ but definitive assessment requires investigation in appropriately powered phase III trials. Intriguingly, subgroup analysis in E4599 suggested a greater survival benefit for male rather than female patients, in patients receiving bevacizumab plus PC versus PC.³ Although these analyses are exploratory, the potential sex differences between bevacizumab and vandetanib merits further investigation.

Vandetanib 300 mg plus PC was considered tolerable, with an adverse event profile generally consistent with other vandetanib studies.^18-20 Importantly, vandetanib treatment did not show an increased incidence of life-threatening hemoptysis and, unlike bevacizumab,³¹ seems to be reasonably safe for all histologies of NSCLC and for patients with brain metastases. Increased rates of hypertension (32% v 4%), rash (50% v 25%), and diarrhea (52% v 33%) occurred with VPC versus PC (Table 3). The rate of grade 3 or 4 hypertension (7%) is similar to that reported in the bevacizumab/PC arm of Eastern Cooperative Oncology Group Trial 4599 (7%).³ It is not clear whether the lack of increased hemoptysis observed in this study reflects differences in the spectrum (ie, dual VEGFR/EGFR inhibition), potency, half-life, or other characteristics relative to other VEGF pathway inhibitors. The increased rash and diarrhea are consistent with the effects of other agents targeting the EGFR pathway. Therefore, in terms of targeting both VEGF and EGFR, a broader population of patients with NSCLC may be treated with vandetanib than with erlotinib plus bevacizumab.

In summary, VPC achieved the predefined end point of prolonging PFS compared with PC in previously untreated advanced NSCLC, whereas vandetanib monotherapy was inferior to PC. VPC was tolerable in a broad population of patients, including those with squamous histology. Additional studies of vandetanib/chemotherapy combinations as first-line therapy for advanced NSCLC, either in unselected patients or subgroups such as female patients or nonsmokers, are currently under consideration. In previously treated advanced NSCLC, four randomized phase III studies of vandetanib are ongoing.³²

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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: Annetta D. Krebs, AstraZeneca (C); James Vasselli, AstraZeneca (C) Consultant or Advisory Role: John V. Heymach, AstraZeneca (C); Luis Paz-Ares, Roche (C), Pfizer (C), Lilly (C); Filippo De Braud, AstraZeneca (C); Wilfried E.E. Eberhardt, AstraZeneca (C); Alan B. Sandler, AstraZeneca (C); Roy S. Herbst, AstraZeneca (C); Bruce E. Johnson, Genzyme (C) Stock Ownership: Annetta D. Krebs, AstraZeneca; James Vasselli, AstraZeneca Honoraria: Wilfried E.E. Eberhardt, AstraZeneca; Philip D. Bonomi, AstraZeneca Research Funding: John V. Heymach, AstraZeneca; Filippo De Braud, IEO; David J. Stewart, AstraZeneca; Anantbhushan A. Ranade, AstraZeneca; Alan B. Sandler, AstraZeneca; Philip D. Bonomi, AstraZeneca; Roy S. Herbst, AstraZeneca Expert Testimony: None Other Remuneration: Bruce E. Johnson, Genzyme

	AUTHOR CONTRIBUTIONS

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Conception and design: John V. Heymach, Bruce E. Johnson

Administrative support: John V. Heymach, Bruce E. Johnson

Provision of study materials or patients: John V. Heymach, Luis Paz-Ares, Filippo De Braud, Martin Sebastian, David J. Stewart, Wilfried E.E. Eberhardt, Anantbhushan A. Ranade, Graham Cohen, Jose Manuel Trigo, Alan B. Sandler, Philip D. Bonomi, Roy S. Herbst, Bruce E. Johnson

Collection and assembly of data: John V. Heymach, Wilfried E.E. Eberhardt, Anantbhushan A. Ranade, Bruce E. Johnson

Data analysis and interpretation: John V. Heymach, Filippo De Braud, Wilfried E.E. Eberhardt, Philip D. Bonomi, Annetta D. Krebs, James Vasselli, Bruce E. Johnson

Manuscript writing: John V. Heymach, Annetta D. Krebs, James Vasselli, Bruce E. Johnson

Final approval of manuscript: John V. Heymach, Luis Paz-Ares, Martin Sebastian, Wilfried E.E. Eberhardt, Anantbhushan A. Ranade, Graham Cohen, Alan B. Sandler, Philip D. Bonomi, Roy S. Herbst, Annetta D. Krebs, James Vasselli, Bruce E. Johnson

	Appendix

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The number of organs was determined from the number of organ systems indicated on the extent of disease clinical report form. Sites of local and metastatic disease were abdominal, ascites, bone, CNS, liver, lung, lymph nodes, pleural effusion, renal, skin and soft tissue, and other.

Smoker included the following: former smoker (no cigarettes for past 5 years); occasional smoker (< one cigarette per day or smokers who have ceased smoking from 6 months through 4 years); and habitual smoker (> one cigarette per day or cessation of smoking for < 6 months).

The following individuals were also investigators in this study: R.P. Abratt, L. Bergmann, E. Dansin, A. Depierre, J. Fischer, R. Govindan, M. Hetzel, F. Kabbinavar, R. Kerr, P. Mali, J.M. López Picazo, E. Quoix, B. Rapoport, P. Rebattu, H. Riska, R. Robles, R. Rosell, P. Ruff, P. Saintigny, H. Safran, R. Salgia, G.V. Scagliotti, C.F. Slabber, S. Thongprasert, H. du Toit, and H. West.

View this table: [in this window] [in a new window]   Table A1. Adverse Events in Both Treatment Arms (vandetanib 200 mg + PC; vandetanib 300 mg + PC) Reported in 10 Patients Overall (run-in phase)

	NOTES

 
published online ahead of print at www.jco.org on October 20, 2008.

Supported by AstraZeneca (including editorial assistance provided by John Matthew of Mudskipper Bioscience). J.V.H. is a Damon Runyan-Lilly Clinical Investigator supported in part by the Damon Runyan Cancer Research Foundation (Grant No. CI 24-04) and the American Society for Clinical Oncology Career Development Award.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL (poster); 11th World Conference on Lung Cancer, July 3-6, 2005, Barcelona, Spain (poster); 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL (poster); and 12th World Conference on Lung Cancer, September 2-6, 2007, Seoul, Korea (oral).

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

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Submitted March 31, 2008; accepted July 7, 2008.

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