Vandetanib in locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind Phase III trial (ZETA)

SA Wells,1 BG Robinson,2 RF Gagel,3 H Dralle,4 JA Fagin,5 M Santoro,6 E Baudin,7 J Vasselli,8

J Read9 and M Schlumberger7

1Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, MD2Kolling Institute of Medical Research, University of Sydney, Australia

3University of Texas MD Anderson Cancer Center, Houston, TX4Martin Luther University Halle-Wittenberg, Halle, Germany

5Memorial Sloan-Kettering Cancer Center, New York, 6Universita' di Napoli Federico II, Naples, Italy

7Institut Gustave Roussy, Villejuif, France8AstraZeneca, Wilmington, DE

9AstraZeneca, Macclesfield, UK

Background• Medullary thyroid carcinoma (MTC) – Comprises 3–5% of all thyroid cancers and occurs

in a hereditary (25%) or sporadic (75%) pattern– Activating RET mutations occur in ~100% of

hereditary MTCs (germline) and in >50% of sporadic MTCs (somatic)

– Vandetanib targets RET, VEGFR and EGFR signaling and in a phase II study demonstrated antitumor activity in patients with advanced hereditary MTC1,2,3

1. Wedge SR et al. Cancer Res 2002;62:4645–46552. Carlomagno F et al. Cancer Res 2002;62:7284–7290

3. Wells SA et al. J Clin Oncol 2010;28:767–772

Key dates and eventsFirst patient randomized 7 December 2006

Last patient randomized 21 November 2007

Data cut-off 31 July 2009

Median duration of follow-up 24 months

Patients randomized 331

Patients progressed 124 (37%)

Patients deceased 48 (15%)

Received open-label vandetanib 300 mg after progression*

102 (31%)

*Progression by investigator’s opinion

Study design

Vandetanib 300 mg/dayn=231

Follow for progression Follow for progression

Optional open-label vandetanib 300 mg/day

Follow for survival

Patients with unresectable locally advanced or metastatic MTC (N=331)

Placebon=100

2:1 randomization

Discontinue blinded treatment at progression

Study objectives• Primary endpoint: progression-free survival (PFS)

– Based on RECIST (1.0) assessments as read by central independent review

– >80% power to detect a doubling of PFS (hazard ratio <0.50)

• Secondary assessments included:– Objective response rate– Disease control rate at 24 weeks– Biochemical response (decreases in serum levels of

calcitonin and carcinoembryonic antigen)– Overall survival– Time to worsening of pain– Safety and tolerability (CTCAE 3.0)

Patient demographics and baseline characteristics

Vandetanib 300 mg

(n=231)

Placebo (n=100)

Male (%)Female (%)

134 (58)97 (42)

56 (56)44 (44)

Mean age, years 50.7 53.4Locally advanced disease (%)Metastatic disease (%)

14 (6)217 (94)

3 (3)97 (97)

No prior systemic therapy for MTC (%)1 prior therapy for MTC (%)

141 (61)90 (39)

58 (58)42 (42)

Hereditary disease (%)Sporadic or unknown disease (%)

28 (12)203 (88)

5 (5)95 (95)

RET mutation positive (%)RET mutation negative (%)RET mutation status unknown (%)

137 (59)2 (1)

92 (40)

50 (50)6 (6)

44 (44)

Summary of PFS analyses

†Other sensitivity analyses (Cox, per protocol, and Whitehead) were consistent with the primary endpoint

Events / patients (n)

HR (95% CIs) P-valueVandetani

b Placebo

Primary analysis 73 / 231(32%)

51 / 100(51%)

0.46 (0.31–0.69)

0.0001

Predefined secondary/sensitivity analyses†

Excluding open-label 64 / 231 59 / 100 0.27 (0.18–0.41)

<0.0001

Investigator RECIST assessments

101 / 231 62 / 100 0.40 (0.27–0.58)

<0.0001

Hazard ratio <1 favors vandetanib

PFS (primary endpoint)

0

Hazard ratio = 0.46 (0.31–0.69); P<0.0001

Median: not reached (vandetanib); 19.3 months (placebo)

Vandetanib 300 mg

Placebo

Time (months)

231 198 171 141 42 1 0100 72 57 45 13 0 0

At risk (n)Vandetanib

Placebo

0.6

0.8

Prog

ress

ion-

free

sur

viva

l

0.9

0

0.1

0.2

0.3

0.4

0.5

0.7

1.0

6 12 18 24 30 36

Hazard ratio <1 favors vandetanib

Objective tumor assessments

Odds ratio >1 favors vandetanib*Including all scans until progression according to central read

Vandetanib 300 mg (n=231)

Placebo (n=100)

Intention to treat analysis*Objective response rate 45% (104) 13% (13)Odds ratio (95% CI) 5.48 (2.99–10.79), P<0.0001

• 12 of 13 responses on the placebo arm occurred while patients were receiving vandetanib in the open-label phase

• Objective responses were durable; median duration of response not reached at 24 months of follow-up

Biochemical response (randomized phase)

Vandetanib 300 mg (n=231)

Placebo (n=100)

Calcitonin 160 (69%) 3 (3%)

Odds ratio (95% CI) 72.9 (26.2–303.2), P<0.0001

Carcinoembryonic antigen 119 (52%) 2 (2%)

Odds ratio (95% CI) 52.0 (16.0–320.3), P<0.0001

Biochemical response: Complete response (confirmed complete normalization of serum levels)

Partial response (≥50% decrease from baseline levels maintained for at least 4 weeks)

Odds ratio >1 favors vandetanib

Time to worsening of pain*

Hazard ratio = 0.61 (0.43–0.87); P=0.006

Median (months): 7.85 (vandetanib); 3.25 (placebo)

Vandetanib 300 mg

Placebo

Time (months)231 88 62 48 10 0100 21 12 8 2 0

At risk (n)Vandetanib

Placebo

0

0.6

0.8

Prop

ortio

n of

eve

nt-fr

ee p

atie

nts 0.9

0

0.1

0.2

0.3

0.4

0.5

0.7

1.0

6 12 18 24 3030

*Determined from patient-reported opioid analgesic use and responses to the Brief Pain Inventory questionnaire

Hazard ratio <1 favors vandetanib

Safety summary

AE, adverse event

• Median duration of treatment in the randomized phase: – 90.1 weeks (vandetanib) and 39.9 weeks (placebo)

• Most common AEs (any grade) more frequent in the vandetanib arm:– Diarrhea (56% versus 26%)– Rash (45% versus 11%)– Nausea (33% versus 16%)– Hypertension (32% versus 5%)

• More patients required dose reduction of vandetanib compared with placebo (35% versus 3%)

• Patients discontinuing randomized treatment due to an AE:– 28 (12%) receiving vandetanib and 3 (3%) receiving placebo

Vandetanib 300 mg (n=231)

Placebo (n=99)

Diarrhea 25 (11%) 2 (2%)Hypertension 20 (9%) 1 (1%)ECG QT prolonged 18 (8%) 1 (1%)Fatigue 13 (6%) 1 (1%)Decreased appetite 10 (4%) 0Rash 8 (3%) 1 (1%)Asthenia 6 (3%) 1 (1%)Dyspnea 4 (2%) 3 (3%)Back pain 1 (0.4%) 3 (3%)Syncope 0 2 (2%)

Most common grade 3+ adverse events (>2% incidence in either arm)

Conclusions• In this Phase III trial, vandetanib demonstrated a statistically

significant advantage in PFS versus placebo (HR=0.46)

• Statistically significant advantages for vandetanib were also evident in the secondary endpoints:– Objective response rate– Disease control rate – Biochemical response– Time to worsening of pain

• AEs were generally manageable, permitting treatment with vandetanib for prolonged periods of time

• Vandetanib demonstrated efficacy in this study of patients with advanced metastatic MTC, a stage of disease for which there is currently no effective therapy

Acknowledgments• Kenneth Ain• Ahmad Awada• Lars Bastholt• Keith Bible• Donald Bodenner• Emilio Bombardieri• Maria João Bugalho• Binh Bui• Antonio Casado• Raju Chacko• Orlo Clark• Ezra Cohen• Svetozar Damjanovic• Lara Iglesias Docampo• Constantin Dumitrache• Radan Dzodic• Barbro Eriksson• Sebastiano Filetti• Jesús García Foncillas• Christelle de la Fouchardière

• Viktor Medvedev• Jeffrey Moley• Bruno Niederle• Furio Pacini• Gabriella Pellegriti• Christoph Reiners • Dean Ruether• Domenico Salvatore• Hans-Joachim Schmoll• Patrick Schöffski• Manju Sengar• Asif Shaikh• Robert Smallridge• Julie Sosa• Jerzy Sowinski• David Steward• Rolf Stoeckli• Petr Vlcek• Eric Winquist• Bernard Zonnenberg

The following individuals were also investigators in this study:• Jessica Gosnell • Ann Gramza • Steven Grunberg• Robert Haddad• Arne Hallqvist• Dae-Seog Heo• Joshua Hornig• Luis Mauricio Hurtado• Izabella Kozlowicz-

Gudzinska• Zyad Kafri• Madeline Kane• Thomas Krause• Monika Krzyzanowska• Marie-France Langlois• Thera P Links• Léa Maciel• Ana Maia• László Mangel• Klaus Mann