1 / 15

Background

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 Read 9 and M Schlumberger 7.

oral
Download Presentation

Background

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. 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,4JA Fagin,5 M Santoro,6 E Baudin,7 J Vasselli,8J Read9 and M Schlumberger7 1Medical Oncology Branch, National Cancer Institute, NIH, Bethesda, MD2Kolling Institute of Medical Research, University of Sydney, Australia3University 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, Italy7Institut Gustave Roussy, Villejuif, France8AstraZeneca, Wilmington, DE9AstraZeneca, Macclesfield, UK

  2. 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;62:4645–4655 2. Carlomagno F et al. Cancer Res 2002;62:7284–7290 3. Wells SA et al. J Clin Oncol 2010;28:767–772

  3. Key dates and events *Progression by investigator’s opinion

  4. Patients with unresectable locally advanced or metastatic MTC (N=331) 2:1 randomization Vandetanib 300 mg/dayn=231 Placebon=100 Follow for progression Follow for progression Discontinue blinded treatment at progression Optional open-label vandetanib 300 mg/day Follow for survival Study design

  5. 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)

  6. Patient demographics and baseline characteristics

  7. Summary of PFS analyses †Other sensitivity analyses (Cox, per protocol, and Whitehead) were consistent with the primary endpoint Hazard ratio <1 favors vandetanib

  8. 1.0 Vandetanib 300 mg Placebo 0.9 0.8 0.7 0.6 Progression-free survival 0.5 0.4 Hazard ratio = 0.46 (0.31–0.69); P<0.0001Median: not reached (vandetanib); 19.3 months (placebo) 0.3 0.2 0.1 0 0 6 12 18 24 30 36 Time (months) At risk (n) Vandetanib 231 198 171 141 42 1 0 Placebo 100 72 57 45 13 0 0 Hazard ratio <1 favors vandetanib PFS (primary endpoint)

  9. Objective tumor assessments • 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 Odds ratio >1 favors vandetanib *Including all scans until progression according to central read

  10. Biochemical response (randomized phase) 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

  11. 1.0 0.9 0.8 0.7 0.6 0.5 Proportion of event-free patients 0.4 0.3 0.2 0.1 0 0 6 12 18 24 30 30 At risk (n) Vandetanib 231 88 62 48 10 0 Placebo 100 21 12 8 2 0 Time to worsening of pain* Vandetanib 300 mg Placebo Hazard ratio = 0.61 (0.43–0.87); P=0.006 Median (months): 7.85 (vandetanib); 3.25 (placebo) Time (months) *Determined from patient-reported opioid analgesic use and responses to the Brief Pain Inventory questionnaire Hazard ratio <1 favors vandetanib

  12. Safety summary • 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 AE, adverse event

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

  14. 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

  15. 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 Acknowledgments 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

More Related