An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline.

Head and Neck Cancer
Session Type and Session Title: 
Clinical Science Symposium, Targeting Therapeutics for Thyroid Cancers
Abstract Number: 


J Clin Oncol 30, 2012 (suppl; abstr 5508)
Patrick Schoffski, Rossella Elisei, Stefan Müller, Marcia S. Brose, Manisha H. Shah, Lisa F. Licitra, Barbara Jarzab, Viktor Medvedev, Michael Kreissl, Bruno Niederle, Ezra E. W. Cohen, Lori J. Wirth, Haythem Y. Ali, Colin Hessel, Yifah Yaron, Douglas Wilmot Ball, Barry Nelkin, Steven I. Sherman, Martin Schlumberger, EXAM Study Group; Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium; University of Pisa, Pisa, Italy; Universitätsklinikum Essen, Essen, Germany; University of Pennsylvania, Philadelphia, PA; The Ohio State University Comprehensive Cancer Center James Cancer Hospital and Solove Research Institute, Columbus, OH; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland; Medical Radiology Research Center, Obninsk, Russia; Klinik und Poliklinik fuer Nuklearmedizin der Universitaet Wuerzburg, Wuerzburg, Germany; Medizinische Universitaet Wien, Universitaetsklinik fuer Chirurgie, Vienna, Austria; The University of Chicago Medical Center, Chicago, IL; Dana-Farber Cancer Institute/Massachusetts General Hospital, Boston, MA; Henry Ford Hospital, Detroit, MI; Exelixis, South San Francisco, CA; The Johns Hopkins University School of Medicine, Baltimore, MD; University of Texas M. D. Anderson Cancer Center, Houston, TX; Institut Gustave Roussy, Villejuif, France

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Abstract Disclosures


Background: MTC arises from parafollicular cells of the thyroid gland, accounts for 5-8% of thyroid cancers and represents an unmet medical need. Cabozantinib (cabo) is an oral inhibitor of MET, VEGFR2, and RET. We conducted a phase III study of cabo vs placebo (P) in pts with progressive, unresectable, locally advanced or metastatic MTC. Methods: Eligible pts were required to have documented RECIST progression within 14 months of screening. The primary efficacy measure was progression-free survival (PFS) as assessed by an independent review facility (IRF) using RECIST. Secondary efficacy measures included objective response rate (ORR) and overall survival (OS). The study has 90% power to detect a 75% increase in PFS and 80% power to detect a 50% increase in OS. Tumor assessments occurred every 12 weeks. Crossover between treatment arms was not allowed. Results: Between Sept 2008 and Feb 2011, 330 pts (median age 55 yrs; 67% male; 96% measureable disease; RET mutation status: pos 48%; neg 12%; unknown 39%; prior TKI exposure: yes 21%, no 78%, unknown 2%) were randomized 2:1 to cabo (140 mg free base [175 mg salt form] qd; n=219) or P (n=111). The planned primary PFS analysis included events through the date of the 138th event. As of 15June2011, 44.7% of pts on cabo and 13.5% on P were still receiving study treatment. Statistically significant PFS prolongation of 7.2 mo was observed; median PFS for cabo was 11.2 mo vs 4.0 mo for P (HR 0.28, 95% CI 0.19-0.40, p<0.0001). PFS results favored the cabo group across subset analyses including RET status and prior TKI use. ORR was 28% for cabo vs 0% for P (p<0.0001). An interim analysis of OS (44% of the 217 required events) did not show a difference between cabo and P. The most frequent grade ≥3 adverse events (cabo vs P) were diarrhea (15.9 vs 1.8%), palmar-plantar erythrodysesthesia (12.6 vs 0%), fatigue (9.3 vs 2.8%), hypocalcemia (9.3 vs 0%), and hypertension (7.9 vs 0%). Conclusions: This phase III study met its primary objective of demonstrating substantial PFS prolongation with cabo vs. P in a patient population with MTC and documented progressive disease in need of therapeutic intervention.