A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: A clinical outcomes and biomarker assessment.
BACKGROUND
Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptors 1 through 3 (VEGFR1-VEGFR3), fibroblast growth factor receptors 1 through 4 (FGFR1-FGFR4), platelet-derived growth factor receptor α (PDGFRα), ret proto-oncogene (RET), and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks implicated in tumor angiogenesis. Positive phase 1 results in solid tumors prompted a phase 2 trial in patients with advanced, radioiodine-refractory, differentiated thyroid cancer (RR-DTC).


METHODS
Fifty-eight patients with RR-DTC who had disease progression during the previous 12 months received lenvatinib 24 mg once daily in 28-day cycles until disease progression, unmanageable toxicity, withdrawal, or death. Previous VEGFR-targeted therapy was permitted. The primary endpoint was the objective response rate (ORR) based on independent imaging review. Secondary endpoints included progression-free survival (PFS) and safety. Serum levels of 51 circulating cytokines and angiogenic factors also were assessed.


RESULTS
After ≥14 months of follow-up, patients had an ORR of 50% (95% confidence interval [CI], 37%-63%) with only partial responses reported. The median time to response was 3.6 months, the median response duration was 12.7 months, and the median PFS was 12.6 months (95% CI, 9.9-16.1 months). The ORR for patients who had received previous VEGF therapy (n = 17) was 59% (95% CI, 33%-82%). Lower baseline levels of angiopoietin-2 were suggestive of tumor response and longer PFS. Grade 3 and 4 treatment-emergent adverse events, regardless of their relation to treatment, occurred in 72% of patients and most frequently included weight loss (12%), hypertension (10%), proteinuria (10%), and diarrhea (10%).


CONCLUSIONS
In patients with and without prior exposure to VEGF therapy, the encouraging response rates, median time to response, and PFS for lenvatinib have prompted further investigation in a phase 3 trial. Cancer 2015;121:2749-2756. © 2015 American Cancer Society.
Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Maria E
ME
Cabanillas
Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy Institute and Université Paris-Sud, Villejuif, France.
Martin
M
Schlumberger
Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice Poland, Wybrzeze Armii Krajowej 15, 44-101 Gliwice, Poland.
Barbara
B
Jarzab
Department of Thoracic/Head and Neck Oncology, School of Medicine, University of Washington, Seattle, Washington.
Renato G
RG
Martins
Section of Endocrinology, University of Siena, Siena, Italy.
Furio
F
Pacini
Faculty of Medicine, Cancer Genetics Unit, Kolling Institute, Royal North Shore Hospital, University of Sydney, New South Wales, Australia.
Bruce
B
Robinson
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Judith C
JC
McCaffrey
Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
Manisha H
MH
Shah
Department of Geriatrics, University of Arkansas for Medical sciences, Little Rock, Arkansas.
Donald L
DL
Bodenner
Department of Endocrinology and Diabetes, The Alfred Hospital, Melbourne, Victoria, Australia.
Duncan
D
Topliss
Eisai Inc, Woodcliff Lake, New Jersey.
Corina
C
Andresen
Eisai Inc, Woodcliff Lake, New Jersey.
James P
JP
O'Brien
Eisai Inc, Woodcliff Lake, New Jersey.
Min
M
Ren
Eisai Inc, Andover, Massachusetts.
Yasuhiro
Y
Funahashi
Cancer Care Services, The Royal Brisbane and Women's Hospital, Herston, Queensland, Australia.
Roger
R
Allison
Department of Endocrinology, University of Pisa, Pisa, Italy.
Rossella
R
Elisei
Department of Oncology, Royal Marsden Hospital, London, United Kingdom.
Kate
K
Newbold
Foundation for Cancer Research and Treatment, National Tumor Institute, Milan, Italy.
Lisa F
LF
Licitra
Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Steven I
SI
Sherman
The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Douglas W
DW
Ball
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D018450:Disease Progression; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000090063:Proto-Oncogene Mas; D011804:Quinolines / Q000009:adverse effects / Q000627:therapeutic use*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007457:Iodine Radioisotopes; C000715470:MAS1 protein, human; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011804:Quinolines; C531958:lenvatinib
biomarkers; differentiated thyroid cancer; lenvatinib; multikinase inhibitor; phase 2; radioiodine refractory