Incidence and timing of common adverse events in Lenvatinib-treated patients from the SELECT trial and their association with survival outcomes.
OBJECTIVE
In the study of (E7080) lenvatinib in differentiated cancer of the thyroid, most patients experienced an adverse event. In this report, we examine common lenvatinib-emergent adverse events in this phase three, randomized, double-blind study.


METHODS
Adverse events were graded per Common Terminology Criteria for Adverse Events v4.0. 392 patients were enrolled (lenvatinib: 261, placebo: 131) and received lenvatinib 24 mg/day or placebo. The main outcome measures were: associations with progression-free survival and overall survival in exploratory univariate and multivariate analyses along with additional variables.


RESULTS
The most common any-grade adverse events (any grade; grade 3) in lenvatinib-treated patients included proteinuria (32%; 10%), diarrhea (67%; 9%), fatigue/asthenia/malaise (67%; 10%), rash (23%; 0.4%), and palmar-plantar erythrodysesthesia syndrome (33%; 3%). There were no grade 4 events for these adverse events. They generally occurred early (median time to first onset [weeks]: proteinuria [6.1], diarrhea [12.1], fatigue/asthenia/malaise [3.0], rash [7.3], and palmar-plantar erythrodysesthesia syndrome [5.9]), and were resolved primarily with dose modifications (median time to resolution [weeks]: proteinuria [8.8], diarrhea [18.1], fatigue/asthenia/malaise [16.3], rash [5.9], and palmar-plantar erythrodysesthesia syndrome [20.0]). Discontinuation due to these adverse events occurred in 2 (1%) patients with proteinuria and 4 (2%) with fatigue. Progression-free survival was not associated with any of the adverse events. Eastern Cooperative Oncology Group performance status (P = 0.001), follicular histology (P = 0.002), and diarrhea (P = 0.023) were associated with overall survival in multivariate analyses (median overall survival for patients with diarrhea: not reached; without: 17.1 months).


CONCLUSIONS
In the study of (E7080) lenvatinib in differentiated cancer of the thyroid, the most common adverse events typically occurred early and were primarily managed with dose modifications. Overall survival was significantly associated with diarrhea.
Head and Neck Oncology Program, Dana Farber Cancer Institute, Brigham and Women's Hospital, Boston, MA, USA. Robert_Haddad@dfci.harvard.edu.
Robert I
RI
Haddad
Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and University Paris-Sud, Villejuif, France.
Martin
M
Schlumberger
Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Lori J
LJ
Wirth
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Eric J
EJ
Sherman
Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
Manisha H
MH
Shah
Kolling Institute of Medical Research, University of Sydney, New South Wales, Australia.
Bruce
B
Robinson
Clinical Development, Oncology Business Group, Eisai Inc., Woodcliff Lake, NJ, USA.
Corina E
CE
Dutcus
Clinical Development, Oncology Business Group, Eisai Inc., Woodcliff Lake, NJ, USA.
Angela
A
Teng
Division of Endocrinology and Metabolism, Harbor-UCLA Medical Center, Torrance, CA, USA.
Andrew G
AG
Gianoukakis
Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Steven I
SI
Sherman
D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D003967:Diarrhea / Q000139:chemically induced / Q000453:epidemiology*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005076:Exanthema / Q000139:chemically induced / Q000453:epidemiology*; D005221:Fatigue / Q000139:chemically induced / Q000453:epidemiology*; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D010671:Phenylurea Compounds / Q000009:adverse effects* / Q000627:therapeutic use; D011507:Proteinuria / Q000139:chemically induced / Q000453:epidemiology*; D011804:Quinolines / Q000009:adverse effects* / Q000627:therapeutic use; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011804:Quinolines; C531958:lenvatinib
Adverse event; Dose interruption; Dose reduction; Lenvatinib