Characterization of Tumor Size Changes Over Time From the Phase 3 Study of Lenvatinib in Thyroid Cancer
Bruce Robinson, Martin Schlumberger, Lori J Wirth, Corina E Dutcus, James Song, Matthew H Taylor, Sung-Bae Kim, Monika K Krzyzanowska, Jaume Capdevila, Steven I Sherman, Makoto Tahara, Bruce Robinson, Martin Schlumberger, Lori J Wirth, Corina E Dutcus, James Song, Matthew H Taylor, Sung-Bae Kim, Monika K Krzyzanowska, Jaume Capdevila, Steven I Sherman, Makoto Tahara
Abstract
Context: Lenvatinib improved the progression-free survival (PFS) and overall response rate of patients with radioiodine-refractory differentiated thyroid cancer vs placebo in the Phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT).
Objective: The objective of the study was to characterize tumor size changes with lenvatinib treatment.
Design: SELECT was a phase 3, randomized, double-blind, multicenter study.
Setting: In this clinical trial, tumor assessments of lenvatinib (n = 261) and placebo-treated (n = 131) patients were performed by independent radiological review per Response Evaluation Criteria in Solid Tumors version, 1.1 at 8-week intervals.
Patients: Patients with complete or partial response were defined as responders to lenvatinib (n = 169). Of the 92 nonresponders, 76 had at least one postbaseline tumor assessment and were included in this analysis.
Interventions: Lenvatinib (24 mg once daily) or placebo in 28-day cycles until unacceptable toxicity, disease progression, or death.
Main outcome measures: This was an exploratory analysis of key end points from SELECT, including PFS, overall response rate, and tumor reduction.
Results: The median maximum percentage change in tumor size was -42.9% for patients receiving lenvatinib (responders, -51.9%; nonresponders, -20.2%). Tumor size reduction was most pronounced at first assessment (median, -24.7% at 8 wk after randomization); thereafter, the rate of change was slower but continuous (-1.3% per mo). In a multivariate model, percentage change in tumor size at the first assessment was a marginally significant positive predictor for PFS (P = .06).
Conclusions: The change in tumor size conferred by lenvatinib was characterized by two phases: an initial, rapid decline, followed by slower, continuous shrinkage.
Trial registration: ClinicalTrials.gov NCT01321554.
Figures
References
- Matsui J, Yamamoto Y, Funahashi Y, et al. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer. 2008;122:664–671.
- Matsui J, Funahashi Y, Uenaka T, Watanabe T, Tsuruoka A, Asada M. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res. 2008;14:5459–5465.
- Okamoto K, Kodama K, Takase K, et al. Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models. Cancer Lett. 2013;340:97–103.
- Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372:621–630.
- Bruzzi P, Del Mastro L, Sormani MP, et al. Objective response to chemotherapy as a potential surrogate end point of survival in metastatic breast cancer patients. J Clin Oncol. 2005;23:5117–5125.
- Jain RK, Lee JJ, Ng C, et al. Change in tumor size by RECIST correlates linearly with overall survival in phase I oncology studies. J Clin Oncol. 2012;30:2684–2690.
- Blumenthal GM, Karuri SW, Zhang H, et al. Overall response rate, progression-free survival, and overall survival with targeted and standard therapies in advanced non-small-cell lung cancer: US Food and Drug Administration trial-level and patient-level analyses. J Clin Oncol. 2015;33:1008–1014.
- Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8:592–603.
- St Bernard R, Zheng L, Liu W, Winer D, Asa SL, Ezzat S. Fibroblast growth factor receptors as molecular targets in thyroid carcinoma. Endocrinology. 2005;146:1145–1153.
- Nikiforov YE. RET/PTC rearrangement in thyroid tumors. Endocr Pathol. 2002;13:3–16.
- Okamoto K, Ikemori-Kawada M, Jestel A, et al. Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization. ACS Med Chem Lett. 2015;6:89–94.
- Dadu R, Waguespack SG, Sherman SI, et al. Efficacy and tolerability of different starting doses of sorafenib in patients with differentiated thyroid cancer. Oncologist. 2014;19:477–482.
Source: PubMed