Subgroup analysis of Japanese patients in a phase 3 study of lenvatinib in radioiodine-refractory differentiated thyroid cancer

Naomi Kiyota, Martin Schlumberger, Kei Muro, Yuichi Ando, Shunji Takahashi, Yasukazu Kawai, Lori Wirth, Bruce Robinson, Steven Sherman, Takuya Suzuki, Katsuki Fujino, Anubha Gupta, Seiichi Hayato, Makoto Tahara, Naomi Kiyota, Martin Schlumberger, Kei Muro, Yuichi Ando, Shunji Takahashi, Yasukazu Kawai, Lori Wirth, Bruce Robinson, Steven Sherman, Takuya Suzuki, Katsuki Fujino, Anubha Gupta, Seiichi Hayato, Makoto Tahara

Abstract

Lenvatinib significantly prolonged progression-free survival (PFS) versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) in the phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial. This subanalysis evaluated the efficacy and safety of lenvatinib in Japanese patients who participated in SELECT. Outcomes for Japanese patients (lenvatinib, n = 30; placebo, n = 10) were assessed in relationship to the SELECT population (lenvatinib, n = 261; placebo, n = 131). The primary endpoint was PFS; secondary endpoints included overall survival, overall response rate, and safety. Lenvatinib PFS benefit was shown in Japanese patients (median PFS: lenvatinib, 16.5 months; placebo, 3.7 months), although significance was not reached, presumably due to sample size (hazard ratio, 0.39; 95% confidence interval, 0.10-1.57; P = 0.067). Overall response rates were 63.3% and 0% for lenvatinib and placebo, respectively. No significant difference was found in overall survival. The lenvatinib safety profile was similar between the Japanese and overall SELECT population, except for higher incidences of hypertension (any grade: Japanese, 87%; overall, 68%; grade ≥3: Japanese, 80%; overall, 42%), palmar-plantar erythrodysesthesia syndrome (any grade: Japanese, 70%; overall, 32%; grade ≥3: Japanese, 3%; overall, 3%), and proteinuria (any grade: Japanese, 63%; overall, 31%; grade ≥3: Japanese, 20%; overall, 10%). Japanese patients had more dose reductions (Japanese, 90%; overall, 67.8%), but fewer discontinuations due to adverse events (Japanese, 3.3%; overall, 14.2%). There was no difference in lenvatinib exposure between the Japanese and overall SELECT populations after adjusting for body weight. In Japanese patients with radioiodine-refractory differentiated thyroid cancer, lenvatinib showed similar clinical outcomes to the overall SELECT population. Some differences in adverse event frequencies and dose modifications were observed. Clinical trial registration no.: NCT01321554.

Keywords: Japanese patients; lenvatinib; progression-free survival; thyroid cancer; treatment efficacy.

© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Figures

Figure 1
Figure 1
Progression‐free survival rates of overall patients with radioiodine‐refractory differentiated thyroid cancer and the Japanese subgroup who participated in the Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial. Kaplan–Meier estimate of progression‐free survival in patients treated with lenvatinib (Japanese, n = 30; overall, n = 261) or placebo (Japanese, n = 10; overall, n = 131). CI, confidence interval; HR, hazard ratio; NE, not estimable.
Figure 2
Figure 2
Overall response and overall survival rates of overall patients with radioiodine‐refractory differentiated thyroid cancer and the Japanese subgroup who participated in the Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial. (a) Kaplan–Meier plot of overall survival adjusted with the rank‐preserving structural failure time model in patients treated with lenvatinib (Japanese, n = 30; overall, n = 261) or placebo (Japanese, n = 10; overall, n = 131). (b) Waterfall graph of maximum percentage change in summed longest diameter of target lesions from baseline to nadir in Japanese patients treated with lenvatinib (n = 30) or placebo (n = 10). Best overall responses in patients were categorized as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or not estimable (NE). CI, confidence interval.
Figure 3
Figure 3
Pharmacokinetic assessments evaluating lenvatinib exposure in Japanese patients versus the overall study population with radioiodine‐refractory differentiated thyroid cancer who participated in the Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial. (a) Scatterplot of model‐predicted lenvatinib clearance and exposure versus body weight in Japanese patients (n = 30) versus the remainder of the overall study population (n = 230). (b) Relationship between model‐predicted lenvatinib exposure and Japanese race. Lenvatinib exposure was evaluated in Japanese patients (n = 30) versus the remainder of the overall study population (non‐Japanese patients [n = 230]). AUC, area under the curve.

References

    1. Sciuto R, Romano L, Rea S, Marandino F, Sperduti I, Maini CL. Natural history and clinical outcome of differentiated thyroid carcinoma: a retrospective analysis of 1503 patients treated at a single institution. Ann Oncol 2009; 20: 1728–35.
    1. Busaidy NL, Cabanillas ME. Differentiated thyroid cancer: management of patients with radioiodine nonresponsive disease. J Thyroid Res 2012; 2012: 618985.
    1. Durante C, Haddy N, Baudin E et al Long‐term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006; 91: 2892–9.
    1. Bergers G, Hanahan D. Modes of resistance to anti‐angiogenic therapy. Nat Rev Cancer 2008; 8: 592–603.
    1. Ebos JM, Lee CR, Cruz‐Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short‐term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 2009; 15: 232–9.
    1. Boelaert K, McCabe CJ, Tannahill LA et al Pituitary tumor transforming gene and fibroblast growth factor‐2 expression: potential prognostic indicators in differentiated thyroid cancer. J Clin Endocrinol Metab 2003; 88: 2341–7.
    1. 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: 1145–53.
    1. Brose MS, Nutting CM, Jarzab B et al Sorafenib in radioactive iodine‐refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double‐blind, phase 3 trial. Lancet 2014; 384: 319–28.
    1. 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: 5459–65.
    1. 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: 664–71.
    1. 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.
    1. Schlumberger M, Tahara M, Wirth LJ et al Lenvatinib versus placebo in radioiodine‐refractory thyroid cancer. N Engl J Med 2015; 372: 621–30.
    1. Ohtsu A, Shah MA, Van Cutsem E et al Bevacizumab in combination with chemotherapy as first‐line therapy in advanced gastric cancer: a randomized, double‐blind, placebo‐controlled phase III study. J Clin Oncol 2011; 29: 3968–76.
    1. Sawaki A, Ohashi Y, Omuro Y et al Efficacy of trastuzumab in Japanese patients with HER2‐positive advanced gastric or gastroesophageal junction cancer: a subgroup analysis of the Trastuzumab for Gastric Cancer (ToGA) study. Gastric Cancer 2012; 15: 313–22.
    1. Hong MH, Kim HS, Kim C et al Treatment outcomes of sunitinib treatment in advanced renal cell carcinoma patients: a single cancer center experience in Korea. Cancer Res Treat 2009; 41: 67–72.
    1. Ueda T, Uemura H, Tomita Y et al Efficacy and safety of axitinib versus sorafenib in metastatic renal cell carcinoma: subgroup analysis of Japanese patients from the global randomized Phase 3 AXIS trial. Jpn J Clin Oncol 2013; 43: 616–28.
    1. Uemura H, Shinohara N, Yuasa T et al A phase II study of sunitinib in Japanese patients with metastatic renal cell carcinoma: insights into the treatment, efficacy and safety. Jpn J Clin Oncol 2010; 40: 194–202.
    1. Escudier B, Eisen T, Stadler WM et al Sorafenib in advanced clear‐cell renal‐cell carcinoma. N Engl J Med 2007; 356: 125–34.
    1. Akaza H, Tsukamoto T, Murai M, Nakajima K, Naito S. Phase II study to investigate the efficacy, safety, and pharmacokinetics of sorafenib in Japanese patients with advanced renal cell carcinoma. Jpn J Clin Oncol 2007; 37: 755–62.
    1. Eskens FA, Verweij J. The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. Eur J Cancer 2006; 42: 3127–39.
    1. Keizer RJ, Gupta A, Mac Gillavry MR et al A model of hypertension and proteinuria in cancer patients treated with the anti‐angiogenic drug E7080. J Pharmacokinet Pharmacodyn 2010; 37: 347–63.
    1. Keizer RJ, Gupta A, Shumaker R, Beijnen JH, Schellens JH, Huitema AD. Model‐based treatment optimization of a novel VEGFR inhibitor. Br J Clin Pharmacol 2012; 74: 315–26.
    1. Shen CT, Qiu ZL, Luo QY. Sorafenib in the treatment of radioiodine‐refractory differentiated thyroid cancer: a meta‐analysis. Endocr Relat Cancer 2014; 21: 253–61.
    1. Pithavala YK, Tortorici M, Toh M et al Effect of rifampin on the pharmacokinetics of Axitinib (AG‐013736) in Japanese and Caucasian healthy volunteers. Cancer Chemother Pharmacol 2010; 65: 563–70.

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