- Email: [email protected]
Comprehensive Analysis of Serum Biomarker and Tumor Gene Mutation Associated with Clinical Outcomes in the Phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (Select)
Annals of Oncology 25 (Supplement 5): v1–v41, 2014 doi:10.1093/annonc/mdu438.31
LBA30
COMPREHENSIVE ANALYSIS OF SERUM BIOMARKER AND TUMOR GENE MUTATION ASSOCIATED WITH CLINICAL OUTCOMES IN THE PHASE 3 STUDY OF (E7080) LENVATINIB IN DIFFERENTIATED CANCER OF THE THYROID (SELECT)
abstracts
Downloaded from https://academic.oup.com/annonc/article-abstract/25/suppl_4/mdu438.31/1746489 by guest on 26 October 2019
M. Tahara1, M. Schlumberger2, L.J. Wirth3, R. Elisei4, M. Brose5, M.A. Habra6, K. Newbold7, N. Kiyota8, C. Dutcus9, J. Zhu10, T. Kadowaki11, Y. Funahashi12, B. Robinson13, S. Sherman14 1 Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, JAPAN 2 Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and University Paris-Sud, Villejuif, FRANCE 3 Department of Medicine, Massachusetts General Hospital, Boston, MA, USA 4 Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, ITALY 5 Department of Otorhinolaryngology: Head and Neck Surgery, Abramson Cancer Center of the University of Pennsylvania Health System, Philadelphia, PA, USA 6 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA 7 National Health Service Trust, Royal Marsden Hospital, London, UK 8 Medical Oncology and Hematology, Kobe University Hospital, Kobe, JAPAN 9 Eisai Inc., Woodcliff Lake, NJ, USA 10 Clinical Department, Eisai Inc., Woodcliff Lake, NJ, USA 11 Tsukuba, Eisai Co., Ltd, Ibaraki, JAPAN 12 Eisai Inc., Andover, MA, USA 13 Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW, AUSTRALIA 14 Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Aim: Lenvatinib (LEN)—an oral multikinase inhibitor of VEGFR1–3, FGFR1–4, PDGFRα, RET, and KIT—significantly prolonged progression-free survival (PFS) vs placebo (PBO) in patients ( pts) with 131I-refractory differentiated thyroid cancer in the phase 3 SELECT study. This analysis investigated potential LEN efficacy biomarkers from SELECT. Methods: Blood samples were collected at baseline, Cycle 1/Day 15 (C1D15), Day 1 of subsequent cycles, and at treatment end. Circulating cytokine/angiogenic factors (CAFs) were measured by ELISA. Tumor tissues were analyzed for mutations of BRAF, NRAS, KRAS and HRAS (Ion Torrent PGM® Sequencer). For prognostic (disease) and predictive (response) biomarker analyses (P for interaction) of baseline CAFs, pts were dichotomized: low (1st quartile) vs high (others). Results: CAF and tissue samples were analyzed from 387 (99%) and 183 (47%) of all randomized pts (N = 392), respectively. PFS hazard ratio (HR) and 95% CI were similar between these groups and the overall study; LEN PFS benefit was maintained in all assessments. Low baseline angiopoietin-2 (Ang2) was significantly associated with tumor shrinkage in LEN (P = 0.017), but not PBO. PFS HR of LEN to PBO for low Ang2 (0.08, 95% CI 0.04–0.17; P < 0.001) was lower than high Ang2 (0.24, 95% CI 0.18–0.33; P < 0.001); low Ang2 was a positive predictive factor for LEN PFS (P = 0.018). High baseline thyroglobulin (Tg) was a negative prognostic factor for PFS (P = 0.023); PFS HR of LEN to PBO for high Tg (0.14, 95% CI 0.10–0.21; P < 0.001) was lower than low Tg (0.32, 95% CI 0.18–0.58; P < 0.001). With LEN, Tg rapidly decreased by C1D15; a large change correlated to better objective response (C1D15 and later). In mutation analyses, no significant differences in clinical outcomes were observed; BRAFMU was an independent positive prognostic factor for PFS in papillary thyroid cancer (P = 0.019). BRAFMU and NRASMU have significantly low and high baseline Tg, respectively, compared with wild type. Conclusions: LEN PFS benefit vs PBO was maintained regardless of baseline CAF or BRAF/RAS mutational status. Baseline Ang2 was predictive of tumor shrinkage and PFS in a subset of patients (lowest quartile, 0-25%) with LEN, indicating that Ang2 may play a predictive role in defining sensitivity to LEN. Additionally, BRAFMU may be a positive prognostic factor in RR-DTC.
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
LBA30
COMPREHENSIVE ANALYSIS OF SERUM BIOMARKER AND TUMOR GENE MUTATION ASSOCIATED WITH CLINICAL OUTCOMES IN THE PHASE 3 STUDY OF (E7080) LENVATINIB IN DIFFERENTIATED CANCER OF THE THYROID (SELECT)
abstracts
Downloaded from https://academic.oup.com/annonc/article-abstract/25/suppl_4/mdu438.31/1746489 by guest on 26 October 2019
M. Tahara1, M. Schlumberger2, L.J. Wirth3, R. Elisei4, M. Brose5, M.A. Habra6, K. Newbold7, N. Kiyota8, C. Dutcus9, J. Zhu10, T. Kadowaki11, Y. Funahashi12, B. Robinson13, S. Sherman14 1 Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, JAPAN 2 Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and University Paris-Sud, Villejuif, FRANCE 3 Department of Medicine, Massachusetts General Hospital, Boston, MA, USA 4 Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, ITALY 5 Department of Otorhinolaryngology: Head and Neck Surgery, Abramson Cancer Center of the University of Pennsylvania Health System, Philadelphia, PA, USA 6 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA 7 National Health Service Trust, Royal Marsden Hospital, London, UK 8 Medical Oncology and Hematology, Kobe University Hospital, Kobe, JAPAN 9 Eisai Inc., Woodcliff Lake, NJ, USA 10 Clinical Department, Eisai Inc., Woodcliff Lake, NJ, USA 11 Tsukuba, Eisai Co., Ltd, Ibaraki, JAPAN 12 Eisai Inc., Andover, MA, USA 13 Kolling Institute of Medical Research, The University of Sydney, Sydney, NSW, AUSTRALIA 14 Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Aim: Lenvatinib (LEN)—an oral multikinase inhibitor of VEGFR1–3, FGFR1–4, PDGFRα, RET, and KIT—significantly prolonged progression-free survival (PFS) vs placebo (PBO) in patients ( pts) with 131I-refractory differentiated thyroid cancer in the phase 3 SELECT study. This analysis investigated potential LEN efficacy biomarkers from SELECT. Methods: Blood samples were collected at baseline, Cycle 1/Day 15 (C1D15), Day 1 of subsequent cycles, and at treatment end. Circulating cytokine/angiogenic factors (CAFs) were measured by ELISA. Tumor tissues were analyzed for mutations of BRAF, NRAS, KRAS and HRAS (Ion Torrent PGM® Sequencer). For prognostic (disease) and predictive (response) biomarker analyses (P for interaction) of baseline CAFs, pts were dichotomized: low (1st quartile) vs high (others). Results: CAF and tissue samples were analyzed from 387 (99%) and 183 (47%) of all randomized pts (N = 392), respectively. PFS hazard ratio (HR) and 95% CI were similar between these groups and the overall study; LEN PFS benefit was maintained in all assessments. Low baseline angiopoietin-2 (Ang2) was significantly associated with tumor shrinkage in LEN (P = 0.017), but not PBO. PFS HR of LEN to PBO for low Ang2 (0.08, 95% CI 0.04–0.17; P < 0.001) was lower than high Ang2 (0.24, 95% CI 0.18–0.33; P < 0.001); low Ang2 was a positive predictive factor for LEN PFS (P = 0.018). High baseline thyroglobulin (Tg) was a negative prognostic factor for PFS (P = 0.023); PFS HR of LEN to PBO for high Tg (0.14, 95% CI 0.10–0.21; P < 0.001) was lower than low Tg (0.32, 95% CI 0.18–0.58; P < 0.001). With LEN, Tg rapidly decreased by C1D15; a large change correlated to better objective response (C1D15 and later). In mutation analyses, no significant differences in clinical outcomes were observed; BRAFMU was an independent positive prognostic factor for PFS in papillary thyroid cancer (P = 0.019). BRAFMU and NRASMU have significantly low and high baseline Tg, respectively, compared with wild type. Conclusions: LEN PFS benefit vs PBO was maintained regardless of baseline CAF or BRAF/RAS mutational status. Baseline Ang2 was predictive of tumor shrinkage and PFS in a subset of patients (lowest quartile, 0-25%) with LEN, indicating that Ang2 may play a predictive role in defining sensitivity to LEN. Additionally, BRAFMU may be a positive prognostic factor in RR-DTC.
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].