TY - JOUR
T1 - Genomic correlates of response to everolimus in aggressive radioiodine-refractory thyroid cancer
T2 - A phase II study
AU - Hanna, Glenn J.
AU - Busaidy, Naifa L.
AU - Chau, Nicole G.
AU - Wirth, Lori J.
AU - Barletta, Justine A.
AU - Calles, Antonio
AU - Haddad, Robert I.
AU - Kraft, Stefan
AU - Cabanillas, Maria E.
AU - Rabinowits, Guilherme
AU - O'Neill, Anne
AU - Limaye, Sewanti A.
AU - Alexander, Erik K.
AU - Moore, Francis D.
AU - Misiwkeiwicz, Krystof
AU - Thomas, Tom
AU - Nehs, Matthew
AU - Marqusee, Ellen
AU - Lee, Stephanie L.
AU - Janne, Pasi A.
AU - Lorch, Jochen H.
N1 - Funding Information:
N.L. Busaidy reports receiving speakers bureau honoraria from and is a consultant/advisory board member for Eisai, reports receiving commercial research grants from Novartis, and reports receiving commercial research support from Bayer. L.J. Wirth is a consultant/advisory board member for Eisai, Loxo and Novartis. R.I. Haddad is a consultant/advisory board member for Astra-Zeneca, Bristol-Myers Squibb, Eisai, Merck and Pfizer. G. Rabinowits is a consultant/advisory board member for EMD Serono and Pfizer. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
We would like to thank Tyler Haddad, Vicky Vergara, Julian Huang, Sarah Reilly, and Marge Suda for their assistance with data gathering. We thank the Center for Cancer Genome Discovery (CCGD) at the Dana-Farber Cancer Institute for their assistance in analyzing the sequencing data. We are grateful to our patients for their participation in this research. This investigator-initiated study was financially supported by Novartis and the National Institutes of Health/National Cancer Institute Cancer Center Support Grant (grant number P30-CA016672; to M.E. Cabanillas and N.L. Busaidy).
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - Purpose: Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer. We evaluated the efficacy of everolimus in aggressive, radioactive iodine–refractory (RAIR) thyroid cancer and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic thyroid cancer cohorts were included. Experimental Design: This single-arm, multi-institutional phase II study was conducted from 2009 to 2013 in patients with incurable RAIR thyroid cancer who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis. Results: Thirty-three patients with differentiated thyroid cancer (DTC), 10 with medullary thyroid cancer (MTC), and 7 with anaplastic thyroid cancer (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3–18.5) with a 2-year PFS of 23.6% (95% CI, 10.5–39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8–85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months after study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt–mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated. Conclusions: Everolimus has significant antitumor activity in thyroid cancer. While genomic profiling does not currently guide therapeutic selection in thyroid cancer patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine.
AB - Purpose: Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer. We evaluated the efficacy of everolimus in aggressive, radioactive iodine–refractory (RAIR) thyroid cancer and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic thyroid cancer cohorts were included. Experimental Design: This single-arm, multi-institutional phase II study was conducted from 2009 to 2013 in patients with incurable RAIR thyroid cancer who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis. Results: Thirty-three patients with differentiated thyroid cancer (DTC), 10 with medullary thyroid cancer (MTC), and 7 with anaplastic thyroid cancer (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3–18.5) with a 2-year PFS of 23.6% (95% CI, 10.5–39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8–85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months after study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt–mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated. Conclusions: Everolimus has significant antitumor activity in thyroid cancer. While genomic profiling does not currently guide therapeutic selection in thyroid cancer patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine.
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UR - http://www.scopus.com/inward/citedby.url?scp=85046553070&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-17-2297
DO - 10.1158/1078-0432.CCR-17-2297
M3 - Article
C2 - 29301825
AN - SCOPUS:85046553070
VL - 24
SP - 1546
EP - 1553
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 7
ER -
