Abstract
Background: There are limited therapeutic options for patients with recurrent/metastatic anaplastic thyroid carcinoma (ATC) and radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC) refractory to multikinase inhibitors. This multicenter trial evaluated sapanisertib, a next-generation oral kinase inhibitor of mTOR complexes 1/2, in ATC and RAIR DTC. Methods: A safety run-in phase I was followed by nonrandomized phase II trial in ATC, with an exploratory cohort in RAIR DTC. The primary endpoint was the proportion of patients with ATC who were without disease progression at 4 months. Safety and survival outcomes were key secondary endpoints. Results: Forty-six patients (20 ATC, 26 DTC) were enrolled including 40 (18 ATC, 22 DTC) who received recommended phase II dose of 5 mg daily. Eleven percent [2/18, 95% confidence interval (CI): 1.4-34.7%] of patients with ATC were progression-free at 4 months; 22.2% (4/18) had stable disease as best response. Enrollment in the ATC cohort stopped early with 18 patients out of the proposed 23 due to overall futility. One confirmed partial response (4.5%, 1/22) occurred in RAIR DTC, with stable disease in 63.6% (14/22) patients. Median progression-free survival was 1.6 (95% CI: 0.9-2.8) months and 7.8 (2.0–not reached) months in ATC and DTC, respectively. Grade 3 treatment-related adverse events occurred in 30% of patients who received the phase II dose, with the most common being anorexia, nausea, diarrhea, fatigue, skin rash, and hyperglycemia. Genomic alterations in the PI3K/AKT/mTOR pathway were not associated with response or progression-free survival. Conclusion: Sapanisertib monotherapy did not meet the primary endpoint of this trial (proportion progression-free at 4 months) in ATC and did not show clinically meaningful activity. Clinical trials with alternative therapeutic strategies are needed.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1315-1323 |
| Number of pages | 9 |
| Journal | Journal of clinical endocrinology and metabolism |
| Volume | 110 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2025 |
Funding
We thank our patients and their families for participation in this clinical trial, as well as the clinical research coordinators and research nursing staff involved in the trial. We also thank Dr. Jacob Thomas for his participation as a subinvestigator in the clinical trial during his affiliation with Hoag Hospital between 2018 and 2020. This trial was funded by Millennium Pharmaceuticals, Inc. (Cambridge, MA), a wholly owned subsidiary of Takeda Pharmaceuticals U.S.A., and subsequently by Calithera Biosciences. K.S. reports receiving consulting fees from Scholar Rock, Inc., AmeriSourceBergen, Guidepoint Global, and Equinox Group, Inc.; receiving personal fees for consulting or advisory board participation from Exelexis Inc., Pfizer, and MedScape; receiving research funding to the institution from Merck; and receiving honorarium from Merck, Gilead, Pri-Med, and BinayTara Foundation. T.P. reports support from Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR002541), and the K12 Building Interdisciplinary Research Careers in the Women's Health program. M.D. reports consulting fees from Lilly/Loxo, Orphagen, Theralink, Bayer, TD2, OnCusp, Pfizer, Aadi, and Boerhinger/Ingelheim; and stock and/or ownership interests in Transmed7. F. W. reports receiving personal fees for consulting or advisory board participation from Regeneron, Coherus, Merck, EMD Serono, Eisai, Eli Lilly, Soligenix, Exelixis; receiving consulting fees from Eisai, EMD Serono; receiving royalties or having patents or other intellectual property from UpToDate; receiving research funding to the institution from Kura Oncology, Merck, Regeneron, Adlai Nortye, Eli Lilly, and LOXO. R.H. reports receiving grants from Bristol Myers Squibb during the conduct of the study; receiving personal fees for consulting or advisory board participation from Bristol Myers Squibb, Merck, EMD, Eisai, Celgene, Kura, AstraZeneca, Genentech, Boehringer Ingelheim, Exelixis, Blue DOT, and Nanobiotix outside the submitted work; having a leadership role in the National Comprehensive Cancer Network; receiving consulting fees from Achilles Therapeutics, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Coherus BioSciences, Eisai, EMD Serono, Genentech, Gilead Sciences, GSK, Immunomic Therapeutics, Loxo, Merck, Mirati, Pfizer, and Vaccinex; receiving royalties or having patents or other intellectual property from UpToDate; receiving research funding to the institution from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Genentech, Kura Oncology, Merck, and Pfizer; and receiving fees for serving as chair of the data safety monitoring board for 2 trials run by Nanobiotix and ISA Pharmaceuticals. J.L. reports research support from Xencor Inst and advisory board participation for BostonGene Corp. No other disclosures were reported.
Keywords
- anaplastic thyroid carcinoma
- mTORC1/2 inhibitor
- radioiodine refractory thyroid cancer
- sapanisertib
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Biochemistry
- Endocrinology
- Clinical Biochemistry
- Biochemistry, medical
