Evaluation of Sapanisertib in Advanced Anaplastic and Radioiodine-Refractory Thyroid Cancer
Overview
This phase I/II study assessed sapanisertib, a dual mTORC1/2 inhibitor, in patients with advanced anaplastic thyroid carcinoma (ATC) and radioiodine-refractory differentiated thyroid carcinoma (RAIR DTC). The drug showed limited efficacy in ATC with only 11% progression-free at 4 months and modest activity in RAIR DTC with one partial response and stable disease in 63.6% of patients. Treatment-related grade 3 adverse events occurred in 30% of patients.
Background
Thyroid carcinoma is the most common endocrine malignancy, with differentiated thyroid cancer (DTC) comprising approximately 90% of cases. A subset of DTC patients develop radioiodine-refractory disease, which is associated with poor survival. Anaplastic thyroid carcinoma (ATC) is rare but highly aggressive, with median survival around 5 months. Current therapies, including tyrosine kinase inhibitors and BRAF-targeted agents, have limited efficacy, especially in BRAF wild-type ATC. The mTOR pathway is implicated in thyroid cancer pathogenesis, making it a therapeutic target. Sapanisertib is a next-generation oral inhibitor targeting both mTORC1 and mTORC2 complexes, potentially overcoming resistance seen with first-generation mTOR inhibitors.
Data Highlights
Parameter
ATC (n=18)
DTC (n=22)
Progression-free at 4 months (%)
11 (2/18)
Not primary endpoint
Best response: Partial response
0
4.5% (1/22)
Best response: Stable disease
22.2% (4/18)
63.6% (14/22)
Median progression-free survival (months)
1.6 (95% CI: 0.9-2.8)
7.8 (95% CI: 2.0–not reached)
Grade 3 treatment-related adverse events (%)
30%
Key Findings
Only 11% of patients with ATC were progression-free at 4 months, failing to meet the primary endpoint.
Stable disease was observed in 22.2% of ATC patients and 63.6% of RAIR DTC patients.
One confirmed partial response (4.5%) occurred in the RAIR DTC cohort.
Median progression-free survival was short in ATC (1.6 months) but longer in RAIR DTC (7.8 months).
Grade 3 treatment-related adverse events occurred in 30% of patients, commonly including anorexia, nausea, diarrhea, fatigue, skin rash, and hyperglycemia.
Genomic alterations in the PI3K/AKT/mTOR pathway did not correlate with response or progression-free survival.
Clinical Implications
Sapanisertib monotherapy demonstrated limited clinical benefit in advanced ATC and modest activity in RAIR DTC, with a manageable safety profile. These findings suggest that targeting mTORC1/2 alone may be insufficient for meaningful disease control in these aggressive thyroid cancers. Alternative therapeutic strategies or combination regimens should be explored in future clinical trials.
Conclusion
Sapanisertib did not achieve the primary efficacy endpoint in ATC and showed limited activity in RAIR DTC, underscoring the need for novel treatment approaches in these difficult-to-treat thyroid cancers.
References
Wirth et al. 2023 -- Evaluation of Sapanisertib in Patients with Advanced Anaplastic and Radioiodine-Refractory Differentiated Thyroid Cancer: A Phase I/II Study
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