Sapanisertib, formerly known as TAK-228, is an inhibitor of the mammalian target of rapamycin (mTOR) pathway that is intended to overcome compensatory feedback loops, which limit the activity of mTOR complex 1 inhibition. Sapanisertib targets both mTOR complex 1 and 2 and has previously demonstrated antitumor activity in advanced renal-cell carcinoma (RCC).1
In this multicenter phase 2 trial, 38 patients with metastatic RCC were enrolled to receive oral sapanisertib 30 mg weekly. Eligible patients had received ≥1 previous lines of therapy, with clear-cell RCC patients previously receiving ≥1 immune checkpoint inhibitors. Overall response rate was the primary end point, and mTOR biomarker correlates of response were assessed.1,2
Of the 38 patients enrolled, 28 had clear-cell RCC, whereas 10 had non–clear-cell RCC. A total of 53% had received ≥3 previous lines of therapy, and 34% had received previous mTOR inhibitors (ie, everolimus or temsirolimus).1
After a median follow-up of 10.4 months, independent review committee–assessed overall response rate was 5.3% (90% confidence interval, 1%-15.6%). Tumor shrinkage was reported in 31.6% of the overall population and 30.7% of those with previous mTOR inhibitor treatment. Median progression-free survival was only 2.5 months.1
Genetic alterations in the mTOR pathway were identified in 6 of 29 patients. Immunohistochemical analysis revealed decreased expression of PTEN in 7 of 19 patients. Neither mTOR pathway alterations nor PTEN loss was associated with response to sapanisertib.1
Grade 3 treatment-related adverse events were reported in 32% of patients, and treatment-related adverse events led to dose reduction in 16% of patients and discontinuation in 11% of patients.1
The researchers concluded that the mTOR pathway inhibitor sapanisertib was not efficacious for metastatic RCC, and alternative approaches to treatment are needed.1
- McGregor BA, Adib E, Xie W, et al. Biomarker-based phase II study of sapanisertib (TAK-228), an mTORC1/2 inhibitor in patients with refractory metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2021;39(suppl 6):Abstract 306.
- ClinicalTrials.gov. Study of TAK-228 in patients with previously treated metastatic renal cell carcinoma. Updated December 9, 2020. https://clinicaltrials.gov/ct2/show/NCT03097328. Accessed November 19, 2021.