Minimal Activity with Sapanisertib in Refractory Renal-Cell Carcinoma

2021 Year in Review - Renal-Cell Carcinoma

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

References

  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.
  2. 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.

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