Sapanisertib Imparts Poor Activity and Toxicity Profile in Refractory mRCC

February 11, 2021 - Sapanisertib failed to show significant activity and a favorable toxicity profile in patients with refractory metastatic renal cell carcinoma regardless of mTOR or PTEN status.

Bradley McGregor, MD

Bradley McGregor, MD

Sapanisertib failed to show significant activity and a favorable toxicity profile in patients with refractory metastatic renal cell carcinoma (mRCC) regardless of mTOR or PTEN status, according to findings from a phase 2 study (NCT03097328) that were presented during the 2021 Genitourinary Cancers Symposium.

At a median follow-up of 10.4 months (range, 1.0-27.4), the objective response rate (ORR) was 5.3% (n = 2; 90% CI, 1.0%-15.6%). The median progression-free survival (PFS) was 2.5 months (95% CI, 1.8-3.7), and the median overall survival (OS) was 11.2 months (95% CI, 9.3-not reached).

“Sapanisertib had poor tolerability and minimal activity in patients with treatment refractory metastatic RCC, and there was no clear benefit among patients with mTOR or PTEN alterations,” Bradley McGregor, MD, lead study author, and clinical director of the Lank Center for Genitourinary Oncology, senior physician at Dana-Farber Cancer Institute, and instructor of medicine at Harvard Medical School, said in a virtual presentation of the data.

Treatment options following progression on a checkpoint inhibitor and VEGF TKI are limited for patients with mRCC. Approved rapalogs, which have modest activity in mRCC, inhibit only mTORC1, whereas sapanisertib inhibits the entire mTOR pathway by targeting mTORC1 and mTORC2.

The multicenter, single-arm study enrolled 38 patients with clear cell mRCC who had received at least 2 prior lines of therapy and non-clear cell mRCC who had received at least 1 prior line of therapy with an ECOG performance status of 0 to 2.

Patients underwent a mandatory baseline biopsy that evaluated PTEN status and over 477 genes, including TSC1, TSC2, mTOR, PIK3CA, and PTEN, prior to receiving 30 mg of oral sapanisertib weekly.

The primary end point was ORR. Secondary end points included PFS, OS, safety, and toxicity. ORR and PFS by PTEN immunohistochemistry status and oncopanel-identified mutations in the mTOR pathway served as correlative end points.

Regarding patient characteristics, the median age at the time of enrollment was 62 (range, 28-75). The majority of patients had clear cell histology (73.7%; n = 28), followed by non-clear cell RCC (26.3%; n = 10), which encompassed chromophobe RCC (n = 2), papillary RCC (n = 6), translocation RCC (n = 1), and unclassified RCC (n = 1). The majority of patients had intermediate-risk disease (76.3%; n = 29) per International Metastatic RCC Database Consortium risk assessment, followed by favorable- (13.2%; n = 5) and poor-risk disease (10.5%; n = 4).

The majority of patients were heavily pretreated, having received 4 or more prior lines of therapy (39.5%; n = 15). Though, patients who received 1 (13.2%; n = 5), 2 (21.1%; n = 8), and 3 (13.2%; n = 5) prior lines of therapy were also represented. A total of 5 patients (13.2%) had an unknown number of prior treatments.

The majority of patients had received a prior checkpoint inhibitor (75.8%; n = 25) but not an mTOR inhibitor (60.6%; n = 20).

Additional results showed that 2 patients experienced an unconfirmed partial response (PR; 5.3%), 15 patients experienced stable disease (SD; 39.4%), 17 patients experienced progressive disease (44.7%), and 2 patients were not evaluable (5.3%).

The median time on treatment was 1.6 months (range, 0.3-13.8). At the time of data cutoff, 2 patients remained on treatment (5.3%), 36 had discontinued treatment (94.7%), 29 had progressive disease (PD; 76.3%), 4 had unacceptable toxicity (10.5%), 1 withdrew (2.6%), 1 discontinued by patient decision (2.6%), and 1 discontinued by physician discretion (2.6%).

No clear benefit between mTOR and PTEN alterations and clinical benefit with sapanisertib was reported.

Among patients with intact PTEN (n = 12), 1 experienced a PR, 6 experienced SD, and 5 experienced PD. Among patients with diminished PTEN expression or PTEN loss (n = 7), 1 experienced an unconfirmed PR, 2 experienced SD, and 4 experienced PD.

Among patients with an mTOR pathway mutation (n = 6), 1 experienced an unconfirmed PR, 1 experienced SD, and 4 experienced PD. Among patients without an mTOR pathway mutation (n = 21), 2 experienced a PR, 1 experienced an unconfirmed PR, 8 experienced SD, and 9 experienced PD.

Treatment-related adverse effects consisted of nausea (50%; n = 19) fatigue (39%; n = 15, vomiting (34%; n = 13), mucositis (32%; n = 12), anorexia (21%; n = 8), diarrhea (18%; n = 7), rash (18%; n = 7), dyspnea (13%; n = 5), hyperglycemia (13%; n = 5), constipation (11%; n = 4), hyperkalemia (11%; n = 4), cough (8%; n = 3), dehydration (8%; n = 3), dry mouth (8%; n = 3), muscle weakness (8%; n = 3), pruritus (8%; n = 3), hyponatremia (5%; n = 2), elevated creatinine (3%; n = 1), myocardial infarction (3%; n = 1), syncope (3%; n = 1), and pneumonitis (3%; n = 1). No grade 4 or 5 toxicities occurred.

“Additional work is needed to find new targets for patients with advanced RCC,” concluded McGregor.


  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(suppl 6):306. doi:10.1200/JCO.2021.39.6_suppl.306
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