Sapanisertib With or Without TAK-117 vs Everolimus for Clear Cell Renal Cell Carcinoma

The investigational mTORC1/2 inhibitor sapanisertib, with or without PI3Ka inhibitor TAK-117, did not demonstrate improved efficacy and was less tolerable compared to everolimus for patients with advanced or metastatic clear cell renal cell carcinoma.

Lead investigator Toni Choueiri, MD, Dana-Farber Cancer Institute, Boston, MA, and coauthors stated that this open-label, phase 2 study aimed to test “the hypothesis that dual mTOR1/2 inhibition, either with or without additional PI3Ka inhibition, will provide better efficacy than single-agent rapalog [rapamycin analog; everolimus] inhibition of mTORC1.”

This open-label, phase 2 study enrolled 95 patients at 35 centers across Europe and North America with advanced clear cell renal cell carcinoma and who had been previously treated with ≥1 line of vascular endothelial growth factor (VEGF)-targeted therapy. Patients were randomized on a 1:1:1 basis, to receive 10 mg single-agent everolimus once daily (n = 32), 30 mg single agent sapanisertib once weekly (n = 32), or 4 mg sapanisertib plus 200 mg TAK-117, both once daily for 3 days per week (n = 31), in 28-day cycles.

The primary study end point was progression-free survival (PFS) with secondary end points including overall survival (OS), overall response rate (ORR), and safety/tolerability.

Enrollment was stopped prematurely after the interim futility analysis determined that there were higher discontinuation rates within the first 2 cycles and unfavorable efficacy for each arm containing sapanisertib compared to everolimus.

There were no significant differences in PFS or OS among any of the 3 groups, or across any subgroups. Median PFS with everolimus was 3.8 months vs 3.6 months with sapanisertib (hazard ratio [HR], 1.33; 95% confidence interval [CI], 0.75 to 2.36; P = .388), and 3.1 months with sapanisertib plus TAK-117 (HR, 1.37; 95% CI, 0.75 to 2.52; P = .667). Median OS in the everolimus group was 22.4 months compared to 16.2 months in the sapanisertib group (HR, 1.76; 95% CI, 0.89 to 3.49; P = .212), and 18.1 months in the sapanisertib plus TAK-177 (HR, 1.51; 95% CI, 0.77 to 2.98; P = .546).

Dr Choueiri and colleagues also noted, “a lower proportion of patients in the everolimus arm (31.3%) received subsequent anticancer therapy compared with those in the single-agent sapanisertib (40.6%) and sapanisertib plus TAK-177 (71.0%) arms.” The overall response rate of everolimus was 16.7% (partial response in 5 of 30 evaluable patients), of sapanisertib was 0%, and of sapanisertib plus TAK-177 was 7.1% (partial response in 2 of 28 evaluable patients).

In the everolimus group, 43.8% of patients reported treatment-related grade ≥3 treatment-emergent adverse events, compared to 34.4% in the sapanisertib arm, and 45.2% in the sapanisertib plus TAK-177 arm. Discontinuations due to treatment-emergent events occurred in 15.6% of patients in the everolimus group, 28.1% in the sapanisertib group, and 29% in the sapanisertib plus TAK-177 group. There were 2 deaths in the everolimus arm considered to be treatment related (due to sepsis and pneumonia), 1 in the sapanisertib arm (septic shock), and 1 in the sapanisertib plus TAK-117 arm (general physical health deterioration).

Dr Choueiri and colleagues concluded, “combined inhibition of mTORC1/2, with or without inhibition of additional targets in the PI3K/AKT pathway, remains an unproven therapeutic approach for these patients.”

Source:

Choueiri T, Porta C, Suárez C, et al. Randomized phase II trial of sapanisertib ± TAK-117 vs. everolimus in patients with advanced renal cell carcinoma after VEGF-targeted therapy. Oncologist. Published online September 23, 2022 doi:10.1093/oncolo/oyac192