Biomarker-Based Phase II Study of Sapanisertib (TAK-228): An mTORC1/2 Inhibitor in Patients With Refractory Metastatic Renal Cell Carcinoma.

PURPOSE: Sapanisertib is a kinase inhibitor that inhibits both mammalian target of rapamycin complex 1 (mTORC1) and mTORC2. In this multicenter, single-arm phase II trial, we evaluated the efficacy of sapanisertib in patients with treatment-refractory metastatic renal cell carcinoma (mRCC; NCT03097328). METHODS: Patients with mRCC of any histology progressing through standard therapy (including prior mTOR inhibitors) had baseline biopsy and received sapanisertib 30 mg by mouth once weekly until unacceptable toxicity or disease progression. The primary end point was objective response rate by RECIST 1.1. Tissue biomarkers of mTOR pathway activation were explored. RESULTS: We enrolled 38 patients with mRCC (clear cell = 28; variant histology = 10) between August 2017 and November 2019. Twenty-four (63%) had received ≥ 3 prior lines of therapy; 17 (45%) had received prior rapalog therapy. The median follow-up was 10.4 (range 1-27.4) months. Objective response rate was two of 38 (5.3%; 90% CI, 1 to 15.6); the median progression-free survival (PFS) was 2.5 months (95% CI, 1.8 to 3.7). Twelve patients (32%) developed treatment-related grade 3 adverse events, with no grade 4 or 5 toxicities. Alterations in the mTOR pathway genes were seen in 5 of 29 evaluable patients (MTOR n = 1, PTEN n = 3, and TSC1 n = 1) with no association with response or PFS. Diminished or loss of PTEN expression by immunohistochemistry was seen in 8 of 21 patients and trended toward shorter PFS compared with intact PTEN (median 1.9 v 3.7 months; hazard ratio 2.5; 95% CI, 0.9 to 6.7; P = .055). CONCLUSION: Sapanisertib had minimal activity in treatment-refractory mRCC independent of mTOR pathway alterations. Additional therapeutic strategies are needed for patients with refractory mRCC.

Clinical, radiographic, and biochemical characterization of multiple myeloma patients with osteonecrosis of the jaw.

PURPOSE: Osteonecrosis of the jaw (ONJ) has been reported in patients with a history of aminobisphosphonate use. This study was conducted in order to define ONJ clinically and radiographically and gain insights into its pathophysiology. EXPERIMENTAL DESIGN: Eleven multiple myeloma (MM) patients with ONJ were included in the study. Patients underwent clinical, biochemical, radiographic, and molecular profiling. Ten MM patients on aminobisphosphonates without ONJ and five healthy volunteers were used as controls for biochemical and molecular studies. RESULTS: MM patients with ONJ were treated with either pamidronate (n = 3), zoledronate (n = 4), or both agents sequentially (n = 4) for a mean of 38.7 months. Radiographic studies showed bone sclerosis and fragmentation on plain films and computerized tomography. Quantitative regional analysis of NaF-PET and FDG-PET scans confirmed an increased standardized uptake value (SUVmax) in areas of ONJ. The target to background ratio of SUVmax was significantly greater for NaF-PET compared with FDG-PET scan. Biochemical bone marker data and transcriptional profiling studies showed that genes and proteins involved in osteoblast and osteoclast signaling cascades were significantly down-regulated in patients with ONJ. CONCLUSIONS: ONJ was associated with a mean duration of 38.7 months of aminobisphosphonate exposure. Radiographic and functional imaging confirmed sites of clinically established ONJ. Gene and protein studies are consistent with altered bone remodeling, evidenced by suppression of both bone resorption and formation.

High-dose zoledronic acid impacts bone remodeling with effects on osteoblastic lineage and bone mechanical properties.

PURPOSE: The increasing incidence of osteonecrosis of the jaw and its possible association with high cumulative doses of bisphosphonate led us to study the effects of high doses of zoledronic acid (ZA) on bone remodeling. EXPERIMENTAL DESIGN: Five-week-old C57BL6 mice were treated with saline or ZA weekly for 3 weeks at increasing doses (0.05-1 mg/Kg). Effects of ZA on bone remodeling were studied using standard assays. RESULTS: We observed an increase in bone mineral density and content in treated animals at doses of 0.05 mg/Kg, which was not further enhanced at higher doses of ZA. Trabecular bone volume at the proximal tibia and the distal femur assessed by histomorphometry and microCT, respectively, increased significantly in ZA-treated groups. There was however no difference between 0.5 and 1 mg/kg, suggesting a ceiling effect for ZA. ZA led to decreased numbers of osteoclasts and osteoblasts per bone perimeter that paralleled a significant reduction of serum levels of TRAC5b and osteocalcin in vivo. Effects on osteoblasts were confirmed in in vitro assays. Mechanical testing of the femur showed increased brittleness in ZA-treated mice. CONCLUSIONS: High doses of ZA inhibit both osteoclast and osteoblasts function and bone remodeling in vivo interfering with bone mechanical properties. No dose response was noted beyond 0.5 mg/kg suggesting that lower doses of ZA may be adequate in inhibiting bone resorption. Our data may help inform future studies of ZA use with respect to alternate and lower doses in the treatment of patients with cancer bone disease.