Naveed Saleh, MD, MS, for MDLinx | September 10, 2018
Combination of the targeted drug vistusertib with paclitaxel chemotherapy was highly effective and well tolerated in patients with squamous non-small cell lung cancer (SqNSCLC) or high-grade serous ovarian cancer (HGSOC), according to a recent study published in the Annals of Oncology.
“We report the first study of the combination of weekly paclitaxel with the dual m-TORC1/2 inhibitor, vistusertib, establishing a safe dose and schedule and preliminary evidence of efficacy in HGSOC and SqNSCLC,” wrote the authors.
Previous studies by these investigators have shown that elevated levels of p-S6K found in serous effusions are significantly linked to chemoresistance in ovarian cancer and poor clinical outcomes in lung cancer. This discovery led the team to hypothesize that the inhibition of m-TOR signaling plus chemotherapy could improve treatment outcomes in patients with these types of cancer.
Vistusertib is a dual m-TORC1/2 inhibitor with a shorter half-life, which makes it a good candidate for intermittent dosing. Paclitaxel is commonly used as chemotherapy for advanced ovarian cancer. During preclinical studies, the investigators found that combining these agents potentiated their effects on tumor growth, and resulted in increased apoptosis and metabolic effects, which is in line with the mechanism of action of vistusertib.
“We report the results of the TAX-TORC study, a phase 1b dose-escalation study, with a pre-planned dose-expansion cohort in HGSOC and an additional expansion cohort in SqNSCLC,” the authors wrote. All patients in the current study were refractory to standard treatment and had metastatic cancer.
During the dose-escalation study in 22 patients with advanced solid tumors, paclitaxel 80 mg/m2 was administered once weekly for 6 weeks in a 7-week cycle along with two intermittent schedules of vistusertib: Schedule A and Schedule B. In Schedule A, vistusertib 50 mg was dosed orally twice a day (BID) for 3 consecutive days per week. In Schedule B, vistusertib 50 mg was dosed orally BID for 2 consecutive days per week.
Dose-limiting toxicities included fatigue and mucositis in Schedule A, and rash in Schedule B. Based on toxicity and pharmacokinetic and pharmacodynamic evaluations, the team determined a recommended phase 2 dose (RP2D) and proceeded with Schedule A dosing during the dose expansion.
The HGSOC expansion cohort consisted of 25 patients, and the sqNSCLC cohort consisted of 40 patients. In this HGSOC expansion cohort, the Response Evaluation Criteria in Solid Tumors (RECIST) response rate was 52% and the GCIG CA125 response was 64%. The median progression-free survival was 5.8 months (95% CI: 3.28-18.54).
The RP2D was not well tolerated by patients with SqNSCLC; however, resulting toxicities became manageable after the daily vistusertib dose was reduced by half—to 25 mg BID—in 23 patients. Among these patients, the RECIST response rate was 35%, and median progression-free survival was 5.8 months (95% CI: 2.76–21.25).
The results of the current study exceeded the efficacy of other standard treatments in refractory patients ith advanced disease. A substantial proportion of patients with lung cancer or ovarian cancer experienced tumor shrinkage, as well as arrest of tumor growth for approximately 6 months.
“The response rates and progression-free survival in these non-randomized phase 1 expansions show promise, and randomized phase 2 studies are recommended to study these combinations further,” the authors concluded.