Vistusertib/Paclitaxel Appears Safe With No OS Benefit in Ovarian Cancer

Although combining vistusertib (AZD2014) and weekly paclitaxel was safe and feasible, it did not improve survival in patients with platinum-resistant high-grade ovarian serous carcinoma, according to results from the phase 2 OCTOPUS trial (ISRCTN16426935).

"In what is to our knowledge the first randomized clinical trial of a dual mTORC1/2 inhibitor in ovarian cancer, findings showed that the addition of vistusertib to weekly paclitaxel was safe and achievable in [platinum-resistant high-grade serous carcinoma] but did not improve PFS or OS in an unselected population," according to the study authors.

Investigators reported that there was no difference in progression-free survival (PFS) between the vistusertib (n = 70) and placebo arms (n = 70), with a median PFS of 4.5 months vs 4.1 months in each respective cohort (Hazard ratio [HR], 0.84; 80% CI, 0.67-1.07; P = .18). Additionally, the median overall survival (OS) was 9.7 months vs 11.1 months (HR, 1.21; 80% CI, 0.91-1.60) in each arm, respectively.

“In what is to our knowledge the first randomized clinical trial of a dual mTORC1/2 inhibitor in ovarian cancer, findings showed that the addition of vistusertib to weekly paclitaxel was safe and achievable in [platinum-resistant high-grade serous carcinoma] but did not improve PFS or OS in an unselected population,” the authors wrote. “Potential predictive biomarkers will need to be evaluated in separate study cohorts.”

Investigators designed the randomized, double-blind, placebo-controlled, multi-center trial to determine the safety and efficacy of vistusertib plus paclitaxel compared with paclitaxel alone in those with platinum-resistant high-grade ovarian serous carcinoma. The study included patients who were 18 years of age or older with histologically confirmed disease of the ovary, fallopian tube, or primary peritoneal region that had relapsed following treatment with or was refractory to platinum-based chemotherapy.

One hundred and forty patients were randomly assigned 1:1 to receive either 80 mg/m2 of intravenous paclitaxel weekly on days 1, 8, and 15 plus 50 mg of vistusertib orally twice daily on days 1 to 3, 8 to 10, and 15 to 17 of every 28-day cycle or weekly paclitaxel and placebo.

The primary end point was PFS in the intent-to-treat population. Secondary end points included overall response rate (ORR), OS, and quality of life (QOL).

Patients were enrolled from January 2016 to March 2018 across 20 sites in the United Kingdom. The median patient age was 63 years (range, 36-86). Investigators reported that 53.6% of patients underwent treatment with 3 or more previous lines of therapy. Additionally, 17.9% of patients were refractory to platinum-based chemotherapy.

The ORR by RECIST 1.1 criteria was 29% for in the vistusertib cohort compared with 30% in the placebo cohort. Moreover, ORR by combined RECIST 1.1/CA-125 criteria were 53% vs 54% in each group, respectively (adjusted odds ratio, 0.86; 80% CI, 0.55-1.36).

A total of 136 patients were included in the safety population, including 68 patients in each arm. There was a significant difference in grade 2 or higher adverse effects (AEs) in over 10% of patients between arms. Additionally, 41.2% of patients in the vistusertib arm experienced grade 3/4 AEs compared with 36.7% of those in the placebo arm. Common high-grade AEs in each respective arm included lymphopenia (13% vs 9%) and fatigue (9% vs 4%).

Several toxicities were more common in the experimental arm compared with the placebo arm, including grade 1/2 gastroesophageal reflux (10% vs 0%), grade 2/3 rash (9% vs 0%), and grade 2 to 4 lymphopenia (47% vs 31%).

Investigators included 126 patients in the QOL analysis. The overall completion rate up to and including week 28 was 79.3%. Reportedly, there were no statistically significant differences in QOL between treatment arms for EQ-5D index or EQ-5D visual analog scale.

Reference

Banerjee S, Giannone G, Clamp AR, et al. Efficacy and safety of weekly paclitaxel plus vistusertib vs paclitaxel alone in patients with platinum-resistant ovarian high-grade serous carcinoma. JAMA Oncol. Published online March 16, 2023. doi:10.1001/jamaoncol.2022.7966