As reported in the Journal of Clinical Oncology by Kathleen N. Moore, MD, and colleagues,1 the phase III IMagyn050/GOG 3015/ENGOT-OV39 trial has shown that the addition of atezolizumab to bevacizumab and chemotherapy did not significantly improve progression-free survival in patients with newly diagnosed stage III or IV ovarian cancer—among all patients or among those with PD-L1–positive disease.
The double-blind trial included 1,301 patients from sites in North and South America, Europe, Asia, and Australia who had undergone primary cytoreductive surgery with macroscopic residual disease or were planned to receive neoadjuvant chemotherapy and interval surgery. They were randomly assigned between March 2017 and March 2019 to receive atezolizumab (n = 651) or placebo (n = 650), both in combination with bevacizumab plus chemotherapy. Treatment consisted of atezolizumab at 1,200 mg or placebo every 3 weeks on day 1 of cycles 1 to 22; paclitaxel at 175 mg/m2 and carboplatin at AUC 6 on day 1 during cycles 1 to 6; and bevacizumab at 15 mg/kg on day 1 during cycles 2 to 22. Bevacizumab was omitted during perioperative cycles among patients receiving neoadjuvant chemotherapy and interval surgery.
Kathleen N. Moore, MD
The co-primary endpoints were investigator-assessed progression-free survival and overall survival in the intention-to-treat population and in the PD-L1–positive population; the PD-L1–positive population consisted of 784 patients (60% of total population; 391 in the atezolizumab group and 393 in the placebo group) with tumor PD-L1–expressing immune cells ≥ 1%. For progression-free survival analysis, a P value of .002 was considered significant. Overall survival was to be formally tested if progression-free survival outcomes achieved significance.
At data cutoff for the primary analysis (March 2020), the median durations of follow-up were 19.9 months in the atezolizumab group and 19.8 months in the placebo group (interquartile range [IQR] = approximately 15–24 months for both); in the PD-L1–positive population, median follow-up was 19.6 months and 19.4 months (IQR = approximately 15–23 months for both).
Median progression-free survival was 19.5 months (95% confidence interval [CI] = 18.1–20.8 months) in the atezolizumab group vs 18.4 months (95% CI = 17.2–19.8 months) in the placebo group in the intention-to-treat population (hazard ratio [HR] = 0.92, 95% CI = 0.79–1.07, P = .28) and 20.8 months (95% CI = 19.1–24.2 months) vs 18.5 months (95% CI = 16.6–21.4 months) in the PD-L1–positive population (HR = 0.80, 95% CI = 0.65–0.99, P = .038). Rates of progression-free survival at 2 years were 35.1% vs 29.1% in the intention-to-treat population and 43.9% vs 32.2% in the PD-L1–positive population.
In a prespecified exploratory analysis, a potential benefit in progression-free survival with atezolizumab was observed among 260 patients (20% of the entire population) with PD-L1 expression on ≥ 5% of immune cells. Median progression-free survival was not reached among atezolizumab patients vs 20.2 months among placebo patients (HR = 0.64, 95% CI = 0.43–0.96).
Immature overall survival results at interim analysis showed no benefit with atezolizumab.
The overall survival rates at 2 years were 81% vs 79% in the intention-to-treat population and 82% vs 83% in the PD-L1–positive population. Follow-up for overall survival is ongoing.
Grade 3 or 4 adverse events occurred in 79% of patients in the atezolizumab group vs 73% of patients in the placebo group, with the most common being neutropenia (21% vs 21%), hypertension (18% vs 20%), and anemia (12% vs 12%). Serious adverse events occurring in at least 2% of patients consisted of febrile neutropenia (8% vs 4%) and pyrexia (4% vs 1%). Adverse events led to discontinuation of any treatment in 26% vs 22% of patients.
Potential immune-mediated adverse events with a numerical difference between treatment groups included rash (any grade = 41% vs 26%, grade 3 or 4 in 6% vs 1%), hypothyroidism (any grade = 26% vs 13%, grade 3 or 4 in 0.5% vs 0.2%), infusion-related reactions (any grade = 12% vs 8%), and hyperthyroidism (grade 1 or 2 in 8% vs 4%, no grade ≥ 3). Grade ≥ 3 cutaneous reactions were reported in 1% of the atezolizumab group vs no patients in the placebo group. One patient in the atezolizumab group died of a potential immune-mediated adverse event (myasthenia gravis).
The investigators noted: “IMagyn050 showed no significant progression-free survival improvement in patients with PD-L1–positive tumors defined as immune cells ≥ 1%. However, in an exploratory analysis using a threshold of PD-L1 immune cells ≥ 5% (the cutoff used in urothelial carcinoma, representing 20% of the [intention-to-treat] population in IMagyn050), the hazard ratio was 0.64 (95% CI = 0.43–0.96). This intriguing signal may warrant further evaluation of atezolizumab in a population with high PD-L1 expression.”
They concluded: “Current evidence does not support the use of immune checkpoint inhibitors in newly diagnosed ovarian cancer. Insight from this trial should inform further evaluation of immunotherapy in ovarian cancer.”
Disclosure: The study was supported by F. Hoffmann–La Roche/Genentech. Dr. Moore has received honoraria from Physician Education Resource, Prime Oncology, Research To Practice; has served as a consultant or advisor to Abbvie, Aravive, AstraZeneca, Eisai, Genentech/Roche, Immunogen, Merck, Mersana, Myriad Genetics, Pfizer/EMD Serono, Tesaro, Vavotar, and VBL Therapeutics; and has received research funding from Abbvie/Stemcentrx, Advaxis, Agenus, AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis Oncology, Forty Seven, Genentech, Immunogen, Lilly, Lilly Foundation, Merck, Novartis Pharmaceuticals UK Ltd., Novogen, PTC Therapeutics, Regeneron, Stem CentRx, Takeda, Tesaro, and Verastem.
1. Moore KN, Bookman M, Sehouli J, et al: Atezolizumab, bevacizumab, and chemotherapy for newly diagnosed stage III or IV ovarian cancer: Placebo-controlled randomized phase III trial (IMagyn050/GOG 3015/ENGOT-OV39). J Clin Oncol 39:1842-1855, 2021.