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Atezolizumab in Patients with Newly Diagnosed Stage III or Stage IV Ovarian Cancer

Conference Correspondent 

Atezolizumab is a monoclonal antibody that targets PD-L1. The IMagyn050A trial was a phase 3, multicenter, double-blind, 2-arm, randomized study examining the safety and efficacy of atezolizumab compared with placebo administered in combination with paclitaxel, carboplatin, and bevacizumab. Participants included in the study were patients with newly diagnosed stage III or stage IV ovarian, fallopian tube, or primary peritoneal cancer, who underwent either primary cytoreductive surgery with gross residual disease or neoadjuvant chemotherapy and interval surgery (this patient subgroup capped at 25% of the total study population). More than 75% of the total patient population had high-grade serous ovarian cancer.

Patients were randomized to either atezolizumab 1200 mg every 3 weeks (n = 650) or placebo for 22 cycles (n = 651), combined with paclitaxel (175 mg/m2) plus carboplatin (at AUC 6; cycles 1-6) and bevacizumab (15 mg/kg for cycles 2-22; with bevacizumab excluded in perioperative cycles). Stratification factors were stage III versus stage IV cancer and European Cooperative Oncology Group performance status of 0 versus 1 or 2. Patients were not stratified by homologous recombination deficiency (HRD) or BRCA status. The primary end points were progression-free survival (PFS) assessed per RECIST and overall survival (OS) in both the intent-to-treat (ITT) population and in the PD-L1–positive population.

The primary end point of improvement of PFS in the ITT population was not met (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.79-1.07] with a median PFS of 19.5 months in the atezolizumab arm and 18.4 months in the placebo arm. PFS in the subgroup of patients with PD-L1–positive tumors was also not significant (HR, 0.80; 95% CI, 0.65-0.99) with a median PFS of 20.8 months in patients receiving atezolizumab (n = 391) and 18.5 months in the placebo arm (n = 393). A subgroup analysis of PFS by baseline characteristic did show a trend toward improvement with atezolizumab treatment in patients with stage III disease. An interim analysis of OS revealed that treatment with atezolizumab did not accord significant benefit in the ITT population (HR, 0.96; 95% CI, 0.74-1.26) or the PD-L1–positive subgroup (HR, 0.98; 95% CI, 0.68-1.41). However, an exploratory analysis for PFS in the subgroup of patients whose tumors had PD-L1 IC ≥5% (defined as the area of PD-L1 stained tumor-infiltrating immune cells as a percentage of the total tumor area) did show a trend favoring atezolizumab treatment (HR, 0.64; 95% CI, 0.43-0.96). The median PFS in this subgroup was 20.2 months in the placebo arm and was not reached in the atezolizumab arm.

The incidence of treatment-emergent adverse events was consistent with previous data with atezolizumab treatment in patients with ovarian cancer. The treatment discontinuation rate due to adverse events (AEs) was comparable between the study arms, with 22% of patients receiving placebo discontinuing due to AEs and 26% of patients receiving atezolizumab doing so. Febrile neutropenia occurred in 8.4% of patients on atezolizumab and in 3.7% of patients in the placebo group. Grade 3 or 4 AEs occurred in 67% and 75% of patients in the placebo and atezolizumab arms, respectively.

Authors concluded that atezolizumab as first-line therapy failed to demonstrate significant activity in patients with newly diagnosed stage III or stage IV ovarian cancer possibly associated with study-related factors, including lack of stratification for HRD/BRCA, timing of PFS assessment, use of PFS as one of the primary study end points, and diagnostic performance limitations of the PD-L1 test. Exploratory biomarker subgroup analyses are ongoing.

Reference

Abstract and Late-Breaking Oral Presentation LBA31. ESMO 2020. September 21, 2020. Primary results from IMagyn050/GOG 3015/ENGOT-OV39, a double-blind placebo (pbo)-controlled randomised phase III trial of bevacizumab (bev)-containing therapy +/- atezolizumab (atezo) for newly diagnosed stage III/IV ovarian cancer (OC).

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