Everolimus Failed to Improve Disease-Free Survival for DLBCL

Adjuvant everolimus did not improve disease-free survival in patients with diffuse large B-cell lymphoma (DLBCL) and confirmed complete response after 1 year of rituximab treatment, according to the results of the PILLAR-2 study published in Annals of Oncology.

“Despite the strong rationale for targeting the PI3K/mTOR pathway with everolimus in patients with high-risk DLBCL, results of the current study failed to demonstrate a significant improvement in disease-free survival with adjuvant everolimus in this patient population who were in a PET-negative remission after rituximab-based chemotherapy,” wrote Thomas E. Witzig, MD, of the Mayo Clinic in Rochester, Minnesota, and colleagues.

However, the researchers did note that there was “a separation of the Kaplan-Meier curves for disease-free survival during the first 18 months, although hazard ratios (95% CIs) and Kaplan-Meier estimates of overall survival and lymphoma-specific survival indicated that everolimus did not significantly improve either outcome.”

According to the study, patients with high-risk DLBCL are at a higher risk for relapse even after achieving complete response to first-line rituximab.

The trial included 742 patients with high-risk DLBCL with PET/CT-confirmed complete response after first-line treatment with rituximab. Patients were randomly assigned to 1 year of everolimus 10 mg per day or placebo. Forty-seven percent of patients were older than 65 years, 50% were men, and 42% had an International Prognostic Index of 4 or 5.

After a median follow-up of 50.4 months, about half of patients (48%) completed treatment with everolimus and 67% completed treatment with placebo. The main reasons for everolimus discontinuation compared with placebo were adverse events (30% vs 12%) and relapsed disease (6% vs 13%).

No significant improvement in disease-free survival was seen with everolimus compared with placebo (hazard ratio, 0.92; 95% CI, 0.69–1.22; P = .276). Treatment on either arm resulted in a disease-free survival rate of about 77%.

The most commonly reported adverse events with everolimus were stomatitis, neutropenia, and decreased CD4 lymphocytes compared with neutropenia, fatigue, and diarrhea with placebo. About half of patients assigned everolimus had grade 3 or worse adverse events compared with about a quarter of patients assigned placebo. Five on-treatment deaths occurred in the everolimus arm compared with two for placebo.

“On-treatment benefit of everolimus could potentially have been sustained with treatment beyond 1 year; however, tolerability of adverse events and motivation for staying on a therapy in the adjuvant setting was generally low,” the researchers wrote.