Surrogacy Endpoint for PFS in Follicular Lymphoma Identified

Complete response at 30 months (CR30) may be a useful surrogate endpoint for progression-free survival (PFS) in trials of first-line follicular lymphoma treatments, according to the results of a pooled analysis of chemotherapy, immunotherapy, and chemoimmunotherapy trials published recently in the Journal of Clinical Oncology.

“The analysis demonstrated that treatment effects on CR30 strongly predict treatment effects on PFS,” wrote researcher Qian Shi, PhD, of Mayo Clinic, Rochester, Minnesota, and colleagues. “The results are highly consistent across various surrogacy estimation methods and sensitivity analyses. The strong association was maintained irrespective of the inclusion of rituximab in the regimen or whether the trials involved random assignment at induction or maintenance.”

According to the study, PFS is the principal endpoint for the regulatory approval of new agents for follicular lymphoma. However, because of the indolent nature of the disease, the median PFS in many clinical trials may be as long as 6 to 8 years, limiting “the ability to expeditiously provide new effective therapeutic options.”

With this analysis, Shi and colleagues wanted to identify alternative endpoints that could be measured earlier in the course of the disease and could reliably predict PFS. They conducted a prospectively planned pooled analysis of data from 3,837 patients included in 13 randomized multicenter trials of induction and maintenance regimens in first-line follicular lymphoma published after 1990.

They used both linear regression (R²_WLS) and bivariate copula (R²_Copula) models to correlate CR30 odds ratios with the PFS hazard ratio (HR). Prespecified criteria for surrogacy required either R²_WLS or R²_Copula of 0.80 or greater.

According to the researchers, the prespecified surrogacy threshold was met with an R²_WLS of 0.88 (95% CI, 0.77–0.96) and an R²_Copula of 0.86 (95% CI, 0.72–1.00). A minimum 11% absolute improvement in CR30 from a 50% control rate predicted a significant treatment effect on PFS (HR, 0.69).

“The relationship between CR30 and PFS was maintained across all evaluated trials, including induction-only trials, which suggests that even if standard-of-care treatment changes from a 30-month total course, the endpoint will be robust for therapeutic strategies that seek durable complete response,” the researchers wrote. “These findings support CR30 as appropriate for use as a primary study endpoint in patients with previously untreated follicular lymphoma, with the intent of bringing novel therapies to this patient population years before PFS results are available.”