Abstract
In April 2023, the U.S. FDA granted regular approval to polatuzumab vedotin-piiq in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (pola+R-CHP) for adult patients who have previously untreated diffuse large B-cell lymphoma, not otherwise specified, or high-grade B-cell lymphoma and who have an International Prognostic Index score of 2 or greater. Approval was based on POLARIX, a randomized, double-blinded, placebo-controlled trial evaluating the superiority of substituting vincristine with polatuzumab vedotin in the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone regimen as first-line therapy for patients with large B-cell lymphoma. Efficacy was based on investigator-assessed progression-free survival (PFS) in 879 patients who were randomized to receive pola+R-CHP or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, followed by two cycles of rituximab alone. PFS was statistically significantly longer with pola+R-CHP, with an HR of 0.73 (95% confidence interval, 0.57-0.95) and log-rank P value of 0.0177 (two-sided α = 0.05). There was no improvement demonstrated in the key secondary endpoints of the complete response rate at the end of therapy or overall survival (OS). Several issues raised uncertainty about the benefit-risk profile of polatuzumab vedotin in this curative-intent setting, including the modest PFS benefit of pola+R-CHP and lack of OS benefit. The application was therefore presented at an Oncology Drugs Advisory Committee. This article summarizes key aspects of the regulatory review, including perspectives on PFS and OS results and other endpoints.