Hope for a New Standard of Care for Newly Diagnosed Diffuse Large B-Cell Lymphoma Free

STUDY TITLE: An Open-Label Study Comparing Glofitamab and Polatuzumab Vedotin + Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone Versus Pola-R-CHP in Previously Untreated Patients with Large B-Cell Lymphoma

CLINICALTRIALS.GOV IDENTIFIER: NCT06047080

PARTICIPATING CENTERS: 268 locations worldwide

SPONSOR: Hoffmann-La Roche

ACCRUAL GOAL: 1,130 randomized participants between two arms

STUDY DESIGN: The goal of this open-label, randomized phase III study is to evaluate the efficacy and safety of the bispecific antibody glofitamab in combination with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) compared to Pola-R-CHP in patients with untreated CD20-positive, International Prognostic Index (IPI) 2-5 diffuse large B-cell lymphoma (DLBCL). The primary endpoint of the study is progression-free survival (PFS), defined as from randomization to the first occurrence of disease progression or relapse (or death due to any cause), whichever occurs first during the predefined time period of approximately 65 months. Important secondary endpoints include event-free survival, overall survival (OS), duration of response, duration of complete response, and quality-of-life assessments.

RATIONALE: DLBCL is the most common lymphoma in the U.S. and western Europe, accounting for approximately 30% of all cases diagnosed.¹  The treatment for DLBCL improved dramatically with the addition of the monoclonal antibody rituximab to the backbone of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).²  This was the standard of care (SOC) in patients aged 80 years and less for more than 20 years, with approximately two-thirds of patients being cured. Due to disparate outcomes based on disease subset, difficulty salvaging those with primary refractory disease, and an overall aim to improve the fraction of patients cured, several attempts have been made to improve upon R-CHOP.³  The POLARIX study,⁴  which substituted the drug antibody conjugate polatuzumab for vincristine (the O in the CHOP backbone), was the first phase III trial to demonstrate an improvement in overall PFS as compared to R-CHOP. This established Pola-R-CHP as an option for patients with untreated DLBCL with an IPI score of 2-5. However, due to a lack of OS benefit as compared to R-CHOP, as well as disparate outcomes based on cell of origin, this regimen did not fully “dethrone” R-CHOP as the standard of care for frontline DLBCL.

The CD20/CD3 bispecific antibodies have made significant impacts on several non-Hodgkin lymphoma subtypes, including DLBCL. Two agents have been approved in third-line or later DLBCL — glofitamab and epcoritamab.^5,6  As approved, glofitamab is a time-limited therapy given every three weeks after initial step-up dosing.⁶  Given the toxicity profile of this class of drugs, they have proven to be combinable with other agents, including chemotherapy.⁷  Considering this factor and the efficacy noted in highly refractory DLBCL, attempts to move these agents into earlier lines of therapy have garnered significant interest. Phase II studies have reported promising efficacy and encouraging safety when CD20/CD3 bispecifics have been combined with a CHOP-like backbone in untreated DLBCL.^8,9  Most encouraging is that the regimen appears to be agnostic to cell of origin. Unfortunately, there is a proverbial graveyard full of promising challengers to R-CHOP from phase II studies that ultimately fell flat when a randomized phase III study was conducted.^10,11  Therefore, despite the promise of glofitamab, a randomized phase III study is the only way to fully determine if it will add any substantial benefit to the Pola-R-CHP backbone.

COMMENT: Improving the efficacy of R-CHOP has proven more difficult than anticipated given the numerous failed randomized phase III studies conducted over the last 20 years. Even now with POLARIX, the first trial to meet its primary endpoint, there is still some resistance to applying the Pola-R-CHP regimen to all patients who would have been eligible for this study. This is driven by the lack of an OS benefit, as well as the results noted in those with germinal center B-cell (GCB) subtype. As such, it has opened up the possibility for use of Pola-R-CHP in those with non-GCB DLBCL and R-CHOP for those with GCB DLBCL. The SkyGLO study, with the addition of glofitamab to the experimental arm, provides an avenue to hopefully establish a new SOC for untreated DLBCL, as well as establish the safety of this bispecific antibody in untreated patients, who in theory should have a healthier immune system and be able to generate a more robust T-cell response compared to those with relapsed/refractory disease. The study is open and accruing. We will anxiously await the results of this potentially practice-changing study.