Bispecific Antibodies in Frontline Large B-cell Lymphoma: Can We Do Better Than Pola-R-CHP?

STUDY TITLE: A Phase III, Multicenter, Randomized, Open-Label Study Comparing the Efficacy and Safety of Glofitamab (RO7082859) in Combination with Polatuzumab Vedotin Plus Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (Pola-R-CHP) Versus Pola-R-CHP in Previously Untreated Patients With Large B-Cell Lymphoma

CLINICALTRIALS.GOV IDENTIFIER: NCT06047080

PARTICIPATING CENTERS: International study with 128 participating centers in the United States, Europe, Australia, and Asia

SPONSOR: Hoffmann-La Roche

ACCRUAL GOAL: 1,130 patients

STUDY DESIGN: This is a phase III, open-label, multicenter clinical trial designed to compare the safety and efficacy of administering glofitamab (a bispecific T-cell engager [BsAb] targeting CD20 and CD3) in combination with polatuzumab vedotin (an antibody-drug conjugate targeting CD79b), rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) versus pola-R-CHP in patients with previously untreated CD20-positive large B-cell lymphoma (LBCL). The primary outcome measure of the trial is progression-free survival (PFS). The secondary outcome measures include event-free survival (EFS), complete response (CR) rates, objective response rates (ORR), overall survival (OS), duration of response, and durations of CR and DFS. This trial will also measure participants’ quality of life via the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-30) and the Functional Assessment of Cancer Therapy – Lymphoma (FACT-Lym LymS) questionnaire.

RATIONALE: For more than two decades, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has been the standard frontline treatment for LBCL. This regimen achieves cure rates of 60 to 70%.¹ 

Attempts to improve upon the backbone of R-CHOP include dose intensification and the addition of novel agents, but these have shown limited benefit. A notable exception has been the randomized phase III POLARIX trial which enrolled patients with previously untreated LBCL with International Prognostic Index scores of 2 or higher. Participants were randomized to receive six cycles of R-CHOP or pola-R-CHP.²  Vincristine was omitted due to its overlapping toxicity profile with polatuzumab vedotin. The rate of two-year PFS was superior in the pola-R-CHP arm than the R-CHOP arm (76.7% vs. 70.2%), with a comparable safety profile. These findings led to the approval of polatuzumab vedotin in the frontline setting and establishing pola-R-CHP as a standard option.

Bispecific T-cell engagers (BsAb) targeting CD20 and CD3 have demonstrated safety and efficacy in patients with relapsed/refractory LBCL.³  In June 2023, the U.S. Food and Drug Administration granted accelerated approval to glofitamab, an anti-CD20/CD3 BsAb, based on the results of a pivotal phase II study that enrolled 155 patients with relapsed/refractory LBCL, including some patients who had prior chimeric antigen receptor T-cell therapy.^4,5  Patients received obinutuzumab to mitigate the risk of cytokine release syndrome (CRS), followed by step-up dosing of glofitamab. After a median follow-up of 12.6 months, the ORR was 52%, with a CR of 39%, and the rate of 12-month PFS was 37%.⁵  The most common adverse event (AE) was CRS, which occurred in 63% of the patients and was primarily grade 1 to 2. Grade 3 or higher AEs occurred in 62% of patients, including CRS in 4% of patients and neurologic events in 3%.

Preclinical studies have shown BsAbs to be effective when co-administered with cytotoxic agents such as cyclophosphamide.⁶  Although the T-cell numbers are decreased with chemotherapy, the surviving T cells are still activated upon engagement by the BsAb.⁷  Several studies combining BsAb with chemotherapy or targeted therapies are ongoing, with the goal of improving outcomes in patients with relapsed/refractory LBCL. For example, glofitamab has been studied in combination with polatuzumab vedotin, with an ORR of 80% and CR of 51%.⁸  Epcoritamab, another CD20/CD3 BsAb, has been found to be effective when combined with a salvage chemotherapy regimen of rituximab, gemcitabine, and oxaliplatin, showing an ORR of 92% and a CR rate of 60%.⁹ 

Given the encouraging results seen in relapsed/refractory LBCL, BsAbs have been studied in the frontline setting. A phase Ib study combining glofitamab with R-CHOP enrolled 56 patients and reported an ORR of 93% and a CR rate of 84%.¹⁰  This combination was tolerable, with CRS reported in 25% of patients. No cases of grade 3/4 CRS were reported. Similar studies are being designed using other BsAbs, such as mosunetuzumab and epcoritamab in combination with cytotoxic chemotherapy (Table). It is worth noting that, in these combination trials, the addition of BsAbs to chemotherapy or antibody drug conjugates has so far not significantly interfered with timely delivery of chemotherapy nor produced new adverse safety signals.

COMMENT: Clinical trials designed to improve outcomes of patients with LBCL have met with limited success until recently. Pola-R-CHP is the first regimen to show an improvement in PFS over R-CHOP. Pola-R-CHP can potentially serve as a platform for building therapies to further improve efficacy. Many targeted therapies have failed to make an impact in the frontline setting, likely due to the molecular heterogeneity of LBCL. Immunotherapy may provide an opportunity to overcome the barriers posed by the molecular heterogeneity of LBCL and improve efficacy. Because polatuzumab vedotin and glofitamab have non-overlapping toxicities, they can potentially be combined in frontline therapy. If glofitamab in combination with pola-R-CHP proves to be tolerable with improved efficacy compared to standard pola-R-CHP, this study could potentially advance BsAb into the frontline management of LBCL.