Giving the Axe to R-CHOP?

A phase III, multicenter, randomized, double-blinded, placebo-controlled trial comparing the efficacy and safety of polatuzumab vedotin in combination with rituximab and CHP (R-CHP) versus rituximab and CHOP (R-CHOP) in previously untreated patients with diffuse large B-cell lymphoma (POLARIX)

NCT03274492

Hoffman-La Roche

More than 250 centers in the United States, Australia, Europe, Canada, New Zealand, and Asia

This is a randomized, placebo-controlled, double-blind phase III study investigating the safety and efficacy of the anti-CD79b antibody drug conjugate, polatuzumab, in combination with rituximab plus cyclophosphamide, doxorubicin, and prednisone (R-CHP) versus rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in previously untreated patients with diffuse large B-cell lymphoma (DLBCL). All patients with an International Prognostic Index (IPI) score of 2 or higher are eligible. Approximately 875 patients will be randomly assigned in a 1:1 fashion to the two treatment arms, after which an additional cohort of 300 patients from China will be randomly assigned in a China-extension cohort. Randomization will be stratified by IPI score, by disease bulk, and by the region of the world in which they are being treated. All patients will receive six cycles of chemotherapy at 21-day intervals followed by two additional doses of single-agent rituximab. The primary objective of this study is to determine the efficacy of polatuzumab plus R-CHP compared with R-CHOP with respect to progression-free survival. Secondary objectives include additional measures of efficacy and safety of therapy, and pharmacokinetics of polatuzumab. Exploratory objectives include biomarker and pharmacokinetic analyses.

R-CHOP has been the standard of care for the treatment of DLBCL since 2006 based on the results of the MInT trial¹  and on results in durable remissions in approximately 65 percent of patients. Patients with high IPIs, double- and triple-hit cytogenetics, and activated B-cell subtype have inferior outcomes with this regimen. Several attempts to improve R-CHOP, including the addition of drugs such as ibrutinib and bortezomib as well as with regimens such as dose-adjusted R-EPOCH (rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), have been unsuccessful when tested in a randomized manner against standard R-CHOP. Polatuzumab vedotin is an antibody against CD79b conjugated to the microtubule inhibitor MMAE that has activity in relapsed/refractory DLBCL as a single agent and in combination with chemotherapy, with complete response rates up to 40 percent when combined with bendamustine and rituximab.²  Polatuzumab has been combined with R-CHP in a phase II study for the treatment of previously untreated DLBCL, with overall and complete response rates of 91 percent and 78 percent, respectively. Responses were comparable regardless of cell of origin determination.³  Vincristine was removed from the R-CHOP backbone in this combination owing to an overlapping risk of neuropathy with polatuzumab. It is based on the promising results that this phase III, randomized, double-blind, placebo-controlled trial was initiated.

Although DLBCL is a curable mature lymphoid malignancy in over half of patients, there remains room for improvement with the greater-than-a-decade-old regimen, R-CHOP. This is especially true for high-risk patients with high IPIs, double- and triple-hit cytogenetics, and the activated B-cell subtype. The discovery of multiple new targeted drugs with activity in these high-risk groups, both as single agents and in combination with an R-CHOP–like backbone, in phase II studies has prompted great enthusiasm for, and anticipation of, the results of phase III studies comparing these combinations to standard R-CHOP. Unfortunately, to date, randomized studies of these combinations with ibrutinib and bortezomib have been met with disappointment, as have randomized studies of alternative regimens such as dose-adjusted R-EPOCH. Although the activity of polatuzumab, both as a single agent and in combination with chemotherapy, makes it the next culprit to combine with an R-CHOP–like backbone, one could argue that history is likely to repeat itself and the results of the POLARIX study will once again disappoint. However, there are reasons to be more hopeful this time around. The activity of this drug in the relapsed/refractory setting is higher than any of the agents that have come before it and its target (CD79b) is more ubiquitous in this heterogeneous group of lymphomas. Furthermore, the addition of antibody-drug conjugates to upfront chemotherapy backbones already has a positive track record, with the results of the recent randomized ESCHELON-1 trial leading to the U.S. Food and Drug Administration approval of brentuximab in combination with doxorubicin, vinblastine, and dacarbazine for the first-line treatment of advanced stage Hodgkin lymphoma. It may be naïve, but the field once again awaits the results of this important study to hopefully confirm the activity of this drug in this disease and to establish a new standard for the upfront treatment of the most common lymphoma.