Polatuzumab-Based Combo Outperforms R-CHOP in Untreated Diffuse Large B-Cell Lymphoma
Standard treatment for diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma, is a regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, up to 40% of patients are refractory to R-CHOP or relapse after initial response to treatment. Researchers have investigated alternative approaches, including intensifying either the chemotherapy or rituximab portions of treatment, adding maintenance therapies, or trying novel agents, none of which have resulted in a meaningful improvement of treatment outcomes. Recently, polatuzumab vedotin, an anti-CD79b antibody–drug conjugate (ADC), has shown promise in DLBCL – both as a single agent and in combination with rituximab and rituximab/bendamustine in patients with relapsed/refractory DLBCL. In the POLARIX study, investigators assessed the efficacy and safety of polatuzumab vedotin in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) compared with R-CHOP, in patients with treatment-naïve DLBCL. The results of this randomized, double-blind, placebo-controlled, international, phase III study were presented at the American Society of Hematology annual meeting in December 2021 and simultaneously published in the New England Journal of Medicine.
In total, 879 adult patients with CD20-positive DLBCL were randomized to receive six cycles of either pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival and safety. After a median follow-up of 28.2 months, 2-year PFS was higher in the pola-R-CHP group at 76.7% vs. 70.2% in the R-CHOP group. The risk of disease progression or death was 27% lower in the pola-R-CHP group (hazard ratio [HR] 0.73; P = 0.02). Interestingly, the results of an exploratory subgroup analysis varied based on demographic and disease characteristics. Clear PFS benefit for pola-R-CHP was seen in patients older than 60 years, those who had an International Prognostic Index score of 3–5, and those with the activated B-cell-like subtype of DLBCL, but not in other subgroups. Overall survival was nearly identical in both groups at 88.7% in pola-R-CHP and 88.6% in R-CHOP (HR 0.94, P = 0.75). Similarly, the percentage of patients who achieved a complete response (CR) at the end of treatment were comparable: 78.0% in the pola-R-CHP group and 74.0% in the R-CHOP group (P = 0.16). However, investigators found that patients who had a CR following pola-R-CHP treatment were more likely to remain in remission than those in the R-CHOP group (HR 0.70).
In general, the safety data were similar in both groups. As expected, the safety profile of pola-R-CHP was consistent with the known safety profiles of the individual drugs. Neutropenia, febrile neutropenia, and anemia were the most common grade 3 or 4 adverse events (AEs) reported. About one-third of patients in both groups experienced serious AEs (34% with pola- R-CHP vs. 30.6 % with R-CHOP). Treatment-related AEs leading to death, most related to infection, occurred in both groups: 13 patients in the pola-R-CHP group and 10 in the R-CHOP group. Despite the occurrence of peripheral neuropathy as an expected AE with the polatuzumab ADC, the incidence did not differ between the pola-R-CHP and R-CHOP groups (52.9% vs. 53.9%), and most were grade 1. In their conclusion, the authors emphasized the PFS benefit of pola-R-CHP over R-CHOP and pointed out the need for longer follow-up to confirm that the 2-year remissions are durable and impact overall survival.
Tilly H, et al. N Engl J Med. 2021 Dec 14. [Online ahead of print.]