Polatuzumab vedotin plus R-CHP as first line treatment for patients with diffuse large B-cell lymphoma
The phase III POLARIX study demonstrated that the addition of polatuzumab vedotin to rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) results in a 27% reduction in the relative risk of disease progression, relapse, or death as compared to the standard of care, R-CHOP, with a similar safety profile in the first-line treatment of patients with diffuse large B-cell lymphoma.
For over 20 years, rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) has been the standard of care frontline treatment for patients with diffuse large B-cell lymphoma (DLBCL). However, only 60-70% of patients are cured with R-CHOP. Over the years, numerous attempts to improve on the outcomes obtained with R-CHOP failed. As a result, there remains to be an unmet need for patients with previously untreated DLBCL.
Polatuzumab vedotin is a CD79b-targeting antibody drug conjugate (ADC) already approved in the relapsed DLBCL setting. Polatuzumab vedotin demonstrated promising first-line activity and safety when combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) in a Phase Ib/II study. Based on these findings, the phase III POLARIX study (NCT03274492) now compared pola-R-CHP with R-CHOP in patients with previously untreated DLBCL.
Study design
POLARIX is a double-blind, placebo-controlled, international study in patients with previously untreated DLBCL, an ECOG performance status of 0-2 and an International Prognostic Index (IPI) of 2–5. Enrolled patients were randomised (1:1) to receive six cycles of pola-R-CHP (with a vincristine placebo) or R-CHOP (with a polatuzumab vedotin placebo). All patients also received two additional cycles of rituximab. Patients received polatuzumab vedotin (1.8 mg/kg) or vincristine (1.4 mg/m²) administered on Day 1, plus intravenous rituximab (375 mg/m2), cyclophosphamide (750 mg/m²), doxorubicin (50 mg/m²), and placebo on Day 1, and oral prednisone 100 mg once daily on Days 1–5. The primary endpoint was investigator-assessed progression-free survival (PFS).
Results
Overall, 879 patients were randomised, 440 to pola-R-CHP and 439 to R-CHOP. Median age was 65 (range 19–80) years, and the majority of patients had an IPI 3–5 disease (62.0%).
After a median follow-up of 28.2 months, POLARIX met its primary endpoint of an improved PFS with pola-R-CHP vs R-CHOP (HR[95%CI]: 0.73[0.57-0.95], p< 0.02). At 24 months, the PFS rates were reported 76.7% for pola-R-CHP and 70.2% with R-CHOP. Event-free survival outcomes were consistent with those observed for PFS, with a hazard ratio of 0.75 (95%CI: 0.58-0.96, p= 0.02). Overall response rates did not significantly differ between pola-R-CHP and R-CHOP. However, disease-free survival results indicated that patients who achieved a complete response with pola-R-CHP were more likely to maintain in remission compared to those who achieved a complete response with R-CHOP (HR[95%CI]: 0.70[0.50-0.98]). There was no difference in overall survival between the two treatment groups (p= 0.75).
At two years, 88.6% of patients were alive in both groups. At the time of data cut-off, 22.5% and 30.3% of patients in the pola-R-CHP and R-CHOP arms, respectively, had received at least one subsequent anti-lymphoma therapy. Fewer patients in the pola-R-CHP than the R-CHOP arm received subsequent anti-lymphoma treatments (radiotherapy, 9.3% vs. 13.0%; stem cell transplantation, 3.9% vs. 7.1%; chimeric antigen receptor T-cell therapy, 2.0% vs. 3.6%).
The safety profile was comparable for pola-R-CHP vs. R-CHOP, with similar rates of grade 3–4 adverse events (AEs; 57.7% vs. 57.5%), serious AEs (34.0% vs. 30.6%), grade 5 AEs (3.0% vs. 2.3%), and AEs leading to dose reduction (9.2% vs. 13.0%). Also the frequency and severity of peripheral neuropathy was similar for pola-R-CHP and R-CHOP (any grade, 52.9% vs. 53.9%; grade 3–4, 1.6% vs. 1.1%).
Conclusion
Pola-R-CHP significantly prolongs the PFS compared to R-CHOP in patients with intermediate and high-risk previously untreated DLBCL. In addition, the safety profiles of pola-R-CHP and R-CHOP were comparable. Overall survival was not different in this analysis, but the burden of additional treatment was higher for patients in the R-CHOP arm. These results support the use of Pola-R-CHP in the initial management of patients with DLBCL.
Reference
Tilly H, et al. The POLARIX Study: Polatuzumab Vedotin with Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (pola-R-CHP) Versus Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP) Therapy in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma. Presented at ASH 2021; Abstract LBA1.
