POLARIX: Pola-R-CHP versus R-CHOP in patients with previously untreated DLBCL

March 2022 Clinical trials Andrea Enguita

Diffuse large B-cell lymphoma (DLBCL) is typically treated with R-CHOP. However, only 60% of patients are cured with this regimen. Therefore, the phase III POLARIX trial evaluated the efficacy and safety of a modified regimen of R-CHOP (pola-R-CHP), in which vincristine was replaced with polatuzumab vedotin, as compared with standard R-CHOP. The risk of disease progression, relapse, or death was lower in patients receiving pola-R-CHP than those receiving R-CHOP.

EXPERT OPINION OF PROF. DR. DOMINIQUE BRON, HAEMATOLOGIST, INSTITUT JULES BORDET

“Among patients with previously untreated intermediate-risk or high-risk DLBCL, the risk of disease progression, relapse, or death was lower among those who received Pola-R-CHP than among those who received R-CHOP.”

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma. The addition of rituximab, an anti-CD20 monoclonal antibody, to the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) has yielded substantial improvement in patient outcomes. Although most patients can be cured with rituximab plus CHOP (R-CHOP), up to 40% of patients will experience refractory disease or relapse after an initial response. Polatuzumab vedotin is an antibody–drug conjugate targeting CD79b, which is ubiquitously expressed on the surface of malignant B cells. A phase Ib–II trial investigated the combination of polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) as first-line therapy for DLBCL. In total, 89% of the patients had an overall response, and 77% had a complete response. The phase III POLARIX trial evaluated the efficacy and safety of pola-R-CHP compared with R-CHOP, in patients with previously untreated DLBCL.

STUDY DESIGN

The POLARIX trial is a randomised, double-blind, placebo-controlled, international phase III trial that enrolled 879 patients. Eligible patients were adults (18-80 years old) with previously untreated intermediate-risk or high-risk CD20-positive DLBCL. Patients were randomised (1:1) to receive six cycles of either pola-R-CHP (N= 440) or R-CHOP (N= 439), plus two cycles of rituximab alone. On day one of each cycle, patients received either intravenous polatuzumab vedotin (1.8 mg/kg) and a placebo matching intravenous vincristine (pola-R-CHP group) or a placebo matching polatuzumab vedotin and intravenous vincristine (1.4 mg/m2) (R-CHOP group), plus intravenous doses of rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), and doxorubicin (50 mg/m2). All patients also received oral prednisone (100 mg once daily on days 1-5 of each of the first six cycles). During cycles seven and eight, both groups received rituximab monotherapy. The primary endpoint was investigator-assessed progression-free survival. Secondary endpoints included overall survival and safety.

RESULTS

After a median follow-up of 28.2 months, the risk of progression, relapse, or death was significantly lower in the pola-R-CHP group than in the R-CHOP group (HR[95%CI]: 0.73[0.57-0.95]; p= 0.02). The percentage of patients surviving without progression at two years was 76.7% in the pola-R-CHP group vs. 70.2% in the R-CHOP group. Two-year event-free survival (EFS) was significantly higher in the pola-R-CHP (75.6%) group than in the R-CHOP group (69.4%) (HR for event or death[95%CI]: 0.75[0.58-0.96]; p= 0.02). The percentage of patients who had a complete response at the end of treatment did not differ significantly between the two groups (78.0% vs. 74.0% in the pola-R-CHP and R-CHOP groups, respectively; p= 0.16). However, the analysis of investigator-assessed disease-free survival indicated that patients who received pola-R-CHP and had a complete response as the best response were more likely to have persistence of remission than those who received R-CHOP and had a complete response (HR for relapse or death[95%CI]: 0.70[0.50-0.98]). Overall survival did not differ significantly between the groups.

The overall safety profile was comparable in the pola-R-CHP and R-CHOP groups, with mostly similar types and incidences of adverse events (AEs). No new safety signals were detected. The most common AEs of grade 3 or 4 were neutropenia (28.3% in the pola-R-CHP group and 30.8% in the R-CHOP group), febrile neutropenia (13.8% and 8.0%, respectively), and anaemia (12.0% and 8.4%, respectively). Adverse events that resulted in death (i.e., AEs of grade 5) were reported in thirteen patients in the pola-R-CHP group and ten patients in the R-CHOP group. These events were primarily related to infections.

CONCLUSION

Among patients with previously untreated DLBCL, treatment with pola-R-CHP resulted in a 27% reduction in the risk of disease progression, relapse, or death, compared to R-CHOP. The overall safety profile was comparable in the pola-R-CHP and R-CHOP groups, with mostly similar AEs types and incidences. No new safety signals were detected, and the safety profile of pola-R-CHP was consistent with the known safety profiles of the individual drugs.

Reference

Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. N Engl J Med. 2022; 386(4):351-63.

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