Despite the use of current first-line treatment i.e., the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for diffuse large B-cell lymphoma (DLBCL), the rates of relapse remain high.¹ Eventually, there came a breakthrough on April 19, 2023, when the United States (US) Food and Drug Administration (FDA) approved polatuzmumab vedotin for the treatment of these patients, which stands to change the front-line regimen from R-CHOP.^2,3 This approval was based on the positive results of the POLARIX trial, demonstrating a significantly longer progression-free survival (PFS) without additional safety concerns.^2,3,4  

DLBCL represents up to 48.4% of all non-Hodgkin lymphoma (NHL) cases in the Asian population.5 R-CHOP was first approved in 2006, offering a cure as the first-line treatment for 60%-70% of patients, but the rest develops resistance and experiences subsequent relapse or refractory disease.^1,6 Over the past 2 decades, numerous approaches including intensifying chemotherapy, the use of second-generation anti-cluster of differentiate (CD)20 monoclonal antibodies (mAbs), the incorporation of novel agents or the addition of maintenance therapy have not shown meaningful improvements in survival outcomes until polatuzumab vedotin is approved.³   

Polatuzumab vedotin is a drug-antibody conjugate that consists of 3 components, including a mAb portion binds to CD79b, a stable protease-cleavable linker, monomethyl auristatin E (MMAE).³ Its efficacy and safety were proven in the POLARIX trial, a double-blinded, randomized, placebo-controlled, international phase 3 trial conducted in previously untreated adult patients with CD20-positive DLBCL.³ These patients had an International Prognostic Index (IPI) score between 2-5 and an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0-2.3 A total of 879 patients were randomized 1:1 to receive R-CHOP (n=439) for 6 cycles or polatuzumab vedotin (Pola), rituximab, cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP; n=440) with matching placebos for polatuzumab vedotin and vincristine,  respectively.³ Vincristine was excluded from the R-CHOP regimen as it had overlapping neurologic toxicities with polatuzumab vedotin.³ Both arms were followed by 2 cycles of rituximab 375kg/m² monotherapy.³ Randomization was stratified by the IPI score, the presence of bulky disease, as well as geographic region.³ The primary endpoint was PFS, while the secondary endpoints included overall survival (OS), event-free survival (EFS), the complete response (CR) by positron emission tomography and computed tomography (PET-CT), and safety.³ 

At a median follow-up of 28.2 months for investigator-assessed PFS, polatuzumab vedotin showed a 27% reduction in the risk of progression, relapse, or death (HR=0.73; 95% CI: 0.57-0.95; p=0.02) in the intention-to-treat (ITT) population when compared with R-CHOP.³ The 24-month PFS rate of Pola-R-CHP was slightly higher at 76.7% (95% CI: 72.7-80.8) vs. 70.2% (95% CI: 65.8-74.6) with R-CHOP.³ When stratified by the IPI score, the PFS benefit is maintained even among patients with poorer prognosis.⁴ The 24-month PFS rate of Pola-R-CHP among patients with an IPI score of 3-5 was 75.2% vs. 65.1% with R-CHOP (HR=0.7; 95% CI: 0.5-0.9).⁴  

Overall, no additional safety concerns were noted in the Pola-R-CHP arm.³ Adverse events (AEs) of any grade were reported in 97.9% and 98.4% of the Pola-R-CHP and R-CHOP arms respectively, of which 60.7% and 59.8% were grade 3-4.³ Serious AEs were reported in 34.0% and 30.6% of the patients, with fatalities recorded at 3.0% and 2.3% in the Pola-R-CHP and R-CHOP arms, respectively.³ Notably the incidence of peripheral neuropathy did not differ significantly between the 2 arms, with the overall rates of 52.9% vs. 53.9% and only 1.6% and 1.1% being grade 3-4, respectively.³ Fewer patients in the Pola-R-CHP arm had AEs leading to dose reductions (9.2% vs. 13.0%).³ A higher percentage of patients stayed on the treatment with Pola-R-CHP.³  

In conclusion, results from the POLARIX trial have demonstrated a significant PFS benefit of Pola-R-CHP over the traditional R-CHOP with no additional safety concerns for DLBCL patients in the first-line setting.^2,3