Five-Year Analysis of the POLARIX Study: Prolonged Follow-up Confirms Positive Impact of Polatuzumab Vedotin Plus Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (Pola-R-CHP) on Outcomes
Authors: Salles Gilles , Morschhauser Franck , Sehn Laurie H. , Herrera Alex F. , Friedberg Jonathan W. , Trněný Marek , Lenz Georg , Sharman Jeff P. , Herbaux Charles , Burke John M. , Matasar Matthew , Collins Graham P. , Song Yuqin , Pinto Antonio , Rai Shinya , Izutsu Koji , Lee Calvin , Chohan Saibah , Sugidono Matthew , Jiang Yanwen , Batlevi Connie Lee , Yan Mark , Hirata Jamie , Tilly Hervé , Flowers Christopher R. 
Published: December 2024

Background: In thePOLARIX study (NCT03274492), Pola-R-CHP showed a significant progression-free survival (PFS) benefit vs R-CHOP in patients (pts) with intermediate- or high-risk DLBCL at a median follow-up of 28 months (Tilly et al. NEJM 2022). Here, we report outcomes after 5 years of follow-up (cut-off, 5 July 2024).

Methods: POLARIX methods were published in Tilly et al. NEJM 2022. Pts 18-80 years were randomized 1:1 to receive 6 cycles of Pola-R-CHP or R-CHOP, plus 2 cycles of rituximab. The primary endpoint was PFS. In this analysis, 1000 pts (expanded population) were evaluated; 879 pts (global ITT population) from the main study (enrolled Nov 2017-Jun 2019) and 121 pts from a Chinese extension cohort (enrolled Jul 2019-Dec 2020; Song et al. Blood 2023). Extended follow-up of efficacy and safety are described. A competing risk analysis assessed the risk of death from lymphoma vs other causes.

Results: In the global ITT population, 879 (Pola-R-CHP, n=440; R-CHOP, n=439) and 873 pts (Pola-R-CHP, n=435; R-CHOP, n=438) were evaluable for efficacy and safety, respectively. In the expanded population, 1000 (Pola-R-CHP, n=500; R-CHOP, n=500) and 993 pts (Pola-R-CHP, n=495; R-CHOP, n=498) were evaluable for efficacy and safety, respectively.

In the global ITT population (median follow-up 60.9 months), the 5-year PFS estimates were 64.2% (95% CI: 58.78-69.53) vs 59.1% (95% CI: 53.87-64.40) with Pola-R-CHP vs R-CHOP, showing a significant benefit (HR 0.78; 95% CI: 0.623-0.980). The 5-year OS estimates were 82.2% (95% CI: 78.53-85.82) vs 79.6% (95% CI: 75.70-83.47) with Pola-R-CHP vs R-CHOP, with an improved HR (0.87; 95% CI: 0.641-1.175) compared with the 2-year follow-up HR (0.94; 95% CI: 0.650-1.370). The 5-year disease-free survival (DFS) estimates were 71.3% (95% CI: 65.46-77.05) vs 65.5% (95% CI: 59.45-71.45) with Pola-R-CHP vs R-CHOP (HR 0.75; 95% CI: 0.570-0.992).

In the expanded population (median follow-up 60.5 months), a similar significant 5-year PFS benefit was observed, with estimates of 63.1% (95% CI: 57.90-68.26) vs 59.1% (95% CI: 54.07-64.15) with Pola-R-CHP vs R-CHOP (HR 0.81; 95% CI: 0.652-0.996). The number of pts requiring subsequent systemic lymphoma therapy was 106 (21%) vs 145 (29%) with Pola-R-CHP vs R-CHOP. The 5-year OS estimates were 82.2% (95% CI: 78.78-85.68) vs 79.0% (95% CI: 75.24-82.70) with Pola-R-CHP vs R-CHOP, with no statistically significant difference (HR 0.84; 95% CI: 0.632-1.119). The 5-year DFS estimates were 69.4% (95% CI: 63.78-75.05) vs 65.1% (95% CI: 59.30-70.92) with Pola-R-CHP vs R-CHOP (HR 0.81; 95% CI: 0.625-1.042).

Safety profiles were comparable with Pola-R-CHP vs R-CHOP across all safety-evaluable pts in the expanded population (n=993), including Grade 3-5 AE rates (62.6% vs 60.8%). Fewer secondary malignancies were observed with Pola-R-CHP (n=5) vs R-CHOP (n=12). No new safety signals were observed during long-term follow-up; similar rates of new serious AEs were reported with Pola-R-CHP and R-CHOP (1.8% and 2.2%, respectively). No new cases of peripheral neuropathy were reported. Serious infections occurred in 4 pts (0.8%) vs 1 (0.2%) pt with Pola-R-CHP vs R-CHOP.

In the expanded population, fewer total deaths were observed in pts treated with Pola-R-CHP vs R-CHOP (90 vs 107). Lymphoma-related deaths occurred in 46 vs 62 pts with Pola-R-CHP vs R-CHOP (during the first 2 years, 32 vs 39 pts; beyond 2 years, 14 vs 23 pts for Pola-R-CHP vs R-CHOP). Similar numbers of deaths from infection (7 vs 11), cardiovascular disease (4 vs 5), and secondary malignancy (7 vs 5) were observed with Pola-R-CHP vs R-CHOP. In a competing risk analysis, with non-lymphoma-related deaths (including death due to study treatment) as competing events, the cumulative incidence of lymphoma-related death at 5 years was 9.1% vs 12.2% for Pola-R-CHP vs R-CHOP.

Conclusions: Extended 5-year follow-up of POLARIX demonstrated sustained and significant PFS and DFS benefits for pts receiving Pola-R-CHP vs R-CHOP. OS was reassuring between pts with Pola-R-CHP and R-CHOP, with more deaths, including lymphoma-related deaths, observed with R-CHOP. With the observation that a higher proportion of pts receiving R-CHOP died beyond 2 years, prolonged follow-up will be of interest. Safety profiles remained similar between arms, and no new safety signals were identified. These outcomes confirm Pola-R-CHP as a standard of care for pts with previously untreated intermediate- or high-risk DLBCL.