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

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.

Salles:BeiGene: Consultancy; AbbVie: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Incyte: Consultancy; BMS/Celgene: Consultancy; Genmab: Consultancy, Research Funding; Ipsen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Kite/Gilead: Consultancy; Merck: Consultancy; Molecular Partners: Consultancy; Nurix: Research Funding. Morschhauser:Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria, Other: Payment for Expert Testimony, Honoraria for Scientific Lectures; Eisai: Honoraria; Chugai: Honoraria. Sehn:F. Hoffmann-La Roche Ltd; Genentech, Inc.; Teva: Research Funding; AbbVie; Amgen; AstraZeneca; Beigene; BMS/Celgene; Genmab; Kite/Gilead; Incyte; Janssen; Merck; Seagen; F. Hoffmann-La Roche Ltd; Genentech, Inc.: Honoraria; AbbVie; Amgen; AstraZeneca; Beigene; BMS/Celgene; Genmab; Kite/Gilead; Incyte; Janssen; Merck; Seagen; F. Hoffmann-La Roche Ltd; Genentech, Inc.: Consultancy. Herrera:AbbVie: Consultancy; Pfizer: Consultancy; Genmab: Consultancy; Takeda: Consultancy; AstraZeneca: Consultancy, Research Funding; Gilead Sciences: Research Funding; Tubulis: Consultancy; Regeneron: Consultancy; Roche/Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy; KiTE Pharma: Research Funding; Allogene Therapeutics: Consultancy; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Caribou Biosciences: Consultancy; Adicet Bio: Consultancy. Trněný:Autolus: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses; SOBI: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses; Caribou Biosciences: Consultancy; Genmab: Consultancy; Novartis: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses; Roche: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses; Incyte: Consultancy; Swixx BioPharma: Honoraria. Lenz:Hexal/Sandoz: Honoraria; Immagene: Honoraria; Incyte: Honoraria; Karyopharm: Honoraria; Lilly: Honoraria; Miltenyi Biotech: Honoraria; MSD: Honoraria; NanoString: Honoraria; PentixaPharm: Honoraria; Pierre Fabre: Honoraria; Sobi: Honoraria, Speakers Bureau; Acerta: Research Funding; Roche, Gilead, BMS, Novartis, AstraZeneca, Abbvie, Incyte, Genmab, Constellation, ADC Therapeutics, Miltenyi, PentixaPharm, Sobi, Immagene, Genase, Hexal-Sandoz, Lilly, Beigene, MSD, Pierre Fabre: Consultancy; ELVESCA: Current equity holder in private company; Roche, Gilead, BMS, Novartis, AstraZeneca, Abbvie, Incyte, Genmab, Constellation, ADC Therapeutics, Miltenyi, PentixaPharm, Sobi, Immagene, Genase, Hexal-Sandoz, Lilly, Beigene, MSD, Pierre Fabre: Membership on an entity's Board of Directors or advisory committees; AbbVie, BeiGene, Sobi, Roche, Gilead, BMS: Other: Travel; Genase: Honoraria; Genmab: Honoraria; Constellation: Honoraria; BeiGene: Honoraria; BMS: Honoraria; MorphoSys: Honoraria, Research Funding; AbbVie: Honoraria; Amgen: Honoraria; ADC Therapeutics: Honoraria; Verastem: Research Funding; Bayer: Honoraria, Research Funding; AGIOS: Research Funding; AQUINOX: Research Funding; AstraZeneca: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Sharman:AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly and Company: Consultancy, Honoraria, Other: Anciliarry supplies, transportation, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; ADC Therapeutics: Honoraria; Pharmacyclics LLC, an AbbVie Company: Honoraria; TG Therapeutics: Honoraria. Herbaux:Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding; Roche/Genentech: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: Travel Support; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel support. Burke:Genmab: Consultancy; Bristol Myers Squibb: Consultancy; Nurix: Consultancy; Eli Lilly and Company: Honoraria, Other: Food/Beverage ; Abbvie: Consultancy; Foresight Diagnostics: Consultancy; Novartis: Consultancy; Genentech/Roche: Consultancy; AstraZeneca: Consultancy; Kymera: Consultancy; SeaGen: Consultancy; Regeneron: Consultancy; BeiGene: Consultancy; Adaptive Biotechnologies: Consultancy. Matasar:Epizyme: Honoraria; IMV Therapeutics: Honoraria; Merck: Current equity holder in publicly-traded company; ADC Therapeutics: Honoraria; Immunovaccine Technologies: Research Funding; BMS/Celgene: Honoraria; Kite: Honoraria; Johnson & Johnson: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Takeda: Honoraria; Bayer: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria; Allogene: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; GM Biosciences: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria. Collins:Sobi: Consultancy, Honoraria; Beigene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Pfizer: Research Funding; Amgen: Research Funding; BMS: Research Funding; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Pinto:Merck Sharp and Dohme: Honoraria; Incyte: Honoraria; IGM Biosciences: Current holder of stock options in a privately-held company; Autolus Therapeutics: Current holder of stock options in a privately-held company; Eli Lilly: Honoraria; BeiGene: Honoraria; Bristol Myers Squibb: Honoraria; Kite-Gilead: Honoraria; Hoffmann-La Roche AG: Consultancy, Honoraria. Izutsu:Ono Pharma, Symbio, Takeda: Consultancy, Honoraria; Incyte, Bayer, O Oncology, Regeneron: Research Funding; Pfizer, Janssen, Gilead, Daiichi Sankyo: Honoraria, Research Funding; Beigene, Yakult, Otsuka: Consultancy, Research Funding; MSD, AstraZeneca, Genmab, Chugai, BMS, Kyowa Kirin, Novartis, AbbVie: Consultancy, Honoraria, Research Funding; AstraZeneca, Eli Lily, Astellas, Ono Pharmaceuticals, Eisai, Chugai, Janssen, Symbio, Bristol Myers Squibb, Daiichi Sankyo, Otsuka, Abbvie, Takeda, Eli Lilly, Genmab, Kyowa Kirin, MSD, Astellas, Pfizer, MeijiSeika Pharma, Novartis, Nihon Kayaku, Gilead,: Honoraria; MSD, AstraZeneca, Abbvie, Incyte, Bristol Myers Squibb, Novartis, Bayer, Pfizer, Janssen, Yakult, Kyowa Kirin, Daiichi Sankyo, Chugai, Beigene, Genmab, LOXO Oncology, Otsuka, Regeneron, Gilead: Research Funding; AstraZeneca, Zenyaku, Ono Pharmaceuticals, Mitsubishi Tanabe Pharma, Eisai, Chugai, Bristol Myers Squibb, Takeda, Otsuka, Abbvie, Zenyaku, Kyowa Kirin, MSD, Carna Biosciences, Novartis, Yakult, Nihon Shinyaku, Abe Pharma, Eisai,Beigene: Consultancy. Lee:Gilead: Current Employment; Genentech, Inc.: Ended employment in the past 24 months; Gilead, F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Chohan:F. Hoffmann-La Roche Ltd: Current Employment. Sugidono:Genentech, Inc.: Current Employment; Genentech, Inc. / F. Hoffmann-La Roche Ltd: Current equity holder in private company. Jiang:Roche/Genentech: Current Employment, Current equity holder in publicly-traded company, Ended employment in the past 24 months. Batlevi:F. Hoffmann-La Roche Ltd/Genentech, Inc.: Current equity holder in publicly-traded company; Regeneron, Moderna: Divested equity in a private or publicly-traded company in the past 24 months; Dava Oncology, TouchIME, Medscape: Honoraria; Epizyme, Autolus, F. Hoffmann-La Roche Ltd, Vincerx: Research Funding; Memorial Sloan Kettering Cancer Center: Ended employment in the past 24 months; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Current Employment; BMS, Seattle Genetics, Kite, Karyopharm, TG Therapeutics, ADC Therapeutics, AbbVie, Genentech, Inc., Treeline Bioscience: Consultancy. Yan:Hoffmann-La Roche Ltd: Current Employment; Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Hoffmann-La Roche Ltd: Patents & Royalties. Hirata:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Tilly:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Flowers:AstraZeneca: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Kite: Research Funding; Iovance: Research Funding; Denovo Biopharma: Consultancy; Adaptimmune: Research Funding; Morphosys: Research Funding; BeiGene: Consultancy; Nektar: Research Funding; Celgene: Consultancy, Research Funding; Spectrum: Consultancy; 4D: Research Funding; BostonGene: Research Funding; Ziopharm National Cancer Institute: Research Funding; Bio Ascend: Consultancy; TG Therapeutics: Research Funding; Amgen: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Takeda: Research Funding; EMD Serono: Research Funding; Pfizer: Research Funding; Genmab: Consultancy; Karyopharm: Consultancy; N-Power Medicine: Consultancy, Current holder of stock options in a privately-held company; Novartis: Research Funding; Bayer: Consultancy, Research Funding; Cellectis: Research Funding; Guardant: Research Funding; Genentech/Roche: Consultancy, Research Funding; Pharmacyclics / Janssen: Consultancy; Pharmacyclics: Research Funding; Sanofi: Research Funding; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Xencor: Research Funding; Allogene: Research Funding; Janssen Pharmaceuticals: Research Funding; Bristol Myers Squibb: Consultancy; Burroughs Wellcome Fund: Research Funding; Seagen: Consultancy; AbbVie: Consultancy, Research Funding.