Polatuzumab Vedotin Plus Bendamustine and Rituximab in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL): Final Results of a Phase Ib/II Randomized Study and Single-Arm Extension (Ext) Study

Background: Polatuzumab vedotin (Pola) is a CD79b-targeting antibody-drug conjugate approved for the treatment of R/R DLBCL based on findings from the GO29365 randomized Phase lb/ll study (NCT02257567), which assessed the efficacy of Pola plus bendamustine and rituximab (Pola+BR) vs BR alone in patients (pts) with R/R DLBCL. The primary endpoint was met, with an independent review committee (IRC)-assessed complete response (CR) rate of 40.0% with Pola+BR vs 17.5% with BR (Sehn LH, et al. J Clin Oncol 2020). A single-arm Ext cohort was later enrolled to receive Pola+BR. Efficacy was consistent with the randomized phase, with a CR rate of 38.7% (Sehn LH, et al. Blood Adv 2022). We report final results from the GO29365 study with extended follow-up of up to 5 years, including updated results from the Phase lb safety run-in, Phase ll randomized, and Ext cohorts.

Methods: This Phase lb/ll, open-label, multicenter, randomized study included pts with R/R DLBCL, who were ≥18 years old, were stem cell transplant ineligible, had an Eastern Cooperative Oncology Group performance status of 0-2 and had received ≥1 prior line of therapy. Pts with Grade (Gr) >1 peripheral neuropathy (PN) were excluded. Pts received Pola 1.8mg/kg with each cycle of BR (full methods have been described; Sehn LH, et al. J Clin Oncol 2020). The primary endpoint was IRC-assessed CR at primary response assessment (PRA) measured by positron emission tomography/computed tomography. Secondary endpoints included safety, best objective response (BoR), best complete response (BCR), duration of response (DoR) and progression-free survival (PFS) assessed by IRC, and overall survival (OS).

Results: At final data cut-off (October 21, 2021), median duration of follow-up for pts treated with Pola+BR was 77.4 months (mo), 59.9 mo, and 29.2 mo, in the safety run-in (N=6), randomized (N=40), and Ext (N=106) cohorts, respectively. Baseline characteristics were similar between cohorts (Sehn LH, et al. Blood Adv 2022). In the randomized cohort (Pola+BR vs BR), final CR rate at PRA was 42.5% (n=17; 95% confidence interval [CI]: 27.0-59.1) vs 17.5% (n=7; 95% CI: 7.3-32.8), BoR rate was 62.5% (n=25; 95% CI: 45.8-77.3) vs 25.0% (n=10; 95% CI: 12.7-41.2), and BCR rate was 52.5% (n=21; 95% CI: 36.1-68.5) vs 22.5% (n=9; 95% CI: 10.8-38.5). Median (95% CI) DoR in the randomized cohort (Pola+BR vs BR) was 10.9 (5.7-40.7) vs 10.6 (4.0-19.7) mo (hazard ratio [HR], 0.6; 95% CI: 0.3-1.4), and PFS was 9.2 (6.0-13.9) vs 3.7 (2.1-4.5) mo (HR, 0.4; 95% CI: 0.2-0.7). The risk of responders progressing or dying was reduced by 40.0% (HR, 0.6; 95% CI: 0.3-1.4) with Pola+BR vs BR alone. Median OS (95% CI) in the randomized cohort was 12.4 (9.0-32.0) vs 4.5 (3.7-6.0) mo (HR, 0.4; 95% CI: 0.2-0.7) with Pola+BR vs BR alone. In the Ext cohort, CR rate at PRA for Pola+BR was 39.6% (n=42; 95% CI: 30.3-49.6), consistent with the randomized cohort. BoR rate was 57.5% (n=61; 95% CI: 47.6-67.1), and BCR rate was 53.8% (n=57; 95% CI: 43.8-63.5). Median DoR, PFS, and OS were 13.4 (95% CI: 8.6-20.0) mo, 7.0 (95% CI: 5.1-9.8) mo, and 12.3 (95% CI: 8.3-17.0) mo, respectively.

No new safety signals were reported; results were consistent with previous analyses. In pts receiving Pola+BR in the safety run-in, randomized, and Ext cohorts, respectively, Gr 3-4 adverse events (AEs) occurred in 5/6 (83.3%), 34/39 (87.2%), and 83/106 (78.3%) pts, and serious AEs occurred in 4/6 (66.7%), 27/39 (69.2%), and 57/106 (53.8%) pts, respectively. The most common Gr 3-4 AEs were neutropenia and thrombocytopenia in both the randomized and Ext cohorts, and for serious AEs were infections, pyrexia, and febrile neutropenia in the randomized cohort, and infections in the Ext cohort. In the randomized and Ext cohorts, respectively, any-grade PN occurred in 17 (43.6%) and 29 (27.4%) pts, and Gr ≥2 PN occurred in 6 (15.4%) and 16 (15.1%) pts. Median time to PN resolution was 0.3 and 2.9 mo in the randomized and Ext cohorts, respectively.

Conclusions: In this planned final analysis, with extended follow up of 5 years in the randomized cohort and 2 years in the Ext cohort, the improved efficacy of Pola+BR persisted. Median DoR was longer with increased follow-up, indicating Pola+BR leads to a durable benefit in responding pts. Median PFS and OS were longer with Pola+BR compared with BR, consistent with previous results. No new safety signals were identified. These findings provide further evidence of the effectiveness of Pola+BR for the treatment of R/R DLBCL.

Sehn:AbbVie, Acerta, Amgen, Apobiologix, AstraZeneca, BMS/Celgene, Debiopharm, Genmab, Gilead, Incyte, Janssen, Kite, Karyopharm, Lundbeck, Merck, Morphosys, Novartis, Sandoz, Seattle Genetics, Servier, Takeda, TG Therapeutics, Verastem: Consultancy; Chugai: Consultancy, Honoraria; AbbVie, Acerta, Amgen, Apobiologix, AstraZeneca, BMS/Celgene, Gilead, Incyte, Janssen, Kite, Karyopharm, Lundbeck, Merck, Morphosys, Sandoz, Seattle Genetics, Servier, Takeda, TG Therapeutics, Verastem: Honoraria; Teva, Roche/Genentech: Consultancy, Honoraria, Research Funding. Hertzberg:Takeda: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Roche, Takeda, Otsuka, Beigene, Gilead, Janssen, Novartis, Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Opat:Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; CSL: Consultancy, Honoraria, Research Funding; Antegene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics, LLC an AbbVie Company: Research Funding; Belgene: Research Funding. Herrera:Caribou: Consultancy; Pfizer: Consultancy; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Regeneron: Consultancy; Tubulis: Consultancy; KiTE Pharma: Research Funding; Takeda: Consultancy; Adicet Bio: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Genmab: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Gilead: Research Funding; Karyopharm: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding. Assouline:Genentech/Roche, Astra Zeneca, Novartis, BMS, Jazz, Gilead, Amgen, Beigene, Abbvie, Paladin: Consultancy, Honoraria; Novartis: Research Funding. Flowers:Xencor: Research Funding; TG Therapeutics: Research Funding; Takeda: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Morphosys: Research Funding; Kite: Research Funding; Iovance: Research Funding; Janssen Pharmaceutical: Research Funding; Sanofi: Research Funding; Ziopharm: Research Funding; Adaptimmune: Research Funding; Amgen: Research Funding; Allogene: Research Funding; EMD: Research Funding; Cellectis: Research Funding; Guardant: Research Funding; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; SeaGen: Consultancy; Spectrum: Consultancy; 4D: Research Funding; Denovo Biopharma: Consultancy; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Genentech/Roche: Consultancy, Research Funding; Genmab: Consultancy; Acerta: Research Funding; NPower: Current holder of stock options in a privately-held company; Gilead: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Celgene: Consultancy, Research Funding; V Foundation, Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; National Cancer Institute: Research Funding; BeiGene: Consultancy; Abbvie: Consultancy, Research Funding; Bayer: Consultancy, Research Funding. Kim:Sanofi: Other: Clinical trial research funding to my institution; Regeneron: Other: Clinical trial research funding to my institution; Merck Sharp & Dohme: Other: Clinical trial research funding to my institution; Merck Serono: Other: Clinical trial research funding to my institution; Genmab: Other: Clinical trial research funding to my institution; Boryung: Other: Clinical trial research funding to my institution; Celgene: Other: Clinical trial research funding to my institution; Boehringer-Ingelheim: Other: Clinical trial research funding to my institution; BMS: Other: Clinical trial research funding to my institution; Bayer: Other: Clinical trial research funding to my institution; AstraZeneca/MedImmune: Other: Clinical trial research funding to my institution; Takeda: Honoraria, Other: Clinical trial research funding to my institution; Roche/Genentech: Honoraria, Other: Clinical trial research funding to my institution; Novartis: Honoraria, Other: Clinical trial research funding to my institution; Hanmi: Honoraria, Other: Clinical trial research funding to my institution; Janssen: Honoraria, Other: Clinical trial research funding to my institution; AstraZeneca: Honoraria; AstraZeneca-KHIDI: Research Funding. McMillan:Amgen: Honoraria; Prosethetics: Honoraria; Takeda: Honoraria, Other: Travel funding; Roche: Honoraria. Özcan:Bayer: Research Funding; Janssen: Research Funding; Acerta: Research Funding; Takeda: Research Funding; Roche: Other: Travel expenses/accommodations, Research Funding; MSD: Research Funding; Reddy's: Research Funding; Abbvie: Other: Travel expenses/accommodations, Research Funding; Pfizer: Research Funding; Jazz: Other: Travel expenses/accommodations. Salles:Roche/Genentech, Gilead Sciences, Janssen, Celgene, Novartis, MorphoSys AG, Epizyme, Alimera Sciences, Genmab, Debiopharm Group, Velosbio, Bristol-Myers Squibb, BeiGene, Incyte, Miltenyi Biotec, Ipsen, Kite, a Gilead Company, Loxo, Rapt: Consultancy; AbbVie, BeiGene, Bristol Myers Squibb, Celgene, Debiopharm, Epizyme, Genentech/Roche, Genmab, Incyte, Kite, a Gilead Company, Miltenyi, MorphoSys, Takeda, and VelosBio: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech, Janssen, Celgene, Gilead Sciences, Novartis, AbbVie, MorphoSys AG, Amgen, Bayer, Epizyme, Regeneron, Kite, a Gilead Company: Honoraria. Hirata:Roche: Current holder of stock options in a privately-held company; Genentech, Inc.: Current Employment. Yang:Genentech / Roche: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Musick:Genentech: Current Employment; Roche/Genentech: Current equity holder in private company, Current holder of stock options in a privately-held company. Matasar:Teva: Consultancy; GlaxoSmithKline: Honoraria, Research Funding; ImmunoVaccine Technologies: Honoraria, Research Funding; Juno Therapeutics: Consultancy; Daiichi Sankyo: Consultancy; F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Merck: Consultancy, Current equity holder in private company; IGM Biosciences: Research Funding; TG Therapeutics: Consultancy; Karyopharm: Consultancy; IMV Therapeutics: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy, Honoraria; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

Polatuzumab vedotin (Polivy) is a CD79b-directed antibody-drug conjugate indicated in combination with bendamustine and a rituximab product for the treatment of adult pts with relapsed or refractory DLBCL, not otherwise specified, after at least two prior therapies. The GO29365 study included patients who had received one prior line of therapy.