FDA Approval Summary: Polatuzumab Vedotin in the First-Line Treatment of Select Large B-Cell Lymphomas.

In April 2023, the U.S. FDA granted regular approval to polatuzumab vedotin-piiq in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (pola+R-CHP) for adult patients who have previously untreated diffuse large B-cell lymphoma, not otherwise specified, or high-grade B-cell lymphoma and who have an International Prognostic Index score of 2 or greater. Approval was based on POLARIX, a randomized, double-blinded, placebo-controlled trial evaluating the superiority of substituting vincristine with polatuzumab vedotin in the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone regimen as first-line therapy for patients with large B-cell lymphoma. Efficacy was based on investigator-assessed progression-free survival (PFS) in 879 patients who were randomized to receive pola+R-CHP or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, followed by two cycles of rituximab alone. PFS was statistically significantly longer with pola+R-CHP, with an HR of 0.73 (95% confidence interval, 0.57-0.95) and log-rank P value of 0.0177 (two-sided α = 0.05). There was no improvement demonstrated in the key secondary endpoints of the complete response rate at the end of therapy or overall survival (OS). Several issues raised uncertainty about the benefit-risk profile of polatuzumab vedotin in this curative-intent setting, including the modest PFS benefit of pola+R-CHP and lack of OS benefit. The application was therefore presented at an Oncology Drugs Advisory Committee. This article summarizes key aspects of the regulatory review, including perspectives on PFS and OS results and other endpoints.

Sarraf Yazdy M ，Kasamon YL ，Gu W ，Rodriguez LR ，Jin S ，Bhatnagar V ，Richardson NC ，Theoret MR ，Pazdur R ，Gormley NJ ... -  《-》

Efficacy and Safety of Polatuzumab Vedotin Plus Rituximab, Cyclophosphamide, Doxorubicin and Prednisone for Previously Untreated Diffuse Large B-Cell Lymphoma: A Real-World, Multi-Center, Retrospective Cohort Study.

Polatuzumab vedotin plus R-CHP (Pola-R-CHP) is approved as a new standard first-line therapy for diffuse large B-cell lymphoma (DLBCL) based on the POLARIX trial. However, real-world data on its efficacy and safety in unselected patients is lacking. We conducted a retrospective cohort study to evaluate Pola-R-CHP versus R-CHOP outcomes in routine clinical practice in China. This is a multi-institutional retrospective cohort study and included all consecutive patients that received at least one dose of polatuzumab vedotin up until February 2024. A total of 600 eligible patients from 6 centers were identified, 131 receiving Pola-R-CHP and 469 R-CHOP. After 1:2 propensity score matching, 128 pairs were obtained for further survival and prognosis analysis. With a median follow-up of 12.8 months, 12-month progression-free survival (PFS) was numerically higher with Pola-R-CHP versus R-CHOP (90.3% vs. 84.1%, p = 0.18). Benefits were consistently observed across molecular subgroups, especially advanced stage, ECOG ≥ 2, extranodal involvement ≥ 2 and non-GCB group. The complete response rate of the Pola-R-CHP group was higher than that of the RCHOP group (86.8% vs. 79.7%; p = 0.09), but there was no statistical difference. Safety profiles were comparable, with no new concerns. Among 128 patients treated with Pola-R-CHP, 96 underwent gene sequencing analysis: MCD (25.0%), EZB (13.5%), combined subtype (12.5%), ST2 (9.4%), and other/unclassifiable subtype (30.2%). The most common mutations (> 25% of cases) were PIM1, TP53, BCL-6, KMT2D, SOCS1, BCL-2. Genetic testing results show the correlation between genotyping, gene mutations in PIM1/TP53 and therapeutic efficacy. This large real-world study supports Pola-R-CHP as an effective frontline option for DLBCL, with sustained efficacy versus R-CHOP observed in unselected populations. While 12-month PFS failed to reach statistical significance, subgroup analyses favor Pola-R-CHP. Further research with a wider population, longer follow-up, and screening of advantageous groups are warranted.

Zhao P ，Zhao S ，Huang C ，Li Y ，Wang J ，Xu J ，Li L ，Qian Z ，Li W ，Zhou S ，Qiu L ，Liu X ，Chen Y ，Jiang Y ，Zheng Y ，Chen D ，Zhou H ，Gao Y ，Zhang Q ，Zhang H ... -  《-》

Zanubrutinib plus R-CHOP for the treatment of newly diagnosed double-expressor lymphoma: A phase 2 clinical study.

Double-expressor lymphoma (DEL) has a poorer prognosis than other subtypes of diffuse large B-cell lymphoma (DLBCL). This study is a multicenter, prospective, single-arm, phase 2 clinical study initiated by investigators to evaluate the efficacy and safety of combined zanubrutinib with R-CHOP, which includes rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for patients with DEL (stage II or more), as well as to explore factors related to efficacy preliminarily. From November 2020 to July 2022, 48 newly diagnosed patients were enrolled. All patients received twice-daily oral zanubrutinib (160 mg) for 6 months and standardized R-CHOP regimen for six to eight cycles. The objective response rate (ORR) was 89.6%, with a complete response rate (CRR) of 83.3%. The median follow-up was 29.3 months. The median progression-free survival (PFS) and overall survival (OS) were not reached. The PFS and OS were 81.25% and 93.75% at 2 years, respectively. Grade ≥3 adverse events (AEs) were reported in 23 of 48 (47.9%) patients. Next-generation sequencing (NGS) results of 33 patients showed that TP53, MYD88, and PIM1 were the most common mutated gene. Multivariate analysis revealed that BCL-6 gene rearrangement was an adverse prognostic factor for both PFS (hazard ratio [HR], 0.247; 95% confidence article [CI], 0.068-0.9; p = .034) and OS (HR, 0.057; 95% CI, 0.006-0.591; p = .016), whereas the number of extranodal involvements also significantly influenced OS (HR, 15.12; 95% CI, 1.07-213.65; p = .044). Zanubrutinib in combination with R-CHOP is an effective option for DEL patients, and the toxicity of zanubrutinib is entirely acceptable for patients.

Yin X ，He Q ，Liu D ，Xie L ，Wang H ，Chen C ，Zhao C ，Shan N ，Shi S ，Wei H ，Ma J ，Lu K ，Wang L ，Wang Y ，Xing L ，Li Z ... -  《-》

The impact of trial inclusion criteria on outcomes in DLBCL patients treated with R-CHOP in the first line: a Danish nationwide study.

Simonsen MR ，Haunstrup LM ，Severinsen FT ，Jensen RK ，Brown PN ，Maurer MJ ，Khurana A ，Jensen P ，Jørgensen JM ，Stauffer Larsen T ，Clausen MR ，Poulsen CB ，Dessau-Arp A ，El-Galaly TC ，Jakobsen LH ... -  《-》

Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is typically treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, only 60% of patients are cured with R-CHOP. Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b, which is ubiquitously expressed on the surface of malignant B cells. We conducted a double-blind, placebo-controlled, international phase 3 trial to evaluate a modified regimen of R-CHOP (pola-R-CHP), in which vincristine was replaced with polatuzumab vedotin, as compared with standard R-CHOP, in patients with previously untreated intermediate-risk or high-risk DLBCL. Patients 18 to 80 years of age were randomly assigned in a 1:1 ratio to receive six cycles of either pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival and safety. Overall, 879 patients underwent randomization: 440 were assigned to the pola-R-CHP group and 439 to the R-CHOP group. After a median follow-up of 28.2 months, the percentage of patients surviving without progression was significantly higher in the pola-R-CHP group than in the R-CHOP group (76.7% [95% confidence interval (CI), 72.7 to 80.8] vs. 70.2% [95% CI, 65.8 to 74.6] at 2 years; stratified hazard ratio for progression, relapse, or death, 0.73 by Cox regression; 95% CI, 0.57 to 0.95; P = 0.02). Overall survival at 2 years did not differ significantly between the groups (88.7% [95% CI, 85.7 to 91.6] in the pola-R-CHP group and 88.6% [95% CI, 85.6 to 91.6] in the R-CHOP group; hazard ratio for death, 0.94; 95% CI, 0.65 to 1.37; P = 0.75). The safety profile was similar in the two groups. 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. (Funded by F. Hoffmann-La Roche/Genentech; POLARIX ClinicalTrials.gov number, NCT03274492.).

Tilly H ，Morschhauser F ，Sehn LH ，Friedberg JW ，Trněný M ，Sharman JP ，Herbaux C ，Burke JM ，Matasar M ，Rai S ，Izutsu K ，Mehta-Shah N ，Oberic L ，Chauchet A ，Jurczak W ，Song Y ，Greil R ，Mykhalska L ，Bergua-Burgués JM ，Cheung MC ，Pinto A ，Shin HJ ，Hapgood G ，Munhoz E ，Abrisqueta P ，Gau JP ，Hirata J ，Jiang Y ，Yan M ，Lee C ，Flowers CR ，Salles G ... -  《-》