Abrisqueta P, González-Barca E, Panizo C, Pérez JMA, Miall F, Bastos-Oreiro M, Triguero A, Banerjee L, McMillan A, Seymour E, Hirata J, de Guzman J, Sharma S, Jin HY, Musick L, and Diefenbach C
Background: Diffuse large B-cell lymphoma comprises nearly 30% of non-Hodgkin lymphoma cases and patients with relapsed or refractory diffuse large B-cell lymphoma who are ineligible for stem-cell transplantation have few treatment options and poor prognoses. We aimed to determine whether the novel combination of polatuzumab vedotin in combination with rituximab and lenalidomide (Pola+R+Len) would provide a tolerable treatment option with enhanced antitumour response in patients with relapsed or refractory diffuse large B-cell lymphoma., Methods: This completed phase 1b/2, open-label, multicentre, single-arm study (GO29834) evaluated the safety and efficacy of Pola+R+Len in patients with relapsed or refractory diffuse large B-cell lymphoma at 19 sites in three countries (USA, Spain, and UK). Patients (≥18 years old) were eligible for inclusion if they had histologically documented CD20-positive relapsed or refractory diffuse large B-cell lymphoma and Eastern Cooperative Oncology Group performance status of 2 or lower, had received at least one previous line of chemoimmunotherapy, including an anti-CD20 agent, and were ineligible for stem-cell transplantation. The dose-escalation phase (1b) used escalating doses of lenalidomide to find the recommended phase 2 dose. Patients received six 28-day cycles of induction treatment with intravenous rituximab 375 mg/m 2 and intravenous polatuzumab vedotin 1·8 mg/kg (all cohorts) plus oral lenalidomide at the following doses: 10 mg (cohort A); 15 mg (cohort B); and 20 mg (cohort C). Rituximab and polatuzumab vedotin were administered on day 1 and lenalidomide on days 1-21 of each 28-day cycle. During the dose-expansion phase (2), patients received six 28-day cycles of Pola+R+Len at the recommended phase 2 dose established during dose escalation. In both phases, patients with a complete response or partial response at the end of induction were eligible for post-induction therapy with rituximab 375 mg/m 2 on day 1 and lenalidomide 10 mg/day on days 1-21 of each 28-day cycle for a maximum of 6 cycles. The primary safety objective of the dose-escalation phase was identification of the maximum tolerated dose through incidence of dose-limiting toxic effects. The primary efficacy outcome of the dose-expansion phase was Independent Review Committee-assessed complete response rate at end of induction, based on PET-CT. Analyses were conducted in the safety population, which included all patients who received at least one dose of any study drug, and the efficacy population, which included all patients who received at least one dose of any study drug at the recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02600897., Findings: Between July 11, 2017 and Feb 3, 2020, 57 patients were enrolled (median age 71 years [IQR 60-75]; 38 [67%] were male and 19 (33%) were female; 47 [82%] were not Hispanic or Latino; and the median previous lines of therapy was 2 [IQR 1-3]). 18 participants were included in phase 1b and 39 were included in phase 2. Phase 1b confirmed a 20 mg recommended phase 2 dose for lenalidomide. After a median follow-up of 11·8 months (IQR 4·7-25·8), the complete response rate, as assessed by the Independent Review Committee, was 31% (90% CI 20-43). The most common grade 3-4 adverse events were neutropenia (35 [61%] of 57) and thrombocytopenia (eight [14%] of 57). Serious adverse events were reported in 23 (40%) of 57 patients and one patient died due to a treatment-related adverse event (neutropenic sepsis)., Interpretation: Although the combination of Pola+R+Len did not meet the prespecified activity threshold, some patients derived clinical benefit and the regimen had a tolerable safety profile in patients with relapsed or refractory diffuse large B-cell lymphoma., Funding: Genentech/F Hoffmann-La Roche., Competing Interests: Declaration of interests PA has held consultancy for and received honoraria from Janssen, AstraZeneca, Bristol Myers Squibb, AbbVie, Genmab and F Hoffmann-La Roche; and has received honoraria from Gilead and Incyte and expenses for travel from AbbVie, Janssen, and F Hoffmann-La Roche. CP has received honoraria from Celgene/Bristol Myers Squibb, Novartis, F Hoffmann-La Roche, AbbVie, Janssen, and Gilead/Kite; received expenses for travel from F Hoffmann-La Roche, Gilead/Kite, and AbbVie; and participated on a Data Safety Monitoring Board or Advisory Board with F Hoffmann-La Roche, Incyte, and BeiGene. JMAP has received honoraria from F Hoffmann-La Roche, Janssen, AbbVie, AstraZeneca, and Amgen. AM has received honoraria for advisory boards from SOBI, Amgen, F Hoffmann-La Roche, and Takeda; received payment or honoraria for lectures, presentations, or speaker bureaus from F Hoffmann-La Roche and Takeda; received payment for expert testimony from Delphi Study: Prosthetics; and received support for attending meetings and/or travel from F Hoffmann-La Roche and Takeda. ES reports expenses for travel and attending meetings from Flatiron Health and BeiGene, and stock or stock options from F Hoffmann-La Roche and BeiGene; is an employee of BeiGene; and was an employee of Wayne State University/Karmanos Cancer institute from September, 2017 to February, 2021, and of Flatiron Health from February, 2021, to March, 2023. HYJ, JH, and LM are employees of Genentech and own F Hoffmann-La Roche stock options. JdG was an employee of Genentech at the time of this analysis. CD has held consultancy for Genentech/F Hoffmann-La Roche; and participated on a Data Safety Monitoring Board or Advisory Board with Genentech/F Hoffmann-La Roche and Celgene (BMS). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)