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B Introduction: b The antibody-like fusion protein RO7227166 simultaneously targets CD19 on B-cells and 4-1BB (CD137) on T cells. RO7227166 doses ranging from 360 ug up to 75 mg were assessed and the maximum tolerated dose was not reached. COMBINING CD19-4-1BBL (RO7227166) WITH GLOFITAMAB IS SAFE AND SHOWS EARLY EFFICACY IN PATIENTS SUFFERING FROM RELAPSED OR REFRACTORY B-CELL NON-HODGKIN LYMPHOMA. [Extracted from the article]

Introduction/background: Leveraging the Follicular Lymphoma Analysis of Surrogacy Hypothesis database of individual patient data from first-line clinical trials, we studied the clinical course of follicular lymphoma (FL) and investigated clinical factors associated with FL outcomes., Patients and Methods: We examined 2428 patients from 8 randomized trials using multistate survival models with 4 states: induction treatment, progression, death from FL, and death from other causes. We utilized Aalen-Johansen estimator and Cox models to assess the likelihood of FL outcomes and quantify predictors' effects., Results: Two-year progression, FL-related death, and death from other causes estimates were 26.5%, 3.4% and 1.4%, respectively. FL-associated deaths were the primary cause of mortality within 10 years of follow-up. Male sex (hazard ratio: 1.25; 95% confidence interval: 1.05-1.47), > 4 involved nodal areas (1.51; 1.23-1.86), elevated LDH (1.20; 1.01-1.43), low hemoglobin (1.44; 1.15-1.81), and elevated β-2 levels (1.23; 1.02-1.47) increased risk of progression. CD20-targeting agents reduced risks for progression (0.29; 0.22-0.39), death from FL (0.05; 0.01-0.20), and death from other causes without progression (0.13; 0.05-0.33) and following progression (0.52; 0.30-0.92). Estimated 2-year progression rates were 22.3% and 43.5% with or without CD20-targeting agents, respectively. Two-year FL-associated mortality rate was 8.3% among patients without CD20-targeting agents, 5.4% with B-symptoms, 4.9% with elevated LDH, and 9.1% with low hemoglobin., Conclusion: This study identified independent contributions of baseline clinical factors to distinct outcomes for patients with FL following first-line therapy on a clinical trial. Similar analytical approaches are needed to increase understanding of factors that influence FL outcomes in other settings., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Progression-free survival (PFS) has been the regulatory primary end-point for recent phase III trials in first-line follicular lymphoma (FL), but requires prolonged follow-up. Complete response (CR) at 30 months after initiation of induction treatment was validated as surrogate end-point for PFS. Our objective was to further evaluate surrogacy of CR measured by [ 18 F] fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at the end of induction (EoI). Individual patient data were analysed from 1505 patients from five randomized trials. Trial-level surrogacy examining the association between treatment effects on EoI-PET-CR and PFS was evaluated using linear regression ( R WLS 2 ) and bivariate Copula ( R Copula 2 ) models. Although EoI-PET-CR strongly predicted PFS at a prognostic level, the trial-level assessment did not show strong correlation ( R WLS 2 = 0.56 , confidence interval [CI]: 0.20-0.88; R Copula 2 = 0.35 , CI: 0.0-0.82). The high uncertainty in estimation was possibly due to the small number of trials and the population of patients with available PET data. Maintenance therapy affecting PFS beyond induction treatment, but not EoI-PET-CR end-point, may have distorted the association between treatment effects. However, there will probably be a number of additional trials approaching completion with available PET response data. Refined evaluation of PET-CR based surrogate end-points is still warranted., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Glofitamab, a novel CD20xCD3, T-cell-engaging bispecific antibody, exhibited single-agent activity in Study NP30179, a first-in-human, phase 1 trial in relapsed/refractory B-cell non-Hodgkin lymphoma. Preclinical studies showed that glofitamab leads to T-cell activation, proliferation, and tumor cell killing upon binding to CD20 on malignant cells. Here, we provide evidence of glofitamab's clinical activity, including pharmacodynamic profile, mode of action, and factors associated with clinical response, by evaluating biomarkers in patient samples from the dose-escalation part of this trial. Patients enrolled in Study NP30179 received single-dose obinutuzumab pretreatment (1000 mg) 7 days before IV glofitamab (5 µg-25 mg). Glofitamab treatment lasted ≤12 cycles once every 2 or 3 weeks. Blood samples were collected at predefined time points per the clinical protocol; T-cell populations were evaluated centrally by flow cytometry, and cytokine profiles were analyzed. Immunohistochemical and genomic biomarker analyses were performed on tumor biopsy samples. Pharmacodynamic modulation was observed with glofitamab treatment, including dose-dependent induction of cytokines, and T-cell margination, proliferation, and activation in peripheral blood. Gene expression analysis of pretreatment tumor biopsy samples indicated that tumor cell intrinsic factors such as TP53 signaling are associated with resistance to glofitamab, but they may also be interlinked with a diminished effector T-cell profile in resistant tumors and thus represent a poor prognostic factor per se. This integrative biomarker data analysis provides clinical evidence regarding glofitamab's mode of action, supports optimal biological dose selection, and will further guide clinical development. This trial was registered at www.clinicaltrials.gov as #NCT03075696., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: Glofitamab is a T-cell-engaging bispecific antibody possessing a novel 2:1 structure with bivalency for CD20 on B cells and monovalency for CD3 on T cells. This phase I study evaluated glofitamab in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). Data for single-agent glofitamab, with obinutuzumab pretreatment ( Gpt ) to reduce toxicity, are presented., Methods: Seven days before the first dose of glofitamab (0.005-30 mg), all patients received 1,000 mg Gpt . Dose-escalation steps were determined using a Bayesian continuous reassessment method with overdose control. Primary end points were safety, pharmacokinetics, and the maximum tolerated dose of glofitamab., Results: Following initial single-patient cohorts, 171 patients were treated within conventional multipatient cohorts and received at least one dose of glofitamab. This trial included heavily pretreated patients with R/R B-NHL; most were refractory to prior therapy (155; 90.6%) and had received a median of three prior therapies. One hundred and twenty-seven patients (74.3%) had diffuse large B-cell lymphoma, transformed follicular lymphoma, or other aggressive histology, and the remainder had indolent lymphoma subtypes. Five (2.9%) patients withdrew from treatment because of adverse events. Cytokine release syndrome occurred in 86 of 171 (50.3%) patients (grade 3 or 4: 3.5%); two (1.2%) patients experienced grade 3, transient immune effector cell-associated neurotoxicity syndrome-like symptoms. The overall response rate was 53.8% (complete response [CR], 36.8%) among all doses and 65.7% (CR, 57.1%) in those dosed at the recommended phase II dose. Of 63 patients with CR, 53 (84.1%) have ongoing CR with a maximum of 27.4 months observation., Conclusion: In patients with predominantly refractory, aggressive B-NHL, glofitamab showed favorable activity with frequent and durable CRs and a predictable and manageable safety profile., Competing Interests: Martin HutchingsConsulting or Advisory Role: Takeda, Roche, GenmabResearch Funding: Celgene, Genmab, Roche, Takeda, Novartis Franck MorschhauserConsulting or Advisory Role: Roche/Genentech, Gilead Sciences, Celgene, Bristol Myers Squibb, AbbVie, Epizyme, ServierSpeakers' Bureau: RocheExpert Testimony: Roche/Genentech Gloria IacoboniHonoraria: Gilead Sciences, Novartis, Roche/Genentech, Celgene/Bristol Myers Squibb, JanssenConsulting or Advisory Role: Novartis, Celgene/Bristol Myers Squibb, Gilead SciencesTravel, Accommodations, Expenses: Gilead Sciences, Novartis, Celgene/Bristol Myers Squibb Carmelo Carlo-StellaHonoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca, Celgene, Takeda, Incyte, Gilead SciencesConsulting or Advisory Role: Sanofi, ADC Therapeutics, Roche, Karyopharm Therapeutics, Celgene/Bristol Myers Squibb, IncyteResearch Funding: ADC Therapeutics, Sanofi, RocheTravel, Accommodations, Expenses: Roche, Janssen, Takeda, ADC Therapeutics Anna SuredaHonoraria: Takeda, Bristol Myers Squibb, Merck Sharp & Dohme, Celgene, Janssen, Sanofi, Roche, Novartis, Gilead Sciences, Janssen-CilagConsulting or Advisory Role: Takeda, Bristol Myers Squibb, Gilead Sciences, Celgene, Janssen, NovartisSpeakers' Bureau: TakedaOther Relationship: Sanofi, Takeda, Roche, Celgene, Gilead Sciences Gilles SallesHonoraria: Roche/Genentech, Janssen, Celgene, Gilead Sciences, Novartis, AbbVie, MorphoSysConsulting or Advisory Role: Roche/Genentech, Gilead Sciences, Janssen, Celgene, Novartis, MorphoSys, Epizyme, Alimera Sciences, Genmab, Debiopharm Group, Velosbio, Bristol Myers Squibb, BeiGene, Incyte, Miltenyi Biotec Joaquín Martínez-LopezSpeakers' Bureau: Roche, Janssen-Cilag, BMSiResearch Funding: Astellas Pharma, Bristol Myers Squibb Michael CrumpHonoraria: Gilead Sciences, Servier/PfizerConsulting or Advisory Role: Servier, Gilead Sciences, Novartis Canada Pharmaceuticals IncResearch Funding: Roche Canada Denise N. ThomasEmployment: Roche TCRC, Genmab, Cellectis Peter N. MorcosEmployment: Roche/Genentech, BayerStock and Other Ownership Interests: Roche/Genentech, Bayer Cristiano FerliniEmployment: Roche/Genentech, AstraZenecaStock and Other Ownership Interests: AstraZeneca, Roche Ann-Marie E. BröskeEmployment: RocheStock and Other Ownership Interests: Roche, BioNTech AG Anton BelousovEmployment: Roche Marina BacacEmployment: RocheStock and Other Ownership Interests: RocheResearch Funding: RochePatents, Royalties, Other Intellectual Property: Coinventor in Roche patentsTravel, Accommodations, Expenses: Roche Natalie DimierEmployment: RocheStock and Other Ownership Interests: RocheTravel, Accommodations, Expenses: Roche David J. CarlileEmployment: Roche, AstraZenecaStock and Other Ownership Interests: AstraZeneca, Roche Linda LundbergEmployment: F. Hoffmann LaRocheStock and Other Ownership Interests: F. Hoffmann LaRoche David Perez-CallejoEmployment: RocheStock and Other Ownership Interests: Roche Pablo UmañaEmployment: RocheLeadership: RocheStock and Other Ownership Interests: RochePatents, Royalties, Other Intellectual Property: Co-inventor in Roche-owned patents on glofitamab and obinutuzumabTravel, Accommodations, Expenses: Roche Tom MooreEmployment: RocheStock and Other Ownership Interests: RocheTravel, Accommodations, Expenses: Roche Martin WeisserEmployment: RocheStock and Other Ownership Interests: RochePatents, Royalties, Other Intellectual Property: I hold patents for biomarkers and drug combinations. These are not related to the present study. I do not receive royalties Michael J. DickinsonHonoraria: Roche, Amgen, MSD, Janssen, Bristol Myers Squibb, NovartisConsulting or Advisory Role: Novartis, Bristol Myers Squibb, Gilead Sciences, Roche, JanssenSpeakers' Bureau: NovartisResearch Funding: Novartis, Roche, Takeda, Celgene, MSDTravel, Accommodations, Expenses: RocheNo other potential conflicts of interest were reported.

In many disease areas, commonly used long-term clinical endpoints are becoming increasingly difficult to implement due to long follow-up times and/or increased costs. Shorter-term surrogate endpoints are urgently needed to expedite drug development, the evaluation of which requires robust and reliable statistical methodology to drive meaningful clinical conclusions about the strength of relationship with the true long-term endpoint. This paper uses a simulation study to explore one such previously proposed method, based on information theory, for evaluation of time to event surrogate and long-term endpoints, including the first examination within a meta-analytic setting of multiple clinical trials with such endpoints. The performance of the information theory method is examined for various scenarios including different dependence structures, surrogate endpoints, censoring mechanisms, treatment effects, trial and sample sizes, and for surrogate and true endpoints with a natural time-ordering. Results allow us to conclude that, contrary to some findings in the literature, the approach provides estimates of surrogacy that may be substantially lower than the true relationship between surrogate and true endpoints, and rarely reach a level that would enable confidence in the strength of a given surrogate endpoint. As a result, care is needed in the assessment of time to event surrogate and true endpoints based only on this methodology., (© 2020 John Wiley & Sons Ltd.)

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Health-related quality of life (HRQoL) data are limited in patients with advanced basal cell carcinoma. To report HRQoL outcomes based on STEVIE (NCT01367665), a phase 2 study of vismodegib safety in patients with metastatic BCC or locally advanced BCC that is unsuitable for surgery or radiotherapy. Skindex-16 and MD Anderson Symptom Inventory (MDASI) questionnaires were completed at baseline and at three subsequent visits. Clinically meaningful improvement was defined as a ≥10-point decrease from baseline (Skindex-16) or improvement of at least 3 points from baseline (MDASI). HRQoL-evaluable patients with locally advanced BCC (n = 730) had ≥10-point improvements in Skindex-16 emotion domain scores at all time points. Changes in symptom and function scores in these patients or in any domain scores at any time point in patients with metastatic BCC (n = 10) were not clinically meaningful. Of 10 patients with symptomatic metastatic BCC at baseline, six had ≥3-point improvements in MDASI symptom severity. Skindex-16 and MDASI showed improvement in HRQoL in vismodegib-treated patients with locally advanced or metastatic BCC or BCC.

Our objective was to evaluate minimal residual disease (MRD) at the end of induction treatment with chemoimmunotherapy as a surrogate end point for progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) based on 3 randomized, phase 3 clinical trials (ClinicalTrials.gov identifiers NCT00281918, NCT00769522, and NCT02053610). MRD was measured in peripheral blood (PB) from treatment-naïve patients in the CLL8, CLL10, and CLL11 clinical trials, and quantified by 4-color flow cytometry or allele-specific oligonucleotide real-time quantitative polymerase chain reaction. A meta-regression model was developed to predict treatment effect on PFS using treatment effect on PB-MRD. PB-MRD levels were measured in 393, 337, and 474 patients from CLL8, CLL10, and CLL11, respectively. The model demonstrated a statistically significant relationship between treatment effect on PB-MRD and treatment effect on PFS. As the difference between treatment arms in PB-MRD response rates increased, a reduction in the risk of progression or death was observed; for each unit increase in the (log) ratio of MRD - rates between arms, the log of the PFS hazard ratio decreased by -0.188 (95% confidence interval, -0.321 to -0.055; P = .008). External model validation on the REACH trial and sensitivity analyses confirm the robustness and applicability of the surrogacy model. Our surrogacy model supports use of PB-MRD as a primary end point in randomized clinical trials of chemoimmunotherapy in CLL. Additional CLL trial data are required to establish a more precise quantitative relationship between MRD and PFS, and to support general applicability of MRD surrogacy for PFS across diverse patient characteristics, treatment regimens, and different treatment mechanisms of action., (© 2018 by The American Society of Hematology.)

Objective: Progression of amyotrophic lateral sclerosis (ALS) depends on several factors linked to the disease. However, both the patient's living place and care organization role need to be evaluated., Methods: We analysed the effect on survival of factors linked to ALS or the socio-geographical context in a prospective cohort of 203 patients followed between 2003 and 2011., Results: Patients were 97 females and 106 males with a mean age of 65.5 years. Survival was longer in younger patients, in case of upper limb involvement, longer time to diagnosis, and initially higher forced vital capacity. Non-invasive positive pressure ventilation (NIPPV) and percutaneous gastrostomy (PEG) failed to demonstrate benefit. Patients who lived at home had longer survival. The nature of non-medical organization at home statistically influenced survival, which was longer with an organized network than with an unorganized one and shorter in absence of non-medical organization. In patients with indication of PEG and NIPPV, the proposition was statistically different according to the care givers., Conclusions: Besides the natural history of ALS, survival depended on home organization and the presence or the nature of a home-care system. Home organization was an important factor of decision for NIPPV and PEG proposals.

Clinical trials of experimental treatments must be designed with primary endpoints that directly measure clinical benefit for patients. In many disease areas, the recognised gold standard primary endpoint can take many years to mature, leading to challenges in the conduct and quality of clinical studies. There is increasing interest in using shorter-term surrogate endpoints as substitutes for costly long-term clinical trial endpoints; such surrogates need to be selected according to biological plausibility, as well as the ability to reliably predict the unobserved treatment effect on the long-term endpoint. A number of statistical methods to evaluate this prediction have been proposed; this paper uses a simulation study to explore one such method in the context of time-to-event surrogates for a time-to-event true endpoint. This two-stage meta-analytic copula method has been extensively studied for time-to-event surrogate endpoints with one event of interest, but thus far has not been explored for the assessment of surrogates which have multiple events of interest, such as those incorporating information directly from the true clinical endpoint. We assess the sensitivity of the method to various factors including strength of association between endpoints, the quantity of data available, and the effect of censoring. In particular, we consider scenarios where there exist very little data on which to assess surrogacy. Results show that the two-stage meta-analytic copula method performs well under certain circumstances and could be considered useful in practice, but demonstrates limitations that may prevent universal use., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: In the primary analysis of the ERIVANCE BCC trial, vismodegib, the first US Food and Drug Administration-approved Hedgehog pathway inhibitor, showed objective response rates (ORRs) by independent review facility (IRF) of 30% and 43% in metastatic basal cell carcinoma (mBCC) and locally advanced BCC (laBCC), respectively. ORRs by investigator review were 45% (mBCC) and 60% (laBCC). Herein, we present long-term safety and final investigator-assessed efficacy results in patients with mBCC or laBCC., Methods: One hundred four patients with measurable advanced BCC received oral vismodegib 150 mg once daily until disease progression or intolerable toxicity. The primary end point was IRF-assessed ORR. Secondary end points included ORR, duration of response (DOR), progression-free survival, overall survival (OS), and safety., Results: At data cutoff (39 months after completion of accrual), 8 patients were receiving the study drug (69 patients in survival follow-up). Investigator-assessed ORR was 48.5% in the mBCC group (all partial responses) and 60.3% in the laBCC group (20 patients had complete response and 18 patients had partial response). ORRs were comparable across patient subgroups, including aggressive histologic subtypes (eg, infiltrative BCC). Median DOR was 14.8 months (mBCC) and 26.2 months (laBCC). Median OS was 33.4 months in the mBCC cohort and not estimable in the laBCC cohort. Adverse events remained consistent with clinical experience. Thirty-three deaths (31.7%) were reported; none were related to vismodegib., Conclusions: This long-term update of the ERIVANCE BCC trial demonstrated durability of response, efficacy across patient subgroups, and manageable long-term safety of vismodegib in patients with advanced BCC., Trial Registration: This study was registered prospectively with Clinicaltrials.gov , number NCT00833417 on January 30, 2009.

We present health-related quality of life (HRQoL) data from GADOLIN, comparing bendamustine (B) alone or combined with obinutuzumab (G-B) in rituximab-refractory indolent non-Hodgkin lymphoma patients. The Functional Assessment of Cancer Treatment-Lymphoma (FACT-Lym) questionnaire was administered on day 1 of cycles 1, 3, and 5 during treatment, at end of induction (EOI), bi-monthly for 2 years during maintenance/follow-up, and annually during extended follow-up until progression/death. Time to first ≥6-point worsening from baseline in the FACT-Lym trial outcome index (TOI) was estimated. Minimally important differences at individual subscale and total score level were used to define the proportion of patients reporting improvement on the FACT-Lym lymphoma-specific subscale (≥3 points), FACT-Lym TOI (≥6 points), and FACT-Lym total score (≥7 points). Overall, 396 patients were randomized. Analysis was conducted when 175 Independent Review Committee-assessed progression-free survival (PFS) events were observed. Questionnaire completion rates were generally balanced between arms at baseline, EOI, and final follow-up. Median time to ≥6-point worsening from baseline on the FACT-Lym TOI was 8.0 months in the G-B arm and 4.6 months in the B arm (HR 0.74; 95% CI 0.56-0.98). More G-B patients reported meaningful improvements on the FACT-Lym questionnaire subscales. Results were similar when follicular lymphoma patients were analyzed separately. The delayed time to worsening and greater proportion of patients reporting meaningful improvement in HRQoL in the G-B arm suggest that benefit in PFS is not at the expense of an increase in treatment-related toxicity that could lead to reduced HRQoL., Competing Interests: Compliance with ethical standards The protocol was approved by the ethics committees of participating centers and is registered at ClinicalTrials.gov. Funding This study was sponsored by F. Hoffmann-La Roche Ltd. Conflict of interest BDC has performed in a consulting or advisory role for Celgene, Gilead, Pharmacyclics, Astra Zeneca, Spectrum, and Astellas, and his institution has received research funding from Pharmacyclics, Acerta, Seattle Genetics, and Gilead. PCT is an employee of Genentech, Inc. and owns stock in Roche/Genentech. JGG has received honoraria from Roche/Genentech, Celgene, Pharmacyclis, Janssen, Gilead, Mundipharma, TG Therapeutics, and Acerta. ND is an employee of Roche and owns stock in Roche and GSK. EK has received honoraria from Janssen, Gilead, Celgene, and AbbVie; has performed in a consulting or advisory role for Janssen, Baxalta, and AbbVie; and has received research funding and drug support from—and worked on transitional research with—Pfizer. PJL has performed in a consulting or advisory role for Celgene, Mundipharma, and Servier. CT has performed in a consulting or advisory role for Janssen, Gilead, and Roche and has received travel, accommodation, and expenses support from Janssen and Gilead. EW-F is an employee of F. Hoffmann-La Roche Ltd. AL is an employee of F. Hoffmann-La Roche Ltd., owns stock in Novartis, and has received travel, accommodation, and expenses support from Roche and Novartis. LHS has received honoraria from Roche/Genentech, Celgene, Seattle Genetics, AbbVie, Janssen, Gilead, Amgen, and TG Therapeutics and has performed in a consulting or advisory role for Roche/Genentech, Celgene, Gilead, Janssen, Pfizer, Amgen, Seattle Genetics, AbbVie, Lundbeck, and TG Therapeutics. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study.

Background: Patients with indolent non-Hodgkin lymphoma who fail to achieve adequate disease control with rituximab-based treatment have few treatment options and a poor prognosis. We aimed to assess a combination of obinutuzumab (GA101), a novel glyco-engineered type II anti-CD20 monoclonal antibody, and bendamustine in this patient population., Methods: In this open-label, randomised, phase 3 study (GADOLIN), patients aged 18 years or older with histologically documented, CD20-positive indolent non-Hodgkin lymphoma refractory to rituximab were enrolled at 83 hospital and community sites in 14 countries in Europe, Asia, and North and Central America. Patients were randomly assigned (1:1) using a hierarchical dynamic randomisation scheme stratified by indolent non-Hodgkin lymphoma subtype, rituximab-refractory type, number of previous therapies, and geographical region, to receive induction treatment (six 28-day cycles) with obinutuzumab plus bendamustine or bendamustine monotherapy, both given intravenously. Obinutuzumab plus bendamustine dosing was obinutuzumab 1000 mg (days 1, 8, and 15, cycle 1; day 1, cycles 2-6) plus bendamustine 90 mg/m(2) per day (days 1 and 2, cycles 1-6), and bendamustine monotherapy dosing was 120 mg/m(2) per day (days 1 and 2, all cycles). Non-progressing patients in the obinutuzumab plus bendamustine group received obinutuzumab maintenance (1000 mg every 2 months) for up to 2 years. The primary endpoint was progression-free survival in all randomised patients, as assessed by an independent review committee. Safety was assessed in all patients who received any amount of obinutuzumab or bendamustine. This study is registered with ClinicalTrials.gov, number NCT01059630, and has stopped recruiting patients., Findings: Between April 15, 2010, and Sept 1, 2014, when the study was stopped after a pre-planned interim analysis, 396 patients were randomly assigned (194 to obinutuzumab plus bendamustine and 202 to bendamustine monotherapy). After a median follow-up time of 21·9 months (IQR 12·1-31·0) in the obinutuzumab plus bendamustine group and 20·3 months (9·5-29·7) in the bendamustine monotherapy group, progression-free survival was significantly longer with obinutuzumab plus bendamustine (median not reached [95% CI 22·5 months-not estimable]) than with bendamustine monotherapy (14·9 months [12·8-16·6]; hazard ratio 0·55 [95% CI 0·40-0·74]; p=0·0001). Grade 3-5 adverse events occurred in 132 (68%) of 194 patients in the obinutuzumab plus bendamustine group and in 123 (62%) of 198 patients in the bendamustine monotherapy group. The most frequent grade 3 or worse adverse events were neutropenia (64 [33%] in the obinutuzumab plus bendamustine group vs 52 [26%] in the bendamustine monotherapy group), thrombocytopenia (21 [11%] vs 32 [16%]), anaemia (15 [8%] vs 20 [10%]) and infusion-related reactions (21 [11%] vs 11 [6%]). Serious adverse events occurred in 74 patients (38%) in the obinutuzumab plus bendamustine group and in 65 patients (33%) in the bendamustine monotherapy group, and deaths due to adverse events occurred in 12 patients (6%) and 12 patients (6%), respectively. Three (25%) of 12 adverse event-related deaths in the obinutuzumab plus bendamustine group and five (42%) of 12 in the bendamustine monotherapy group were treatment related., Interpretation: Obinutuzumab plus bendamustine followed by obinutuzumab maintenance has improved efficacy over bendamustine monotherapy in rituximab-refractory patients with indolent non-Hodgkin lymphoma, with manageable toxicity, and is a new treatment option for patients who have relapsed after or are no longer responding to rituximab-based therapy., Funding: F Hoffmann-La Roche Ltd., (Copyright © 2016 Elsevier Ltd. All rights reserved.)