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Obinutuzumab reduces POD24 risk in FL patients
Patients with early PD have a much poorer survival than those with later disease progression.4,5 The glycoengi- neered anti-CD20 antibody obinutuzumab (GA101; G) has reduced complement-dependent cytotoxicity com- pared with R, but its direct cell-killing ability, as well as its antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis, are stronger than those of R.6,7 In the recently reported GALLIUM study (clinicaltrials.gov identifier: 01332968) in previously untreated patients with advanced FL, investigator- assessed progression-free survival (PFS) was significantly improved with G-based immunochemotherapy (G- chemo) relative to R-chemo [hazard ratio (HR), 0.68; 95% confidence interval (CI): 0.54-0.87; P=0.002].8
The aims of this exploratory analysis of patients with FL in GALLIUM were to evaluate early PD and its impact on overall survival (OS), and to investigate the impact of G-chemo versus R-chemo treatment on the incidence of early PD.
Methods
GALLIUM was an open-label, randomized, parallel-group study in which patients with previously untreated grade 1-3a FL were randomized to receive induction therapy with G or R plus chemotherapy [cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), cyclophosphamide, vincristine and pred- nisone (CVP) or bendamustine] for 6 or 8 cycles, depending on the selected chemotherapy, followed in responders by two years of maintenance with the same antibody. GALLIUM was con- ducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice. The pro- tocol was approved by the ethics committees of all participating centers. All patients provided written informed consent. Patient selection, study methods and treatment are described in detail in the Online Supplementary Methods, and elsewhere.9
The principal end point in the current exploratory analysis was PD or death due to PD within 24 months of randomization (“POD24”); “noPOD24” was defined as patients who had complet- ed 24 months of follow up with no PD or death due to PD during that time. Details of analyses to assess PD or suspected transfor- mation are described in the Online Supplementary Appendix. Deaths from causes other than PD during the 24-month window in patients without prior PD, e.g. fatal adverse events or deaths from unrelated causes, contributed as events in noPOD24 mortality, but patients with these events are not included in the description of baseline characteristics for noPOD24 patients.
Analyses were based on investigator assessments and were undertaken using SAS® 9.4 software.
For all randomized patients, the effect of POD24 status on OS was quantified using a time-varying Cox regression model with POD24 status as a time-dependent co-variate. Other co-variates were allocated study treatment and age at randomization; chemotherapy regimen and Follicular Lymphoma International Prognostic Index (FLIPI) score were stratification factors. In this model (and for the calculation of crude death rates), all patients were considered POD24-free until transition to the POD24 group after a POD24 event, or until the end of survival follow up. The effect of the study treatment on the risk of POD24 was estimated by cause-specific Cox regression accounting for POD24 events and censoring for non-PD related deaths within the first 24 months. Analysis was stratified by chemotherapy regimen and FLIPI score.
6, 12, 18, and 24 months post randomization) was estimated using Kaplan-Meier (KM) methods. These estimates allow a descriptive, non-randomized comparison of OS in patients with PD who were still alive versus those with no PD at the landmark. The 24-month landmark analysis was carried out using a Cox regression model, with the same co-variates and stratification factors as the time-dependent model, but with POD24 status as a time-fixed covariate. The risk of a PFS event within 24 months of randomization was also estimated, and the 24-month KM rates were compared across treatment arms.
Post-progression mortality rates in POD24 patients were esti- mated for all patients and for each treatment arm separately, and for patients who progressed between 0-6, >6-12, >12-18, and >18-24 months from randomization. NoPOD24 mortality rates (overall and by treatment arm) were also calculated.
Results
Patients’ characteristics
Of 1202 patients with FL randomized in GALLIUM (Online Supplementary Figure S1), 1071 were followed for response until at least 24 months post randomization and evaluated for POD24 status. For the remaining 131 patients, follow up was incomplete (mostly due to study discontinuation): 23 of these patients died from non-PD related causes without prior PD. POD24 events occurred in a total of 155 patients (12.9%), of whom 41 died within 24 months of randomization; 916 patients had no POD24 event after at least 24 months of follow up (Online Supplementary Table S1). The data cutoff for this analysis was September 10, 2016, giving a median follow up of 41 months.
Baseline characteristics for POD24 and noPOD24 patients showed some notable differences (Table 1). Compared with noPOD24 patients, POD24 patients were more likely to have the following features: male sex, stage IV disease, grade 3a histology, high FLIPI risk, elevated serum lactate dehydrogenase (LDH), and bulky disease. Relatively more POD24 patients than noPOD24 patients were treated with CVP and fewer were treated with ben- damustine. Baseline characteristics for those patients who progressed within six months of randomization are shown in Online Supplementary Table S2.
Progressive disease or death due to progressive disease and progression-free survival by treatment arm Progressive disease or death due to progressive disease at 24-months post randomization events occurred in 57 of 601 patients (9.5%) treated with G-chemo and 98 of 601 patients (16.3%) treated with R-chemo; cumulative incidence rates were 10.1% (95%CI: 8-12%) and 17.4% (95%CI: 14-20%), respectively. The average HR-based reduction in the risk of a POD24 event with G-chemo relative to R-chemo was 46.0% (95%CI: 25.0-61.1%; P=0.0003, Gray’s test for equality) (Figure 1). The risk of a PFS event in the 24 months after randomization was 18.9% (95%CI: 15.9-22.4%) for R-chemo and 12.5% (95%CI: 10.1-15.6%) for G-chemo; the relative risk reduction for PFS events was 33.9% (95%CI: 12.8- 49.8%) (Figure 1). In the noPOD24 group, with a median subsequent follow up of 24 months, 88 out of 916 patients had POD events after the 24-month time point [G-chemo, 40 out of 478 (8.4%); R-chemo, 48 out of 438
(11.0%)].
Overall survival from 4 specified time points (“landmarks”; at
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