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AIMS: Obinutuzumab (G) is a humanized type II, Fc-glycoengineered anti-CD20 monoclonal antibody used in various indications, including patients with previously untreated front-line follicular lymphoma. We investigated sources of variability in G exposure and association of progression-free survival (PFS) with average concentration over induction (CmeanIND ) in front-line follicular lymphoma patients treated with G plus chemotherapy (bendamustine, CHOP, or CVP) in the GALLIUM trial. METHODS: Individual exposures (CmeanIND ) were obtained from a previously established population pharmacokinetic model updated with GALLIUM data. Multivariate Cox proportional hazard models and univariate Kaplan-Meier plots investigated relationships of PFS with exposure and other potential prognostic factors. RESULTS: Overall, G exposure was lower in high body-weight patients and in males, and slightly lower in patients with high baseline tumour burden. Analysis of clinical outcomes showed that variability in G exposure did not impact PFS in G-bendamustine-treated patients; PFS was inferior in males and patients with FCGR2a/2b T232 T low-affinity receptor variant, and superior in patients with FCGR2a/2b I232T variant. In G-CHOP/CVP arms, PFS improved with increasing CmeanIND (hazard ratio = 1.74 and 0.394 at 5th and 95th percentile compared to median CmeanIND ) and was inferior in patients with high baseline tumour size and B symptoms. CONCLUSIONS: It remains unclear whether for G-CHOP/CVP patients lower G exposure is a consequence of adverse disease biology and/or resistance to chemotherapy backbone (higher clearance in nonresponder patients, as demonstrated for rituximab) rather than being the cause of poorer clinical outcome. A study with >1 dose level of G could help resolve this uncertainty.

Introduction: The Phase III Gallium study has shown that induction with the anti-CD20 monoclonal antibody obinutuzumab (GA101; G) plus chemotherapy followed by maintenance with G alone significantly prolongs PFS relative to the corresponding rituximab-containing regimen in previously untreated pts with follicular lymphoma (FL). However, FL remains incurable, and most pts eventually relapse. Atezolizumab (atezo), which targets programmed death-ligand 1 (PD-L1), has a complementary mechanism of action to G and has the potential to improve outcomes when added to G-chemotherapy in FL. We report interim data from a single FL cohort from our Phase Ib/II study (NCT02596971) of the safety and efficacy of induction with G-bendamustine (benda)-atezo followed by maintenance with Gatezo. Method(s): Pts (>=18 yrs old, ECOG PS 0-2) with FL (previously untreated grade 1, 2 or 3a disease requiring therapy or relapsed/refractory [R/R]) received induction with infusions of G 1000 mg on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2-6, benda 90 mg/m2 on days 1 and 2 of cycles 1-6, and atezo 840 mg on days 1 and 15 of cycles 2-6 (28-day cycles). Maintenance in pts with CR or PR consisted of G 1000 mg on day 1 of every other month and atezo 840 mg on days 1 and 2 of each month for <=24 months. Enrollment included an initial safety run-in phase with intensive safety monitoring in 6 pts before the main enrolment (expansion phase) began; R/R pts were permitted in the safety run-in phase only. The primary endpoint was CR (PET-CT) rate at end of induction (EOI) determined by independent review committee (IRC) using modified Lugano 2014 criteria. Secondary endpoints included CR rate at EOI assessed by investigator (INV) using modified Lugano 2014, CR rate at EOI by IRC and INV using modified Cheson 2007, ORR at EOI by IRC and INV using modified Lugano 2014 and modified Cheson 2007, DoR, and PFS and EFS by INV. MRD as an exploratory endpoint was centrally assessed by next generation sequenc

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 MRD2 rates between arms, the log of the PFS hazard ratio decreased by 20.188 (95% confidence interval, 20.321 to 20.055; P 5 .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.

BACKGROUND: Rituximab-based immunochemotherapy has improved outcomes in patients with follicular lymphoma. Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody. We compared rituximab-based chemotherapy with obinutuzumab-based chemotherapy in patients with previously untreated advanced-stage follicular lymphoma. METHOD(S): We randomly assigned patients to undergo induction treatment with obinutuzumab-based chemotherapy or rituximab-based chemotherapy. Patients with a response received maintenance treatment for up to 2 years with the same antibody that they had received in induction. The primary end point was investigator-assessed progression-free survival. RESULTS: A total of 1202 patients with follicular lymphoma underwent randomization (601 patients in each group). After a median follow-up of 34.5 months (range, 0 to 54.5), a planned interim analysis showed that obinutuzumab-based chemotherapy resulted in a significantly lower risk of progression, relapse, or death than rituximab-based chemotherapy (estimated 3-year rate of progression-free survival, 80.0% vs. 73.3%; hazard ratio for progression, relapse, or death, 0.66; 95% confidence interval [CI], 0.51 to 0.85; P=0.001). Similar results were seen with regard to independently reviewed progression-free survival and other time-to-event end points. Response rates were similar in the two groups (88.5% in the obinutuzumab group and 86.9% in the rituximab group). Adverse events of grade 3 to 5 were more frequent in the obinutuzumab group than in the rituximab group (74.6% vs. 67.8%), as were serious adverse events (46.1% vs. 39.9%). The rates of adverse events resulting in death were similar in the two groups (4.0% in the obinutuzumab group and 3.4% in the rituximab group). The most common adverse events were infusion-related events that were considered by the investigators to be largely due to obinutuzumab in 353 of 595 patients (59.3%; 95% CI, 55.3 to 63.2) and to rituximab in 292 of 597 patients (

Obinutuzumab (G) is a glycoengineered type II anti-CD20 monoclonal antibody with promising activity and manageable toxicity when combined with chemotherapy in relapsed iNHL. GALLIUM (NCT01332968) is an open-label, randomised Phase 3 study comparing the efficacy and safety of rituximab (R) or G with chemotherapy followed by maintenance as first-line treatment in iNHL. Patients (pts) were aged >=18 years with previously untreated follicular lymphoma (FL) (grades 1-3a) or chemotherapy-nave marginal zone lymphoma (MZL), stage III/IV disease or stage II with tumour diameter >=7 cm, ECOG PS 0-2, and requiring treatment according to GELF criteria. CHOP, CVP, or bendamustine (B) were allocated according to centre (FL) or pt (MZL). Pts were randomised 1:1 and stratified by chemotherapy, FLIPI/IPI group, and geographic region to receive R 375 mg/m2 on D1 of each cycle or G 1000 mg on D1, 8, 15 of Cycle 1 and D1 of subsequent cycles, for either 8 x 21-day cycles (CHOP, CVP) or 6 x 28-day cycles (B). Pts with a CR or PR at the end of induction (EOI) received R or G every 2 months for 2 years or until disease progression. The primary endpoint was investigator-assessed PFS in FL pts. The current data are from an interim efficacy analysis done when a planned 67% of 370 PFS events had occurred (cut-off date: Jan 31, 2016) after which the study was unblinded on IDMC recommendation. Results are reported for 1202 FL pts (R-chemo, 601; G-chemo, 601); median age 59 years, 53.2% female. Treatment arms were well balanced by disease stage (Ann Arbor: I, 1.5%; II, 7.1%; III, 34.9%; IV, 56.5%) and prognostic factors (FLIPI: 0 + 1, 21.0%; 2, 37.2%; >=3, 41.8%; FLIPI-2: 0, 9.1%; 1 + 2, 50.3%; >=3, 40.6%). 686 patients (57.1%) received B, 33.1% CHOP, and 9.8% CVP. CR and ORR at EOI were similar for the two arms. There was a 34% reduction in the risk of progression or death (HR 0.66; 95% CI, 0.51-0.85; p = 0.001; median follow-up 34.5 months, range 0-54.5). Although the median PFS has not been r

Introduction: DLBCL pts with tumours co-expressing BCL2 and MYC (dual-expressor, DE) or with dual gene translocations (double-hit, DH) have poor outcomes but prognostic relationships between cell-of-origin (COO) subtype (ABC vs GCB) and BCL2/MYC are unclear. We report predefined exploratory analyses of the prognostic effects of BCL2 positivity (+), MYC+, DE and DH, in relation to COO, in the Phase III GOYA study (NCT01287741). Method(s): Pts with previously untreated DLBCL were randomised 1:1 to receive obinutuzumab or rituximab plus 6 or 8 cycles of CHOP. Using a Ventana investigational-use IHC assay (BCL2 antibody clone, 124; c-MYC, Y69), pretreatment tumour samples were analysed at a central laboratory. Samples stained within the limit of BCL2 (<=4 months, 30degreeC) and MYC (<=12 months, 30degreeC) antigen stability were included in primary analyses; sensitivity analyses included all samples. Scoring algorithm incorporated % of tumour cells stained and intensity: BCL2 IHC+, moderate/strong in >=50% of tumour cells; MYC IHC+, >=40% of tumour cells. Vysis LSI Dual Color Break Apart FISH Probes identified BCL2 and MYC translocations: FISH+, >=50%. COO classification of RNA extracts used a NanoString Lymphoma Subtyping gene expression assay. Univariate Cox regression analysis of investigator-assessed PFS was performed. Covariates for multivariate analysis were treatment arm (Tx), IPI score, no. of CHOP cycles and COO. (Figure Presented) Results: Baseline characteristics, including IPI score, were similar for biomarker evaluable and ITT populations. Prevalence of BCL2 IHC+, MYC IHC+, DE and DH was 49%, 83%, 42% and 3.6%, respectively. Prevalence by COO: BCL2 IHC+, 75% in ABC and 38% in GCB; MYC IHC+, 95% in ABC and 76% in GCB; DE, 72% in ABC and 29% in GCB; DH, 7% in GCB and 0% in ABC (19/20 DH pts were GCB; 1 unclassified). In univariate analysis, BCL2 IHC+, DE and DH were associated with poorer prognosis (Table). Multivariate analysis confirm the poor prognosis of