A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL

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

Dual CD20-targeted therapy with concurrent CD20-TCB and obinutuzumab shows highly promising clinical activity and manageable safety in relapsed or refractory B-cell non-Hodgkin lymphoma : preliminary results from a phase Ib trial

CD20-TCB (RG6026) is a novel T-cell-engaging bispecific (TCB) antibody with a '2:1' molecular format comprising two fragment antigen binding regions that bind CD20 (on the surface of B cells) and one that binds CD3 (on the surface of T cells). CD20-TCB offers the potential for increased tumor antigen avidity, rapid T-cell activation, and enhanced tumor cell killing versus other bispecific formats, and the ability to combine with another CD20-targeted agent. Preclinical studies of concurrent therapy with CD20-TCB plus obinutuzumab (G) in diffuse large B-cell lymphoma (DLBCL) models demonstrate strong and sustained tumor regression driven by multiple mechanisms of action. These include induction of direct tumor cell death and antibody-dependent cellular cytotoxicity/cellular phagocytosis mediated by G, as well as recruitment of T-cells into the tumor and T-cell cytotoxicity mediated by CD20-TCB. NP30179 (NCT03075696) is a multicenter Phase I/Ib dose-escalation trial investigating the safety, tolerability, pharmacokinetics, biomarker responses, and anti-tumor activity (assessed by objective response rate [ORR] and complete response [CR] rate per modified Lugano 2014 criteria) of CD20-TCB in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) patients (pts). For the first time, we report preliminary data from Arm B, evaluating dual CD20-targeted therapy with concurrent CD20-TCB and G. All pts receive a single dose of 1000mg G as pre-treatment (Gpt) 7 days before the start of CD20-TCB therapy (Cycle 1) to mitigate cytokine release syndrome (CRS). From Cycle 2 onwards, 1000mg G is administered on the same day as CD20-TCB, which constitutes the start of an initial 28-day dose-limiting toxicity (DLT) window, in 3-weekly cycles. Pts receive escalating doses of CD20-TCB, guided by a model implementing the Bayesian continuous reassessment method with overdose control. As of May 22, 2019, a total of 28 pts with R/R aggressive (a) NHL (DLBCL/primary mediastinal large B-cell lymphoma/transformed follicular lymphoma [FL]/mantle cell lymphoma/Richter´s transformation; n=22) or FL (n=6) had received concurrent G in combination with CD20-TCB doses ranging from 0.6 to 16mg for 8-12 cycles. Median age was 65 years (range, 34-81), 15 (54%) were male, 19 (68%) were refractory to prior therapy, and median prior lines of therapy was 2 (range, 1-6). Twenty-three CRS events (according to Lee criteria, Lee et al. Blood 2014) occurred in 16 (57%) pts (maximum Grade [Gr]: Gr 1, 5 [18%]; Gr 2, 9 [32%]; Gr 3, 1 [4%]; Gr 4, 1 [4%]). CRS events were confined to Cycle 1 in all but two pts. Neurotoxicity was rare (Gr 1, 4 [14%]; Gr 2, 2 [7%]; Gr 3, 1 [4%]) and all events resolved. Apart from CRS, the most frequent adverse events were anemia (all Gr, 6 [21%]; Gr 3, 3 [11%]), thrombocytopenia (all Gr, 6 [21%]; Gr ≥3, 3 [11%]; no hemorrhages reported), neutropenia (all Gr, 4 [14%]; Gr ≥3, 3 [11%]), pyrexia (all Gr, 4 [14%], all Gr 1-2), and hypokalemia (all Gr, 4 [14%]; Gr ≥3, 1 [4%]). No DLTs were reported and no new safety signals were observed. The overall safety profile overlapped with that reported in the single arm of the same study. Twenty-one pts reached their first response assessment or withdrew early and were eligible for efficacy analysis. Overall, the ORR and CR rate by investigator assessment was 48% [10/21 pts] and 43% [9/21], respectively (aNHL: ORR, 38% [6/16]; CR, 31% [5/16]; FL: ORR and CR, 80% [4/5]). CD20-TCB exposure and receptor occupancy (RO%) increased dose-dependently across the investigated dose range, and consistent with the RO%-efficacy model (Djebli et al. ASH 2019), clinically relevant CD20-TCB RO% and increased clinical activity was observed at a dose of 16mg when combined with concurrent G. In the 16mg cohort that included 10 R/R pts, 70% of whom were refractory to prior therapy and median prior lines of therapy was 4, the ORR and CR rate were 90% (9/10 pts) and 80% (8/10), respectively (aNHL: CR, 71% [5/7]; FL: CR, 100% [3/3]), and all CRs were ongoing at the time of abstract submission. This is the first study to demonstrate that CD20-TCB can be safely combined with an anti-CD20 monoclonal antibody and further supports the promise of the '2:1' format for allowing combination therapy with therapeutic levels of other anti-CD20 antibodies, such as G. CD20-TCB plus G provides highly promising clinical activity in heavily pre-treated R/R B-cell NHL. Updated clinical and biomarker data will be presented

Glofitamab, a Novel, Bivalent CD20-Targeting T-Cell-Engaging Bispecific Antibody, Induces Durable Complete Remissions in Relapsed or Refractory B-Cell Lymphoma: A Phase I Trial

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