Phase 2


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In this multicenter, open-label, phase 2 trial (ClinicalTrials.gov Identifier: NCT01741792), 25 patients with relapsed/refractory DLBCL received 112 μg/day of blinatumomab by continuous infusion for up to 8 weeks. After 4 treatment-free weeks, patients with a response to the first cycle could receive an additional 4-week consolidation with blinatumomab.3

Patients were treated in 3 cohorts: cohort 1 received a stepwise dose beginning with 9 μg/day of blinatumomab during week 1, 28 μg/day during week 2, and 112 μg/day thereafter; cohort 2 received a flat-dose of 112 μg/day throughout the cycle; cohort 3 received the selected dose from cohorts 1 and 2, which was the step-wise dosing.

All patients received prophylactic dexamethasone for each blinatumomab infusion start, and dexamethasone was administered to patients who demonstrated signs of cytokine release syndrome (CRS) or neurologic events.

The median age at baseline was 66, the median number of lines of treatment was 3 (range, 1-7), and 28% of patients had undergone a prior autologous hematopoietic stem cell transplant.

The ORR in both cohorts among evaluable patients (20 in cohorts 1 and 3, 1 in cohort 2) was 42.9%, which included CR among 19% of patients, and PR among 23.8%.

The median DOR was 11.6 months (95% CI, 0.9-not estimable) and the median progression-free survival was 3.7 months (95% CI, 1.4-7.7 months) with a median follow-up time of 15.0 months. The median overall survival among all patients was 5.0 months (95% CI, 2.3-not estimable).

Safety

The main safety concerns of blinatumomab in the NHL population is neurologic events and cytokine release syndrome.

“At this time, the cause of potential neurologic adverse events is unclear,” Dr Barnes said, though “similar neurologic events are also seen in other T cell mediated therapies including CAR T cells.”

In the phase 1 trial, grade 3 and 4 adverse events (AEs) of any cause occurred among 90% and 66% of patients, respectively. The most common AEs were lymphopenia, pyrexia, and C-reactive protein disease. Neurologic events occurred in 71% of patients, 22% of which were grade 3.

In the phase 2 trial, all patients experienced a treatment-emergent AE (TEAE) of any grade and 95.7% experienced grade 3 or worse AEs.

Serious AEs deemed related to blinatumomab treatment occurred among 35% of patients.3

Neurologic events were reported most commonly within the first 2 days of the first blinatumomab infusion of each cycle or dose step, and most resolved to grade 1 or better after treatment discontinuation.

In the phase 2 study, the median time to any neurologic event was 18 days and most resolved with a median time to resolution of 4.5 days.

Dr Barnes said that “the key for management is early identification and discontinuation of the drug for patients with significant toxicity.”

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Conclusion

Although blinatumomab shows promising antitumor activity among patients with varying subtypes of NHL, the incidence of neurologic toxicity is high despite step-wise dosing and corticosteroid co-administration.

“Further studies of safe dosing schedules and predicting toxicity across different subtypes of NHL are needed,” Dr Barnes said.

Reference

  1. Sanders S, Stewart DA. Targeting non-Hodgkin lymphoma with blinatumomab. Exp Opin Biological Ther. 2017 Jun 1. doi: 10.1200/JCO.2016.72.1340 [Epub ahead of print]
  2. Goebler ME, Knop S, Viardot A, et al. Bispecific T-cell engager (BiTE) antibody construct blinatumomab for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma: final results from a phase I study. J Clin Oncol. 2016;34:1104-11. doi: 10.1200/JCO.2014.59.1586
  3. Viardot A, Goebeler ME, Hess G, et al. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood. 2016;127:1410-6. doi: 10.1182/blood-2015-06-651380