Combination Brentuximab Vedotin and Bendamustine Safe and Effective for Heavily Pretreated HL

Coupling the anti-CD30 antibody drug conjugate brentuximab vedotin with bendamustine may offer an effective salvage regimen for patients with relapsed/refractory Hodgkin lymphoma (HL), according to results from a phase I/II study published in The Lancet Oncology.

The findings “show a substantial clinical benefit with a high proportion of patients achieving a complete response,” wrote Owen A. O’Connor, MD, PhD, director of the Center for Lymphoid Malignancies at Columbia University Medical Center in New York, and co-authors. This combination could potentially serve as an “efficacious and safe alternative to platinum-based chemotherapy before autologous hematopoietic cell transplantation (AHCT),” they added.

This international, multicenter, single-arm trial enrolled 65 adult patients from three institutions in the U.S. and Canada between July 26, 2012, and May 31, 2017. Eligible participants had histologically confirmed relapsed/refractory HL or anaplastic large T-cell lymphoma, biopsy-proven CD30-positive tumors, an Eastern Cooperative Oncology Group performance status score of ≤2, and prior treatment with at least one multi-agent chemotherapy regimen.

Patients were excluded if they previously received this drug combination or received either drug as monotherapy within three months of enrollment, or if disease progression occurred within the first three cycles of treatment with brentuximab vedotin or bendamustine monotherapies.

Participants in each study phase were heavily pretreated, with a median of five prior therapies (range = 2-12 therapies) in phase I and three prior therapies (range = 1-8 therapies) in phase II.

In phase I, 28 patients (median age = 38 years; range = 25-70 years) received the combination regimen in a 3+3 dose-escalation design:

  • brentuximab vedotin 1.2 mg/kg and bendamustine 70 mg/m2 (cohort 1; n=7; 25%)
  • brentuximab vedotin 1.2 mg/kg and bendamustine 80 mg/m2 (cohort 2; n=3; 11%)
  • brentuximab vedotin 1.8 mg/kg and bendamustine 80 mg/m2 (cohort 3; n=7; 25%)
  • brentuximab vedotin 1.8 mg/kg and bendamustine 90 mg/m2 (cohort 4; n=11; 39%)

Grade 3 adverse events (AEs) included anemia (n=5; 18%), decreased platelet count (n=4; 14%), and infusion-related reactions (n=2; 7%). Three patients (11%) experienced dose-limiting toxicities (co-primary endpoint; defined as any missed dose within treatment cycle 1 or toxicity that was possibly related to the study drug occurring up to 7 days after cycle 1 that led to treatment delay). These included grade 4 neutropenia (n=2 in cohorts 3 and 4; 7%) and diffuse rash (n=1 in cohort 1; 4%).

The maximum tolerated dose (co-primary endpoint) was not reached, and the researchers recommended dosing cohort 4 for phase II.

The second phase included 37 patients (median age = 34 years; range = 18-72 years); 29 (78%) achieved a response (primary endpoint). See TABLE for all phase II efficacy outcomes.

The median duration of response was 4.3 months (range = 0-7.1 months) in phase I and 3.95 months (range = 7.5 months to not reached) in phase II. “Responses were durable, with several patients being in remission for more than two years after receiving the combination treatment,” the authors noted.

Median overall survival and progression-free survival were 43.3 months (range = 11.3 months to not reached) and 7.5 months (range = 4.8-12.1 months), respectively, in phase I, and were not reached in phase II. “These results compare favorably with those obtained for various other conventional salvage regimens used before HCT in this setting,” they added.

AEs occurring in phase II were decreased neutrophil count (n=10; 27%) and lung infection (n=5; 14%). Three (8%) grade 4 events (decreased neutrophil counts) were observed.

Four patients discontinued treatment because of toxicity (2 in each phase). Twenty-three patients (35%) died, 20 (31%) of which were because of disease progression (14 in phase I and 6 in phase II); two progressions were related to HCT. No deaths were related to treatment or AEs.

“With only 14 percent of patients reporting a grade 3 AE in phase I and 18 percent of patients reporting grade 3 or 4 toxicities in phase II, [these data suggest] the combination of brentuximab vedotin plus bendamustine is not more toxic than the single agents alone,” the authors reported.

An exploratory analysis of changes in biomarker concentrations demonstrated that the mean baseline CD30 concentration in complete responders, compared with non-responders, was significantly different. However, the percentage change in CD30 concentration from baseline to end of treatment was not significantly different, suggesting that “traditional biomarkers that might predict clinical outcomes in treatment-naïve patients, or [in] patients who received one previous therapy, might not be predictive in heavily pretreated patients.”

The study is limited by its small patient population and lack of a comparator arm. Randomized trials that allow formal cross-regimen efficacy comparisons are warranted, the researchers added.

Teva and Seattle Genetics supported the study.

The authors report financial relationships with Seattle Genetics.


Reference

O’Connor OA, Lue JK, Sawas A, et al. Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin’s lymphoma: an international, multicentre, single-arm, phase 1–2 trial. Lancet Oncol. 2017 December 21. [Epub ahead of print]

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