Brentuximab Vedotin Plus Nivolumab May Be an Alternative to Salvage Chemotherapy in Relapsed/Refractory Hodgkin Lymphoma

In a phase I/II study published in Blood, the combination of brentuximab vedotin plus nivolumab was an effective first salvage therapy in patients with relapsed/refractory Hodgkin lymphoma (HL), with 83 percent of patients responding to treatment.

The response rates reported in this study “are higher than those observed with brentuximab vedotin or nivolumab alone in relapsed/refractory HL and are higher than with brentuximab vedotin … as initial salvage therapy,” noted lead author Alex F. Herrera, MD, from the Department of Hematology/Hematopoietic Cell Transplantation at the City of Hope Medical Center in Los Angeles, California, and co-authors. The findings suggest this combination could provide an alternative to traditional chemotherapy.

The open-label, multicenter study included adults who were eligible for autologous hematopoietic cell transplantations (AHCT), had disease that relapsed or was refractory to standard frontline chemotherapy, and had an Eastern Cooperative Oncology Group performance status score of 0-1. Patients were excluded if they received prior salvage therapy (brentuximab vedotin or immunotherapy), had a prior HCT, had radiation therapy within three weeks prior to the study, or had chest radiation within 12 weeks of first study drug dose.

Sixty-two patients (median age = 36 years; range = 18-69 years) were enrolled between October 20, 2015, and November 23, 2016, from 12 U.S. sites. Participants received brentuximab vedotin 1.8 mg/kg via a 30-minute intravenous (IV) infusion and nivolumab 3.0 mg/kg via a 60-minute IV infusion in three-week cycles for up to 12 weeks. Additional salvage therapy was administered as part of pre- and post-AHCT care and was performed at the discretion of the treating physician.

Most patients (n=56; 90%) had received ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) as frontline therapy, and 31 percent had relapsed within one year of prior treatment.

As of July 21, 2017 (data cutoff), 58 patients completed all four planned treatment cycles. Four patients discontinued treatment because of investigator decision (n=1), peripheral neuropathy (n=1), and patient decision (n=2).

Patients were followed for a median of 7.8 months (range = 1-17 months) following first treatment dose, and researchers assessed response at 30 to 37 days after last dose. Among 60 patients evaluable for efficacy:

  • 37 (61.7%) experienced a complete response (CR; primary endpoint)
  • 13 (21.7%) experienced a partial response (PR)
  • 5 (8.3%) experienced progressive disease
  • 5 (8.3%) did not respond

Seventeen patients received subsequent salvage therapy, most of whom received ICE (ifosfamide, carboplatin, etoposide; n=12). Response rates were similar in this subset: overall response rate was 80 percent (95% CI 52-96), with a 40 percent CR rate (95% CI 16-68).

At analysis, 54 patients had undergone AHCT: 41 (76%) had CR, 11 (20%) had PR, and one (2%) had stable disease (1 patient was not evaluable). Most (n=42) were able to proceed directly to AHCT after treatment with brentuximab vedotin and nivolumab, suggesting that “[this combination] is an effective bridge to AHCT that replaced the need for cytotoxic chemotherapy for the majority of patients,” the authors wrote.

At six months, the median duration of response and median progression-free survival (secondary endpoints) were not reached.

Most patients (n=60; 98%) experienced treatment-related adverse events (AEs) prior to AHCT or alternative salvage therapy. The most common AEs were nausea (49%), infusion-related reactions (IRRs; 44%), and fatigue (41%). Nineteen patients (31%) reported grade ≥3 AEs, most common of which were anemia, febrile neutropenia, hypophosphatemia, and neutropenia (n=2 [3%] for each). Twelve patients (20%) reported peripheral neuropathy. Six patients (10%) experienced serious AEs, including pneumonitis, pneumonia, pyrexia, malaise, nausea, and rash.

Because of the high rate of IRRs (which occurred more frequently and severely with the combination than with individual agents alone), the study protocol was amended to include mandatory premedication with low-dose corticosteroids, antihistamine, and hydrocortisone at cycles two through four. “Nonetheless, the rate of [IRRs at] cycle two was largely unchanged before and after premedication,” the authors wrote, “while the rate of IRRs during cycles three through four remained low, irrespective of premedication.”

During study follow-up, 16 patients discontinued one of the study drugs: seven (11%) discontinued brentuximab vedotin and nine (15%) discontinued nivolumab due to asymptomatic laboratory abnormalities (n=8), pneumonia (n=2), thrombosis (n=2), chills (n=1), pneumonitis (n=1), syncope (n=1), and urticaria (n=1). IRRs did not lead to treatment discontinuation, the researchers noted, but led to brentuximab vedotin dose interruptions in 16 people (26%).

Except for IRRs, the safety profile of the brentuximab vedotin and nivolumab were similar to those observed with each agent administered individually.

“Our results are promising in the context of other salvage therapy studies in relapsed/refractory HL, a setting in which no randomized studies have been performed to define a single standard of care regimen prior to AHCT,” the authors concluded.

However, they noted that the study is limited by its short-term follow-up and lack of a comparator arm. “Long-term follow-up of the durability of disease control will be critical in assessing the full therapeutic impact of [this combination],” the researchers added. Also, the study population only included patients who were naïve to prior brentuximab vedotin and nivolumab, and outcomes may not be generalizable to other patients with relapsed/refractory HL.

An ongoing trial is evaluating brentuximab vedotin plus nivolumab in patients with relapsed/refractory HL who are ineligible for AHCT or after AHCT failure.

Seattle Genetics and Bristol-Myers Squibb supported the study.

The corresponding authors report financial support from Seattle Genetics, Bristol-Myers Squibb, MedImmune, Merck, Immune Design, Genentech, Pharmacyclics, Janssen, Affimed, ImaginAb, KITE, Forty Seven, Celgene, AstraZeneca, Millennium, Pfizer, and Novartis. Some of the authors are employees of and have equity ownership in Seattle Genetics, which provided editorial support for the original manuscript.


Reference

Herrera AF, Moskowitz AJ, Bartlett NL, et al. Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2017 November 30. [Epub ahead of print]

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