On December 11, 2017, Alex F. Herreraof City of Hope National Medical Centerin Duarte, Californiaand colleagues published onlinein Blood, interim results from a phase I/II study in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (HL). In this multicenter clinical trial, brentuximab vedotin (BV) and nivolumab (NIV) were administered in combination and evaluated as initial salvage therapy ( NCT02572167).
The purpose of this study was to determine if this combination is an effective treatment regimen for R/R HL, and one that may spare patients traditional chemotherapy prior to autologous stem cell transplantation (ASCT). The primary efficacy endpoint was the complete response (CR) rate following the completion of study treatment. Secondary endpoints included the objective response rate (ORR), progression-free survival (PFS) after ASCT, and duration of response (DOR).
Highlights:
- BV + NIV salvage therapy proved well-tolerated in R/R HL patient, with <10% of patients treated with systemic steroids for immune-related adverse events (IrAE)
- CR rate was 61%, with 82% ORR, and patients were able to undergo stem cell transplant without additional adversity
Treatment:
- Study enrollment included 62, ASCT-eligible patients, >18 years of age, with biopsy-proven R/R disease after failure of first-line chemotherapy, measurable disease >5 cm, and Eastern Cooperative Oncology Group (ECOG) score 0,1
- Patients received BV (1.8 mg/kg; IV, 30-minute infusion) and NIV (3.0 mg/kg; IV, 60-minute infusion) in 3 week cycles for up to 12 weeks (4 cycles)
- Adverse events (AEs) and serious adverse events (SAEs), regardless of relationship to study drug, were recorded from study Day 1 through 100 days after the last dose of NIV
- CT scan was performed at Cycle 2 to assess for progressive disease (PD)
- Response assessed by both PET and CT at the end of treatment (EOT), which occurred 30– 37 days after the last dose of study drug, per the Revised Response Criteria for Malignant Lymphoma
Efficacy:
- CR rate:
- All treated patients = 61% (95% CI: 47%, 73%)
- Efficacy evaluable patients = 62% (95% CI: 48%, 74%)
- ORR rate:
- All treated patients = ORR of 82% (95% CI: 70%, 91%)
- Efficacy evaluable patients = 83% ORR (95% CI: 72%, 92%)
- Overall best response rate to post-study alternative salvage chemotherapy was 80% (95% CI: 52%, 96%), with 40% CR rate (95% CI: 16%, 68%)
- Median DOR, which included the ASCT period as appropriate, was not reached
- Estimated PFS rate was 89% (95% CI: 75%, 95%), but median PFS had not been reached
Safety:
- Sixty patients (98%) experienced treatment-emergent AEs prior to undergoing ASCT or receiving alternative salvage therapy
- Most common were nausea (49%), fatigue (41%), and infusion-related reactions (IRR, 44%)
- Grade >3 events occurred in 19 patients (31%), with grade 3 anemia, febrile neutropenia, hypophosphatemia, and neutropenia experienced by 2 patients (3%) each
- Treatment-emergent peripheral neuropathy (PN) occurred in 12 patients (20%), 11 of whom had grade 1 symptoms
- Treatment-related serious adverse events, which occurred prior to ASCT or salvage therapy, were seen in 6 patients (10%), and included pneumonitis, pneumonia, pyrexia, malaise, nausea, and rash
- IRR occurred in 44% of patients, with 41% of patients experiencing an IRR during at least one infusion of BV
- Five patients (8%) were treated with systemic steroids for immune-related AEs
In this phase I/II clinical trial in R/R HL, the salvage therapy combination of BV and NIV proved well-tolerated and highly active. The ORR and CR rates achieved in this study (82% and 61%, respectively), while using an outpatient regimen free of traditional combination chemotherapy, are notable. In addition, the frequency and severity of AEs were similar to those observed with each agent administered individually. The only exception was the relatively higher proportion of patients who experienced IRRs, the etiology of which is unclear. The relative tolerability and strong activity of BV + NIV warrants further evaluation. An ongoing study (CheckMate 812), evaluating this combination in patients with R/R HL who are ineligible for ASCT or after failure of ASCT, is currently recruiting patients ( NCT03138499).
Abstract
In this phase 1/2 study, brentuximab vedotin (BV) and nivolumab (Nivo) administered in combination were evaluated as initial salvage therapy in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (HL) (ClinicalTrials.gov # NCT02572167). Patients received up to 4 cycles of combination treatment, with BV administered on Day 1 and Nivo on Day 8 of the first cycle. For Cycles 2-4, BV and Nivo were both administered on Day 1. Following study treatment, responses were evaluated by investigators per the 2014 Lugano classification, and patients could proceed to autologous stem cell transplantation (ASCT). Sixty-two patients were enrolled; the CR rate among all treated patients (n=61) was 61%, with an overall response rate (ORR) of 82%. Prior to ASCT, adverse events (AEs) occurred in 98% of patients, mostly Grades 1 and 2. Infusion related reactions (IRRs) occurred in 44% of patients overall, with 41% of patients experiencing an IRR during at least one infusion of BV. Five patients (8%) were treated with systemic steroids for immune-related AEs. A reduction of T cell subsets including regulatory T cells was observed after the first dose of BV, and reduced serum TARC levels concurrent with an increase in pro-inflammatory cytokines and chemokines were seen after the first BV and Nivo infusions. The combination of BV and Nivo was an active and well-tolerated first salvage regimen, potentially providing patients with R/R HL an alternative to traditional chemotherapy.