Results from a phase II study: brentuximab plus DTIC is a good choice in elderly, front-line HL patients

On December 28, 2017, Jonathan W. Friedberg of the Wilmot Cancer Institute in Rochester, New York and colleagues published in Blood, results from a phase II study in patients with treatment-naïve classic Hodgkin lymphoma (HL). In this multi-center, open-label clinical trial, classic HL patients who were ineligible for or declined frontline chemotherapies were administered either brentuximab vedotin (BV) plus dacarbazine (DTIC), or BV plus bendamustine (NCT01716806). The primary endpoint was overall response rate (ORR) per investigator based on Revised Response Criteria for Malignant Lymphoma. Key secondary endpoints were safety, complete response (CR) rate, response duration, progression-free survival (PFS), B symptom resolution, and selected pharmacokinetic (PK) parameters. Overall survival (OS) was an additional endpoint.

 Highlights:

• BV plus DTIC is an active and well-tolerated combination for patients aged >60 years with HL
• Although highly active at the doses evaluated, BV plus bendamustine is an unacceptably toxic combination in HL patients > 60 years of age

Treatment:

• Twenty-two (22) patients received 1.8 mg/kg BV and 375 mg/m² DTIC for up to 12 cycles
• 20 more patients received 1.8 mg/kg BV plus 90 or 70 mg/m² bendamustine for up to 6 cycles
  • Subsequent BV monotherapy was allowed
• Approximately 30 patients were scheduled to receive BV plus bendamustine; however, there was a high incidence of serious adverse events and 2 deaths on the study, which led to discontinuation of bendamustine and cessation of enrollment

Efficacy:

• Efficacy-evaluable patients treated with BV plus DTIC (n = 21), ORR = 100%, and CR rate = 62% 
  • Median PFS = 17.9 months
• Efficacy-evaluable patients treated with BV plus bendamustine (n = 17), ORR = 100%, with CR rate = 88%
  • Median PFS and OS was not reached

Safety:

• All patients who received BV plus DTIC experienced at least 1 treatment-related TEAE, 45% experienced grade ≥3 AEs, and 18% had SAEs
• Peripheral sensory neuropathy (PSN) was the most common TEAE overall (77%) and the most frequently occurring grade ≥3 TEAE
• Five patients (8%) were treated with systemic steroids for immune-related AEs
• Nearly all patients who received BV plus bendamustine experienced a treatment-related TEAE (95%)
  • 90% had a grade ≥3 AE, and 65% had SAEs

 The results of this study ought to serve as a template and give rise to additional studies of novel induction regimens for elderly HL patients. Because poor outcomes have been well-documented in these vulnerable patients, it is vitally important to refine these patient-specific induction treatment strategies. Demonstrable activity was seen with BV in combination with DTIC or bendamustine in elderly, frail patients with newly diagnosed HL, however, BV plus bendamustine was poorly tolerated by these patients at the frequency and dose levels studied. BV plus DTIC was not only highly active, with 13 of 21 patients achieving a relatively well-tolerated CR and an overall median PFS of 17. 9 months. This study demonstrated favorable tolerability and activity compared with historical chemotherapy regimens in this patient type. Confirmation of these data in larger trials is certainly warranted; nevertheless, given the poor outcomes currently seen with standard chemotherapy, these results suggest BV plus DTIC may be a viable treatment option for elderly patients with newly diagnosed HL.

Abstract

Patients aged ≥60 years with treatment-naive Hodgkin lymphoma (HL) have few treatment options and inferior survival due to treatment-related toxicities and comorbidities. This phase 2, nonrandomized, open-label study evaluated brentuximab vedotin (BV) monotherapy (results previously reported), BV plus dacarbazine (DTIC), and BV plus bendamustine. Patients had classical HL and were ineligible for or declined frontline chemotherapy. Twenty-two patients received 1.8 mg/kg BV and 375 mg/m2 DTIC for up to 12 cycles, and 20 more patients received 1.8 mg/kg BV plus 90 or 70 mg/m2 bendamustine for up to 6 cycles (dose reduced due to toxicity). Subsequent BV monotherapy was allowed. Approximately 30 patients were to receive BV plus bendamustine; however, the incidence of serious adverse events (65%) and 2 deaths on study led to discontinuation of bendamustine and cessation of enrollment. Most patients had stage III/IV disease, and approximately half had ≥3 comorbidities or were impaired in ≥1 aspect that significantly interfered with quality of life. For BV plus DTIC, the objective response rate (ORR) was 100% and the complete remission (CR) rate was 62%. To date, the median progression-free survival (PFS) is 17.9 months. For BV plus bendamustine, the ORR was 100% and the CR rate was 88%. Neither the median PFS nor overall survival was reached. For elderly patients with HL, BV plus DTIC may be a frontline option based on tolerability and response duration. Despite activity, BV plus bendamustine is not a tolerable regimen in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01716806.