November-December 2016, Volume 13, Issue 6
Checkpoint Inhibition in Hodgkin Lymphoma: Time to Check at Which Point to Use It
Published on: October 28, 2016
Study Title: Study of Pembrolizumab (MK-3475) vs. Brentuximab Vedotin in Participants With Relapsed or Refractory Classical Hodgkin Lymphoma (MK-3475-204/KEYNOTE-204)
ClinicalTrials.gov Identifier: NCT02684292
Sponsor: Merck Sharp & Dohme Corp.
Accrual Goal: 300
Participating Centers: 22 Centers across the United States, Europe, Japan, and Australia
Study Design: This is a phase III, randomized, open-label clinical trial that compares the PD-1 inhibitor pembrolizumab with brentuximab vedotin in subjects with relapsed or refractory classical Hodgkin lymphoma (HL). The primary outcome measures are progression-free survival and overall survival. A secondary outcome measure will be the objective response rate. Pembrolizumab will be given as 200-mg doses administered intravenously on day 1 of each three-week cycle, and brentuximab vedotin will be given at a dose of 1.8-mg/kg intravenously (maximum, 180 mg per dose) on day 1 of each three-week cycle. Both treatments can be given for up to 35 cycles.
Rationale: Blockade of PD-1 with antibodies such as pembrolizumab or nivolumab has been shown to be highly effective in patients with relapsed HL. Such treatment is well tolerated and relatively easy to administer. However, these studies have been performed in patients with late stage disease, so it is not clear how they will perform in patients at an earlier stage of the disease course. The anti-CD30 antibody-drug conjugate brentuximab is effective for patients who relapse after autologous stem cell transplantation or who are not suitable for this procedure. This study now compares the use of pembrolizumab directly against brentuximab at the same stage of disease.
Comment: Hematologists might be excused for thinking that they pioneered the introduction of almost all forms of modern cancer therapy. Single-agent chemotherapy, combination chemotherapy, monoclonal antibodies, and kinase inhibitors all have their roots in the management of leukemia and lymphoma. However, solid tumor oncology has forged a leading position in the deployment of immunotherapy. Here, the monoclonal antibody “checkpoint inhibitors” such as anti-PD-1 or anti-PD-L1 are poised to overturn the conventional approach to cancer therapy.
Within hematology, PD-1 blockade has been most effective in the treatment of relapsed classical HL (cHL). PD-L1 expression is increased in many cases of cHL through genetic amplification at chromosome 9p24.1. The pioneering study of Dr. Stephen M. Ansell and colleagues revealed a response rate of 87 percent following administration of nivolumab — another antibody that blocks PD-1.1 Pembrolizumab is also effective, with a 67 percent response rate seen in cHL patients for whom brentuximab has failed.2 However, patients in these trials had advanced disease; therefore, the exciting aspect of this study is that PD-1 blockade is being introduced earlier in the cHL treatment pathway, and in direct comparison to brentuximab. Furthermore, if the results of this study are indeed positive, it moves us closer to considering checkpoint blockade as a potential frontline therapy for HL. Such incremental improvements cannot be assumed; for example, nivolumab recently failed to show improvement against chemotherapy for the first-line treatment of non–small-cell lung cancer 3. Additionally, although response rates to checkpoint blockade in cHL are impressive, only a minority of patients currently achieve complete remission. Checkpoint blockade is now being combined with chemotherapy in several settings, although the optimal sequential approach remains to be determined. Much work needs to be done, but if progress is maintained, we may perhaps move from ABVD to C-ABVD (or perhaps ABCD-V). Now there is an abecedarian acronym to make even hematologists take note.
Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372:311-319.
Armand P, Shipp MA, Ribrag V, et al. Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol. 2016;pii:JCO673467. [Epub ahead of print].
Bristol-Myers Squibb Company. Bristol-Myers Squibb Presents Results From CheckMate -026, a Phase 3 Study of Opdivo (nivolumab) Monotherapy Versus Chemotherapy as First-Line Therapy in a Broad PD-L1 Positive Population With Advanced Lung Cancer. Brist-Myers Squibb. 2016.
Conflict of Interests
Dr. Moss indicated no relevant conflicts of interest.
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