Diana M. Byrnes, MD
Craig H. Moskowitz, MD
For patients with relapsed or refractory classic Hodgkin lymphoma (HL), salvage chemotherapy followed by autologous hematopoietic stem cell transplant (HSCT) is the standard of care and can induce long-term remissions in at least 60% of patients.1,2 Patients with progression of disease after transplantation or those who are ineligible for transplantation historically have a poor prognosis; however, disease control can be substantially prolonged with novel agents such as the antibody-drug conjugate brentuximab vedotin and the PD-1 inhibitors nivolumab and pembrolizumab.3,4
The median survival of these patients is currently unclear. Treatment after transplantation is generally considered “palliative”; however, with newer agents, treatment can be considered “long-term therapy,” not dissimilar to that in relapsed low-grade B-cell lymphoma. Defining a long-term treatment regimen that produces minimal short-term toxicity as well as lasting disease control is critical in this generally young patient population. As reported in The Lancet Oncology by Kuruvilla et al—and reviewed in this issue of The ASCO Post—KEYNOTE-204 is a study evaluating pembrolizumab vs brentuximab vedotin in relapsed or refractory classic HL.5
Brentuximab vedotin is an antibody-drug conjugate composed of an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to monomethyl auristatin E, a microtubule-disrupting agent.6,7 It was approved by the U.S. Food and Drug Administration for the treatment of relapsed or refractory classic HL based on the results of a pivotal phase II trial by Younes et al.6 This study included patients after transplantation and with median of 3.5 prior lines of therapy, including 71% with primary refractory disease. Brentuximab vedotin induced responses in 75% of patients, with complete remission in 34%. The most common treatment-related adverse event was peripheral neuropathy, which occurred in 42% of patients.6
Checkpoint inhibitors are an attractive therapeutic target in classic HL because PD-L1 and PD-L2 are overexpressed on Reed-Sternberg cells due to alterations in chromosome 9p24.1.8 Approval for pembrolizumab in the relapsed or refractory setting in classic HL was based on the phase II KEYNOTE-087 study. This trial showed objective responses in 71.9% of patients and a median progression-free survival of 13.7 months, with a median follow up of 27.6 months.9 The most commonly reported immune-mediated adverse effects were hypothyroidism (15.7%), pneumonitis (4.8%), and hyperthyroidism (3.8%).9
KEYNOTE-204: Primary Endpoint Met
KEYNOTE-204 is a randomized, open-label, phase III study that enrolled 304 adults with relapsed or refractory classic HL who were ineligible for or had relapsed after autologous HSCT.4 This was a large, multicenter, international study. Nearly one-third of study participants were treated in Europe, and 18% were treated in North America. Patients were randomly assigned to pembrolizumab at 200 mg intravenously every 3 weeks (n = 151) or brentuximab vedotin at 1.8 mg/kg intravenously every 3 weeks (n = 153) for up to 35 cycles.
Patients were stratified within treatment groups according to whether they received prior autologous HSCT. Additionally, patients were stratified by lines of treatment, primary refractory disease after first-line treatment, and relapse within at least 12 months after first-line treatment. The dual primary endpoints assessed in the intention-to-treat population were progression-free survival and overall survival. The results presented are from the second interim analysis on progression-free survival.
This was a positive study that met its primary endpoint, with pembrolizumab showing a statistically significant and clinically meaningful improvement in progression-free survival compared with brentuximab vedotin, with a median of 13.2 months in the pembrolizumab arm (95% confidence interval [CI] = 10.9–19.4 months) compared with 8.3 months in the brentuximab vedotin arm (95% CI = 5.7–8.8 months; hazard ratio = 0.65, 95% CI = 0.48–0.88, P = .0027). For the patients who responded to treatment, the median duration of response was 20.7 months (95% CI = 12.4 months to not reached) with pembrolizumab and 13.8 months (95% CI = 5.8 months to not reached) with brentuximab vedotin.
In this study cohort, 37% of patients had undergone previous autologous HSCT. The most common reason for ineligibility was chemorefractory disease (44%). Only 5% of the 304 patients had received brentuximab vedotin previously, which is unusual in today’s treatment landscape, where most patients would receive brentuximab vedotin either in first-line treatment or for relapsed or refractory disease. The median number of cycles for pembrolizumab was 15, whereas the median number of cycles for brentuximab vedotin was 7. A low percentage of patients in both groups were able to complete 35 cycles of treatment (17% in the pembrolizumab group and 2% in the brentuximab vedotin group).
Comparison With Phase II Data
The patient population in this study is unique. For comparison, in the pivotal trial reported by Younes et al, the median number of prior chemotherapy regimens was 3.5, and all patients in the study had undergone prior autologous HSCT. The rate of peripheral neuropathy secondary to brentuximab vedotin in KEYNOTE-204 is unusually low at 3%, compared with 42% in the pivotal trial. Here, only 19% of patients in the brentuximab arm discontinued treatment due to adverse effects. The reason for such unusually low rates of peripheral neuropathy in this study is unclear.
Additionally, the rate of complete response in this trial was 24% with brentuximab vedotin, which is lower than that in the pivotal phase II trial (34%).6 The complete response rate for pembrolizumab in this trial was 26%, which is similar to prior trials.
Support for Pembrolizumab as Long-Term Therapy
There is a need for minimally toxic chronic therapeutic options when HL has progressed after multiple lines of therapy including autologous HSCT or for those patients unfit for transplant. This study has proved the effectiveness and safety of pembrolizumab when compared with brentuximab vedotin, a drug that is not realistically palliative and cannot be tolerated for extended periods due to its neurotoxic effects. The most ideal long-term therapeutic option would produce minimal toxicity with a greater percentage of patients moving forward with curative-intent therapy, whether that be autologous HSCT, allogeneic HSCT, or CD30 chimeric antigen receptor T-cell therapy. The results published in this study by Kuruvilla et al5 establish pembrolizumab as the preferred long-term treatment option in the relapsed or refractory classic HL setting.
Dr. Byrnes and Dr. Moskowitz work in the Department of Medicine in the Division of Hematology/Oncology at the University of Miami Sylvester Comprehensive Cancer Center, Miami.
DISCLOSURE: Dr. Byrnes reported no conflicts of interest. Dr. Moskowitz has served as a consultant or advisor to AstraZeneca, Incyte, Merck Sharp & Dohme, Molecular Templates, and Takeda; and has received institutional research funding from AstraZeneca and Merck Sharp & Dohme.
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