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Pembrolizumab vs Brentuximab Vedotin in Relapsed or Refractory Classical Hodgkin Lymphoma: KEYNOTE-204 Trial


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As reported in The Lancet Oncology by John Kuruvilla, MD, and colleagues, an interim analysis of the phase III KEYNOTE-204 trial has shown significantly improved progression-free survival with pembrolizumab vs brentuximab vedotin in patients with relapsed or refractory classical Hodgkin lymphoma.

The study supported the October 2020 U.S. Food and Drug Administration approval of pembrolizumab for treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma and pediatric patients with refractory classical Hodgkin lymphoma or classical Hodgkin lymphoma that has relapsed after two or more lines of therapy.

John Kuruvilla, MD

John Kuruvilla, MD

Study Details

The open-label trial included 304 patients from sites in 20 countries who had measurable disease and who were ineligible for or had relapsed after autologous hematopoietic stem cell transplantation (HSCT). Patients were randomly assigned between July 2016 and July 2018 to receive pembrolizumab at 200 mg every 3 weeks (n = 151) or brentuximab vedotin at 1.8 mg/kg every 3 weeks (n = 153). Treatment continued for up to 35 cycles or until disease progression or unacceptable toxicity.

The co-primary endpoints of the trial were progression-free survival on blinded independent central review and overall survival in the intention-to-treat population. The primary analysis of progression-free survival included clinical and imaging data following autologous or allogeneic HSCT; a secondary analysis excluded clinical and imaging data following autologous or allogeneic HSCT. The findings published in The Lancet Oncology report are those from the preplanned second interim analysis of progression-free survival (database cutoff in January 2020); overall survival was not analyzed at this interim analysis.

Progression-Free Survival

Median follow-up was 25.7 months (interquartile range = 23.4–33.0 months). In the primary analysis, median progression-free survival was 13.2 months (95% confidence interval [CI] = 10.9–19.4 months) in the pembrolizumab group vs 8.3 months (95% CI = 5.7–8.8 months) in the brentuximab vedotin group (hazard ratio [HR] = 0.65, 95% CI = 0.48–0.88, P = .0027; surpassing predefined P value threshold for significance of .0043). 

On investigator assessment, median progression-free survival was 19.2 months (95% CI = 13.8–28.1 months) in the pembrolizumab group vs 8.2 months (95% CI = 5.7–8.6 months) in the brentuximab vedotin group (HR = 0.49, 95% CI = 0.36–0.67).

After treatment in the study, 64 patients (21%) subsequently underwent autologous HSCT and 27 (9%) underwent allogeneic HSCT. On secondary analysis (excluding clinical and imaging data following transplant), median progression-free survival was 12.6 months (95% CI = 8.7–19.2 months) vs 8.2 months (95% CI = 5.6–8.6 months; HR = 0.62, 95% CI = 0.46–0.85).

Subgroup analyses according to blinded independent central review were similar to the overall analysis. Hazard ratios were 0.72 (95% CI = 0.42–1.23) among 56 patients treated with pembrolizumab vs 56 patients treated with brentuximab vedotin with prior autologous HSCT and 0.61 (95% CI = 0.42–0.89) among 95 vs 97 patients without prior autologous HSCT. Among patients with available data on PD-L1 expression, 142 vs 133 patients had expression ≥ 1%; the hazard ratio among these patients was 0.66 (95% CI = 0.48-0.91). Too few patients (n = 3) had PD-L1 expression < 1% to permit analysis. 

Objective response on blinded independent central review was observed in 65.6% vs 54.2% of patients (P = .023; considered nonsignificant due to not meeting predefined significance threshold of .0060), with compete response observed in 25% vs 24%. Median duration of response was 20.7 months (95% CI = 12.4 months–not reached) vs 13.8 months (95% CI = 5.8 months–not reached), with 62.4% vs 50.0% of responses lasting for ≥ 12 months.

KEY POINTS

  • Pembrolizumab significantly improved progression-free survival vs brentuximab vedotin.
  • Median progression free survival was 13.2 months vs 8.3 months per blinded independent central review (primary endpoint) and 19.2 vs 8.2 months per investigator assessment.

Adverse Events

Treatment-related grade ≥ 3 adverse events occurred in 20% of patients in the pembrolizumab group vs 25% of the brentuximab vedotin group, with the most common being pneumonitis (4% vs 1%), neutropenia (2% vs 7%), decreased neutrophil count (1% vs 5%), and peripheral neuropathy (1% vs 3%). Serious treatment-related adverse events occurred in 16% vs 11% of patients, with the most common being pneumonitis (5% vs 1%).

Treatment-related adverse events led to permanent discontinuation of treatment in 13% vs 16% of patients, with the most common cause being pneumonitis (6% vs 0%) in the pembrolizumab group and peripheral neuropathy (0% vs 5%) in the brentuximab vedotin group. Immune-mediated adverse events of any grade occurred in 33% vs 7% of patients, with the most common being hypothyroidism (19% vs 3%) and pneumonitis (11% vs 3%).

Fatal adverse events occurred in three patients in the pembrolizumab group (due to pneumonia, hypovolemic shock, and unknown cause) and two patients in the brentuximab vedotin group (due to respiratory failure and unknown cause); only the death due to pneumonia in the pembrolizumab group was considered related to treatment.

The investigators concluded, “Pembrolizumab showed statistically significant and clinically meaningful improvement in progression-free survival compared with brentuximab vedotin, with safety consistent with previous reports. These data support pembrolizumab as the preferred treatment option for patients with relapsed or refractory classical Hodgkin lymphoma who have relapsed post–autologous HSCT or are ineligible for autologous HSCT.”

Dr. Kuruvilla, of Princess Margaret Cancer Centre, Toronto, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Merck Sharp & Dohme Corp (a subsidiary of Merck & Co, Inc). For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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