Elsevier

The Lancet Oncology

Volume 22, Issue 4, April 2021, Pages 512-524
The Lancet Oncology

Articles
Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicentre, randomised, open-label, phase 3 study

https://doi.org/10.1016/S1470-2045(21)00005-XGet rights and content

Summary

Background

PD-1 blockade via pembrolizumab monotherapy has shown antitumour activity and toxicity in patients with relapsed or refractory classical Hodgkin lymphoma. Here, we present interim analyses from the KEYNOTE-204 study evaluating pembrolizumab versus brentuximab vedotin for relapsed or refractory classical Hodgkin lymphoma.

Methods

In this randomised, open-label, phase 3 study, patients aged 18 years or older with relapsed or refractory classical Hodgkin lymphoma with measurable disease and an Eastern Cooperative Oncology Group performance status of 0 or 1 who were ineligible for or had relapsed after autologous haematopoietic stem-cell transplantation (HSCT) were enrolled at 78 hospitals and cancer centres in 20 countries and territories. Patients were randomly assigned (1:1) with an interactive voice response system to pembrolizumab 200 mg intravenously every 3 weeks or brentuximab vedotin 1·8 mg/kg intravenously every 3 weeks. Randomisation was stratified by previous autologous HSCT and status after front-line therapy. Results from the second interim analysis are presented here, with a database cutoff of Jan 16, 2020. The dual primary endpoints assessed in the intention-to-treat population were progression-free survival as assessed by blinded independent central review, and overall survival (not analysed at this interim analysis). Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT02684292. Recruitment for this trial is closed.

Findings

Between July 8, 2016, and July 13, 2018, 151 patients were randomly assigned to pembrolizumab and 153 to brentuximab vedotin. After a median time from randomisation to data cutoff of 25·7 months (IQR 23·4–33·0), median progression-free survival was 13·2 months (95% CI 10·9–19·4) for pembrolizumab versus 8·3 months (5·7–8·8) for brentuximab vedotin (hazard ratio 0·65 [95% CI 0·48–0·88]; p=0·0027). The most common grade 3–5 treatment-related adverse events were pneumonitis (six [4%] of 148 patients in the pembrolizumab group vs one [1%] of 152 patients in the brentuximab vedotin group), neutropenia (three [2%] vs 11 [7%]), decreased neutrophil count (one [1%] vs seven [5%]), and peripheral neuropathy (one [1%] vs five [3%]). Serious treatment-related adverse events occurred in 24 (16%) of 148 patients receiving pembrolizumab and 16 (11%) of 152 patients receiving brentuximab vedotin. One treatment-related death due to pneumonia occurred in the pembrolizumab group.

Interpretation

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.

Funding

Merck Sharp & Dohme Corp (a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA).

Translation

For the Portuguese translation of the Article see Supplementary Materials section.

Introduction

Patients with relapsed or refractory classical Hodgkin lymphoma who progress after autologous haematopoietic stem-cell transplantation (HSCT) have poor prognosis, with a median overall survival of 2·4 years according to historical data.1, 2, 3, 4 Overall survival is similarly poor in patients with primary refractory disease and those ineligible for autologous HSCT.5, 6

Brentuximab vedotin, an antibody–drug conjugate targeting CD30, is approved for patients with untreated, relapsed, or refractory classical Hodgkin lymphoma.7, 8, 9, 10 In relapsed or refractory classical Hodgkin lymphoma after autologous HSCT, brentuximab vedotin induced responses in 75% of patients; however, median progression-free survival was 5·6 months, and 42% of patients had peripheral neuropathy.7 Although brentuximab vedotin has become an important component of therapy for classical Hodgkin lymphoma, patients would benefit from additional approaches that further improve progression-free survival and minimise toxic effects that can affect quality of life, such as peripheral neuropathy.

Research in context

Evidence before this study

We searched PubMed with the keywords “classical Hodgkin lymphoma” and “programmed death 1” filtered by “article type: clinical trial” and “publication dates: 01/01/2015 to 05/01/2020” with no language restrictions, which yielded six results. All publications identified were phase 1 or 2 clinical trials in the non-curative setting. One publication was from the phase 1 KEYNOTE-013 study, which evaluated the PD-1 inhibitor pembrolizumab in patients with classical Hodgkin lymphoma after progression on brentuximab vedotin. Two publications were for the phase 2 KEYNOTE-087 study, which evaluated pembrolizumab in relapsed or refractory classical Hodgkin lymphoma, two publications were for the phase 2 CheckMate 205 study of the PD-1 inhibitor nivolumab in relapsed or refractory classical Hodgkin lymphoma after failure of autologous haematopoietic stem-cell transplantation (HSCT), and one study included multiple phase 1/2 cohorts of nivolumab monotherapy or combination therapy in several relapsed or refractory haematological malignancies. Results from these studies showed clinical benefit and favourable safety with both PD-1 inhibitors. In both the KEYNOTE-087 and CheckMate 205 studies, patients with previous brentuximab vedotin treatment had response rates similar to those of patients without previous brentuximab vedotin, indicating that anti-PD-1 antibodies are efficacious regardless of previous brentuximab vedotin treatment. Pivotal data with brentuximab vedotin in patients with classical Hodgkin lymphoma provided a benchmark for progression-free survival and acceptable toxicity that established brentuximab vedotin in this setting.

Added value of this study

We evaluated pembrolizumab monotherapy versus brentuximab vedotin in patients with relapsed or refractory classical Hodgkin lymphoma who had relapsed after autologous HSCT or who were ineligible for autologous HSCT. In this study, progression-free survival was significantly improved with pembrolizumab compared with brentuximab vedotin, and patients receiving pembrolizumab showed a consistent benefit in progression-free survival compared with those receiving brentuximab vedotin across multiple subgroups, including those with primary refractory disease and those ineligible for autologous HSCT.

Implications of all the available evidence

Results from the KEYNOTE-204 study add further evidence for the utility of PD-1 blockade in the treatment of relapsed or refractory classical Hodgkin lymphoma and establish a new potential standard of care for patients with relapsed or refractory classical Hodgkin lymphoma who relapse after autologous HSCT or who are ineligible for autologous HSCT.

PD-L1 and PD-L2 are overexpressed on tumour cell surfaces in classical Hodgkin lymphoma, and are therefore attractive therapeutic targets for this disease.11, 12, 13, 14 Two anti-PD-1 antibodies are currently approved in classical Hodgkin lymphoma, pembrolizumab and nivolumab,15, 16, 17 and both have been found to provide long-term efficacy in patients with relapsed or refractory classical Hodgkin lymphoma.18, 19 Pembrolizumab is a monoclonal antibody targeting PD-1 approved for treatment of refractory classical Hodgkin lymphoma and in patients who have disease relapse after three or more lines of therapy (including brentuximab vedotin in EU countries and the UK).15, 17, 20, 21, 22, 23 Approval was based on results for tumour response and durability of response from the phase 2 KEYNOTE-087 study (NCT02453594).21, 22 This study showed antitumour activity and durable responses in relapsed or refractory classical Hodgkin lymphoma, with objective responses observed in 72% of patients and a median progression-free survival of 13·7 months after 27·6 months of follow-up.22 The most frequent treatment-related adverse events were hypothyroidism, fatigue, pyrexia, and rash.20, 21, 22 Efficacy of PD-1 blockade suggests that this strategy might provide more durable responses than brentuximab vedotin in this patient population.

The KEYNOTE-204 trial compared pembrolizumab with brentuximab vedotin in patients with relapsed or refractory classical Hodgkin lymphoma. Here, we present the interim efficacy and safety analyses.

Section snippets

Study design and participants

KEYNOTE-204 was an open-label, randomised, phase 3 trial at 78 hospitals and cancer centres in 20 countries and territories (appendix 2 pp 2–3). Patients aged 18 years or older with relapsed (defined as disease progression after most recent therapy) or refractory (defined as lack of complete or partial response to most recent therapy) classical Hodgkin lymphoma as determined by the investigator were eligible. Patients had received previous therapy with autologous HSCT or were ineligible for

Results

338 patients were screened between July 8, 2016, and July 13, 2018, and 34 were not eligible (figure 1). Therefore, 304 patients were randomly assigned (151 to pembrolizumab, to 153 brentuximab vedotin), of whom 300 received treatment (figure 1). 112 (37%) of 304 patients had undergone previous autologous HSCT and 192 (63%) were ineligible for autologous HSCT on the basis of investigator assessment, most commonly due to chemorefractory disease (133 [44%]; table 1). Early progression on

Discussion

KEYNOTE-204, a multicentre, randomised, phase 3 study of pembrolizumab versus brentuximab vedotin, showed a significant improvement in progression-free survival after a median follow-up of 2 years (HR 0·65 [95% CI 0·48–0·88]; p=0·0027) with pembrolizumab versus brentuximab vedotin in patients with relapsed or refractory classical Hodgkin lymphoma who had relapsed after or were ineligible for autologous HSCT. The progression-free survival benefit extended to key subgroups, including patients who

Data sharing

Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA (MSD), is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company's clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with

References (32)

  • KA Goodman et al.

    Long-term effects of high-dose chemotherapy and radiation for relapsed and refractory Hodgkin's lymphoma

    J Clin Oncol

    (2008)
  • S Arai et al.

    Defining a Hodgkin lymphoma population for novel therapeutics after relapse from autologous hematopoietic cell transplant

    Leuk Lymphoma

    (2013)
  • N Puig et al.

    Different response to salvage chemotherapy but similar post-transplant outcomes in patients with relapsed and refractory Hodgkin's lymphoma

    Haematologica

    (2010)
  • D Villa et al.

    Second-line salvage chemotherapy for transplant-eligible patients with Hodgkin's lymphoma resistant to platinum-containing first-line salvage chemotherapy

    Haematologica

    (2012)
  • A Younes et al.

    Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma

    J Clin Oncol

    (2012)
  • ADCETRIS (brentuximab vedotin) for injection, for intravenous use [prescribing information]

    (2019)
  • Cited by (0)

    Complete list of investigators provided in the appendix (pp 2–3)

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