Pembrolizumab Shows Better PFS Compared With Brentuximab Vedotin in R/R Classical Hodgkin Lymphoma

Patients with relapsed or refractory classical Hodgkin lymphoma had better outcomes when treated with pembrolizumab (Keytruda) versus brentuximab vedotin (Adcetris), according to a new head-to-head phase 3 trial.

The study, which was published in Lancet Oncology,¹ supports the use of pembrolizumab as the preferred therapy in patients who experience relapse following autologous hematopoietic stem cell transplant (HSCT) or who are ineligible for the procedure.

Corresponding author John Kuruvilla, MD, of the Princess Margaret Cancer Centre in Canada, and colleagues showed that while brentuximab vedotin has been a significant step forward in the treatment of patients with relapsed and refractory classical Hodgkin lymphoma, the CD30–directed antibody-drug conjugate has significant limitations. For instance, while three-quarters of patients prescribed the drug following HSCT experienced a response, the median progression-free survival (PFS) was just 5.6 months, and nearly half of patients (42%) experienced peripheral neuropathy.²

In searching for a better therapeutic option, the investigators turned to pembrolizumab, an anti–PD-1 antibody, which is currently approved by the FDA to treat classical Hodgkin lymphoma. In the phase 2 KEYNOTE-087 (NCT02453594) trial,3 objective responses were observed in 72% of patients with relapsed or refractory classical Hodgkin lymphoma, and patients had a median PFS of 13.7 months after 27.6 months of follow-up.

Given the apparent efficacy of pembrolizumab in that setting, Kuruvilla and colleagues sought to understand how the therapy stood up against brentuximab vedotin in a direct comparison.

The open-label KEYNOTE-204 trial (NCT02684292) compared the 2 systemic therapies in adult patients with relapsed or refractory classical Hodgkin lymphoma who had measurable disease, had an ECOG performance status of 0 or 1, and were ineligible for or relapsed following HSCT.

The investigators enrolled 304 patients from across 78 hospitals in 20 countries, randomly assigning patients 1:1 to receive either pembrolizumab at 200 mg intravenously every 3 weeks or brentuximab vedotin at 1.8 mg/kg intravenously every 3 weeks. The patients were randomized between July 2016 and July 2018, with a median time from randomization to data cutoff of 25.7 months.

In the pembrolizumab group, PFS was 13.2 months (95% CI 10.9-19.4) versus 8.3 months (5.7-8.8) in the brentuximab vedotin group (HR, 0.65; 95% CI, 0.48-0.88; P = .0027). PFS benefit was apparent in most patient subgroups.

By blinded independent central review, objective responses were noted in 65.6% of patients receiving pembrolizumab versus 54.2% of those receiving brentuximab vedotin, resulting in an estimated percentage difference of 11.3% (95% CI, 0.2-22.1; P = .023). This was considered not significant as the predefined threshold for significance was .006.

The most common grade 3 or greater treatment-related adverse events (AEs) in the pembrolizumab versus brentuximab vedotin groups were pneumonitis (4% vs 1%, respectively), neutropenia (2% vs 7%), decreased neutrophil count (1% vs 5%), and peripheral neuropathy (1% vs 3%). In all cases but pneumonitis, the AEs were more common in the brentuximab vedotin group. However, serious treatment-related adverse events were more common in the pembrolizumab group (16%) than in the brentuximab vedotin group (11%), with 1 patient in the pembrolizumab group suffering a grade 5 event of pneumonia.

Kuruvilla and colleagues wrote that both brentuximab vedotin and PD-1 inhibitors like pembrolizumab should be seen as significant advances for patients who relapse after HSCT or are ineligible for the procedure. However, they said the new data show pembrolizumab could be a preferable option for many patients.

“Although previous studies with brentuximab vedotin have shown responses in patients after two or more previous lines of therapy who are ineligible for autologous HSCT owing to chemorefractory disease, results from the KEYNOTE-204 show that pembrolizumab monotherapy can induce responses in a substantial proportion of patients in the second-line setting, including those who have received one previous line of therapy, have chemoresistant disease, or both, and could allow patients to avoid exposure to more conventional salvage chemotherapy and radiotherapy,” the authors wrote.

References

1. Kuruvilla J, Ramchandren R, Santoro A, et al. 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. Lancet Oncol. 2021;22(4):512-524. doi:10.1016/S1470-2045(21)00005-X
2. Younes A, Gopal AK, Smith SE, 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;30(18):2183-2189. doi: 10.1200/JCO.2011.38.0410
3. Chen R, Zinzani PL, Fanale MA, et al. Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. J Clin Oncol. 2017;35(19):2125-2132. doi:10.1200/JCO.2016.72.1316