Phase 3 Study Supports Pembrolizumab in Treatment of Relapsed/Refractory Classical Hodgkin Lymphoma

Findings from the phase 3 KEYNOTE-204 study (NCT02684292), published recently in The Lancet Oncology, support pembrolizumab (Keytruda) as the preferred treatment option for patients with relapsed or refractory classical Hodgkin lymphoma (cHL) who have relapsed post-autologous haematopoietic stem-cell transplant (HSCT) or who are ineligible for HSCT, over brentuximab vedotin (Adcetris).

Significantly, the study revealed that the median progression-free survival (PFS) was 13.2 months for pembrolizumab and 8.3 months for brentuximab vedotin. A secondary analysis, assessed by blinded independent central review, found PFS to be 12.6 months for pembrolizumab and 8.2 months for brentuximab vedotin. In October 2020, the FDA, based on findings from this study, granted an expanded label approval for pembrolizumab as treatment of adult patients with relapsed or refractory cHL.

“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 minimize toxic effects that can affect quality of life,” John Kuruvilla, MD, hematologist and associate professor of medicine, Princess Margaret Cancer Centre and University of Toronto, and co-authors wrote in the published report.

The randomized, open-label phase 3 study was conducted between July 8, 2016, and July 13, 2018, and enrolled patients aged 18 or older, with relapsed/refractory cHL, and an ECOG performance status of 0 or 1. The patients were enrolled from 78 hospitals and cancer centers in 20 countries and territories.

The cut-off date on the interim analysis was January 16, 2020. The dual primary end points were progression-free survival (PFS), as assessed by blinded independent central review, and OS; however, data for OS were not yet mature at the time of the interim analysis. Safety of both pembrolizumab and brentuximab vedotin are well established and was assessed in all patients who received at least 1 dose of the study drug.

Overall, 338 patients were screened for the study, with 34 deemed ineligible to participate. Of the remaining 304 patients, 151 were randomly assigned to pembrolizumab; 153 to brentuximab vedotin. Of those, 148 patients were treated with pembrolizumab; while 152 patients were treated with brentuximab vedotin.

Pembrolizumab was administered intravenously at 200 mg every 3 weeks; brentuximab vedotin, also administered intravenously, was given at 1.8 mg/kg, or a max of 180 mg, every 3 weeks. All patients were treated for up to 35 cycles or until documented disease progression, unacceptable toxicity, or investigator decision.

Treatment was discontinued in 110 (4%) pembrolizumab-treated patients and in 146 (96%) of brentuximab vedotin–treated patients, most often because of investigator-determined progressive disease (n = 58 [39%] and n = 75 [49%], respectively) or adverse events (AEs; n = 20 [14%] and n = 29 [19%], respectively).

The primary PFS analysis revealed that 169 events occurred in 81 (54%) patients in the pembrolizumab group as compared with PFS events in 88 (58%) patients in the brentuximab vedotin group; the HR was 0.65 (95% CI, 0.48-0.88; P = .0027). A secondary PFS analysis, assessed by blinded independent central review, revealed 173 events in 81 (54%) patients receiving pembrolizumab for a median PFS of 12.6 months, and in 92 (60%) patients receiving brentuximab vedotin for a median PFS of 8.2 months (HR, 0.62; 95% CI, 0.46-0.85).

An objective response, as assessed by blinded independent central review, was achieved in 99 (65.6%) of patients in the pembrolizumab group and 83 (54.2%) in the brentuximab vedotin group. By investigator review, responses were observed in 103 (68.2%) patients in the pembrolizumab arm versus in 92 (60.1%) of the brentuximab vedotin arm.

The median duration of response was 20.7 months with pembrolizumab versus 13.8 months with brentuximab vedotin.

Serious treatment-related AEs occurred in 24 patients (16%) receiving pembrolizumab and in 16 patients (11%) receiving brentuximab vedotin. The most common grade 3-5 treatment-related AEs were pneumonitis, experienced by 6 patients (4%) in the pembrolizumab group and 1 (1%) in the brentuximab vedotin; neutropenia in 3 (2%) vs 11 (7%); decreased neutrophil count in 1 (1%) vs 7 (5%); and peripheral neuropathy in 1 (1%) vs 5 (3%).

Five patients died of AEs: 3 in the pembrolizumab group (due to pneumonia, hypovalaemic shock, and unknown cause) and 2 in the brentuximab vedotin group (due to respiratory failure and unknown cause). However, only 1 death in the study was considered related to study treatment by the investigators, which was the death due to pneumonia in the pembrolizumab group.

Limitations for the study include that it contains 3 subpopulations with different treatment approaches and in which the next best line of treatment has not been established: patients who did not receive autologous HSCT and had relapse; patients with non-responsive disease that might become sensitive after treatment, enabling them to proceed to transplantation; and patients who have relapsed after autologous HSCT. In most studies of cHL, these patients are grouped together, however the treatment goals, patients, and outcomes are different.

“Given the rarity of Hodgkin lymphoma, it is challenging to perform randomized controlled trials in all of these populations,” Kuruvilla et al wrote. “Therefore, including them together in KEYNOTE-204 was reasonable, as brentuximab vedotin is ostensibly used as the standard of care where available for comparison. In addition, there is a treatment heterogeneity in classical Hodgkin lymphoma as relapse approaches vary—there is no gold standard—and are driven by clinician, institutional and national practice patterns. Transplantation is an established treatment but there are variations in practice by age, comorbidities, previous therapy goals of care and use of allogeneic HSCT.”

In conclusion, the study authors suggest that pembrolizumab is an effective treatment option. Although previous studies with brentuximab vedotin have shown responses in patients after 2 or more previous lines of therapy who are ineligible for autologous HSCT owing to chemotherapy-refractory disease, results from the KEYNOTE-204 study show that pembrolizumab monotherapy can induce responses in a substantial proportion of patients in the second-line setting—including those who have received 1 previous line of therapy, have chemotherapy-resistant disease, or both, and could allow patients to avoid exposure to more conventional salvage chemotherapy and radiotherapy.

_Reference

_{Kuruvilla J, Ramcandren R, Santoro A, et al; KEYNOTE-204 Investigators. Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicentre, , open-label, phase 3 study. Published online March 12, 2021. Lancet Oncol. doi:10.1016/S1470-2045(21)00005-X}