As reported in The Lancet Oncology by John Kuruvilla, MD, of Princess Margaret Cancer Centre, Toronto, 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 classic Hodgkin lymphoma (HL).¹

John Kuruvilla, MD

The study supported the October 2020 approval of pembrolizumab for treatment of adults with relapsed or refractory classic HL and pediatric patients with refractory classic HL or those with classic HL who have relapsed after two or more lines of therapy.

Study Details

In the open-label trial, 304 patients aged ≥ 18 years from sites in 20 countries who had measurable disease and who were ineligible for or had relapsed after autologous hematopoietic stem cell transplantation (HSCT) 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. Randomization was stratified according to previous autologous HSCT (yes vs no) and status after front-line therapy (primary refractory vs relapsed at < 12 months vs relapsed at ≥ 12 months after front-line therapy).

The co-primary endpoints of the trial are progression-free survival on blinded independent central review and overall survival in the intention-to-treat population. The primary analysis of progression-free survival was done in two ways, including or excluding results of autologous or allogeneic transplant. The findings presented 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

The 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 the predefined P value threshold for significance of .0043). On investigator assessment, the 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 autologous or allogeneic HSCT), 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 vs 56 patients with prior autologous HSCT and 0.61 (95% CI = 0.42–0.89) among 95 vs 97 patients without prior transplantation. According to status after front-line therapy, hazard ratios were 0.52 (95% CI = 0.33–0.83) among 61 vs 62 patients with primary refractory disease, 0.82 (95% CI = 0.45–1.48) among 42 vs 42 with relapse at < 12 months, and 0.72 (95% CI = 0.41–1.25) among 48 vs 49 with relapse at ≥ 12 months. Among patients with available data on PD-L1 expression, 142 vs 133 patients had expression ≥ 1%; the hazard ratios 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 the predefined significance threshold of .0060), with a complete response observed in 25% vs 24%. The median duration of response was 20.7 months (95% CI = 12.4 months to not reached) vs 13.8 months (95% CI = 5.8 months to not reached), with 62.4% vs 50.0% of responses lasting for at least 12 months.

Adverse Events

Treatment-related grade ≥ 3 adverse events occurred in 20% of the pembrolizumab group vs 25% of the brentuximab vedotin group, 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, the most common being pneumonitis (5% vs 1%). Treatment-related adverse events led to permanent discontinuation of treatment in 13% vs 16% of patients, 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, 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.” 

DISCLOSURE: The study was funded by Merck Sharp & Dohme Corp (a subsidiary of Merck & Co, Inc). Dr. Kuruvilla has received honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Gilead, Janssen, Karyopharm Therapeutics, Merck, Novartis, Pfizer, Roche, and Seattle Genetics; has served as a consultant or advisor to AbbVie, Bristol Myers Squibb, Gilead Sciences, Karyopharm Therapeutics, Merck, Roche, and Seattle Genetics; and has received research funding from Celgene, Janssen, and Roche.

REFERENCE

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 22:512-524, 2021.