For patients with relapsed or refractory classic Hodgkin lymphoma (R/R cHL), the standard of care (SOC) is salvage chemotherapy followed by autologous stem cell transplant (auto-SCT), which can induce long-term remissions in approximately 50% of patients. However, for patients who are ineligible for auto-SCT due to chemotherapy-refractory disease, comorbidities or advanced age, there is no established SOC. The antibody drug conjugate, brentuximab vedotin (BV), is a treatment option for patients who relapse after auto-SCT and is now increasingly being used in curative settings. The immune checkpoint inhibitors, nivolumab and pembrolizumab, are also effective in R/R cHL and are approved for patients who have failed two or more previous therapies.

The international, randomized, open label phase III KEYNOTE-204 trial compared the efficacy and safety of pembrolizumab versus BV in patients with R/R cHL who had either relapsed after auto-SCT or were ineligible for transplant and had failed one prior line of therapy. Previous exposure to BV was permitted. Results from a second interim analysis were presented at the ASCO 2020 virtual meeting by John Kuruvilla, MD (Princess Margaret Cancer Centre, Toronto, Canada). The trial enrolled 304 patients, who were stratified according to history of prior auto-SCT, and status after first-line therapy (i.e. primary refractory, relapsed <12 months, relapsed ≥12 months). Patients were randomized to receive either pembrolizumab or BV for up to 35 cycles. The primary endpoints include progression free survival (PFS) per blinded independent central review (BIRC) and overall survival (OS); secondary endpoints include overall response rate (ORR) per BIRC, duration of response (DoR) and safety.

At a median follow up of 25 months, pembrolizumab treatment resulted in a statistically significant and clinically meaningful improvement in median PFS compared with BV (13.2 versus 8.3 months, respectively; hazard ratio [HR] 0.65, P = 0.00271), with a 12-month PFS rate of 53.9% in the pembrolizumab arm versus 35.6% with BV. A consistent benefit in PFS with pembrolizumab was seen across all patient subgroups, including those who were ineligible for autologous transplant, patients with primary refractory disease, and patients who were BV-naïve. While the ORR favored pembrolizumab, the difference was not statistically significant (65.6% versus 54.2%); complete response rates were similar with both agents (24%). DoR was extended in the pembrolizumab arm, with an increase of 6.9 months when compared with BV (20.7 versus 13.8 months, respectively). The safety profiles of both agents were consistent with previous experience, and treatment-related adverse events (TRAEs) were similar in both arms (74.3% versus 77.0%). Serious TRAEs were slightly higher with pembrolizumab (16.2% versus 10.5%) and led to patient discontinuations in 8.8% of patients versus 3.9% with BV; there was one treatment-related death in the pembrolizumab arm. The most common immune-mediated adverse events in the pembrolizumab and BV arms were hypothyroidism (18.9% versus 2.6%, respectively) and pneumonitis (10.8% versus 2.5%, respectively). Half of the pneumonitis cases were grade 3 or 4.

Based on these data, Dr Kuruvilla concluded that “pembrolizumab should be considered the preferred treatment option and new SOC for the treatment of R/R cHL in patients that have relapsed post auto-SCT or are ineligible for auto-SCT.” A discussant of the KEYNOTE-204 trial results, Mark Roschewski, MD (National Cancer Institute, Bethesda, Maryland, USA) commented that in patients with R/R cHL “pembrolizumab is clearly more effective than BV” and that the data are practice defining; however, he cautioned physicians that patients who are at high risk for lung toxicity may not be suitable for pembrolizumab therapy due to the risk of pneumonitis.

Reference

Kuruvilla J, et al. J Clin Oncol. 2020; 38 (suppl; abstract 8005).