Pembrolizumab Improves PFS in Relapsed/ Refractory Classical Hodgkin Lymphoma


John Kuruvilla, MD, FRCPC, Princess Margaret Cancer Centre, Toronto, Canada, discusses the results from the phase 3 KEYNOTE‑204 trial, which compared pembrolizumab, an anti-PD-1 antibody, against brentuximab vedotin in relapsed/refractory classical Hodgkin lymphoma.

These results were presented at both the virtual 2020 ASCO Annual Meeting and virtual 2020 EHA Annual Congress.


I would like to share with you a quick update of the KEYNOTE‑204 randomized clinical trial. This was a phase 3 study in relapsed or refractory classical Hodgkin's lymphoma that compared pembrolizumab, an anti‑PD‑1 antibody, against brentuximab vedotin, which is a well‑known anti‑CD30 antibody drug conjugate.

The patient population consisted of patients who had relapsed post‑autologous stem cell transplant or patients that were ineligible for autologous stem cell transplant but had at least one prior line of therapy before getting into the study.

The trial was stratified to look at duration of relapse after primary treatment, whether you were primary refractory, an early relapser with progression within 12 months, or a late relapser with progression after 12 months, as well as if you'd had a prior stem cell transplant or not.

The primary end point of the trial was progression‑free survival. The goal of the study was to show superiority or pembrolizumab over brentuximab, which was a well‑established standard based on the pivotal phase 2 trial that had been done in patients that had had a prior transplant and had experienced disease progression.

When you look at the results of the study, pembrolizumab was statistically significant in its improvement in progression‑free survival over brentuximab, with a median progression‑free survival of just over 13 months compared to just over 8 months for the control population getting brentuximab vedotin.

When you looked at all of the relevant subgroups, whether that was transplant or not, early versus late relapse, or the presence of primary refractory disease, or any other subtype, we saw benefits for all of those patient subgroups.

Importantly, a very small number of the patients had had prior brentuximab exposure. The trial was also significant in patients whether they'd had brentuximab exposure or not.

Looking at other key secondary end points, duration of response was favorable for the patients with pembrolizumab. When you looked at progression‑free survival and removed patients that went on to have a subsequent stem cell transplant for whatever reason, the benefit was still significantly in favor of the pembrolizumab arm.

When you look at response rate, there was numerically an improvement for pembrolizumab versus brentuximab, but that did not reach the pre‑defined statistical level of significance.

Looking at toxicity, both drugs performed much as they would have been expected to based on the clinical experience with the drugs, with, typically, peripheral neuropathy being the main issue with the brentuximab‑treated patients and immune‑mediated side effects more common with pembrolizumab.

These were typically minor ones, things like hypothyroidism that can be easily managed, but an important one to mention is that of pneumonitis. This was seen in a little over 10% of patients. This was grade 3-4 in about 5.4% of patients. Importantly, there were no pneumonitis‑related deaths on the study, although there was 1 death on the study in the pembrolizumab arm.

Looking at the toxicity, a majority of the patients were treated with corticosteroids, and a majority of patients had resolution of pneumonitis at the time of current study follow‑up. We're also still waiting to see the survival analysis mature because we haven't had enough events at this point.

To summarize, this was a large, randomized multi‑center, international phase 3 trial that is positive and showed significant clinical benefit in progression‑free survival for pembrolizumab over brentuximab vedotin.

What this means for clinicians in the field treating Hodgkin's lymphoma is this represents a new standard for that patient population where we had typically used brentuximab vedotin.

Brentuximab has moved forward in the treatment of Hodgkin's lymphoma and is now used in the curative setting as consolidation post‑transplant based on the AETHERA trials and now in the frontline setting based on ECHELON‑1. We would expect similar things to happen with checkpoint inhibitors, including pembrolizumab, as they are now being studied earlier in the disease course.

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