Lead Investigator Highlights Pembrolizumab Activity in Relapsed/Refractory Hodgkin Lymphoma

John Kuruvilla, MD, FRCPC

Pembrolizumab (Keytruda) could potentially be a new standard treatment for patients with classical Hodgkin lymphoma who relapse post-transplant or are ineligible for transplant, according to John Kuruvilla, MD, FRCPC.

Results of the KEYNOTE-204 trial, which were presented at the 2020 ASCO Virtual Scientific Program, showcased the benefit of pembrolizumab compared with brentuximab vedotin (Adcetris) in this patient population.

The median PFS with pembrolizumab was 13.2 months versus 8.3 months in the brentuximab vedotin arm, leading to a 35% reduction in the risk of disease progression or death (HR, 0.65; 95% CI, 0.48-0.88; P = .00271). The PFS benefit was observed across all prespecified subgroups.

“These data [show] favorable PFS for pembrolizumab, as well as a good safety profile, which supports [the agent as the] standard for patient who relapsed posttransplant or for those who were ineligible for transplant,” said Kuruvilla, who is also the lead study author of KEYNOTE-204.

In an interview with OncLive, Kuruvilla, a clinician investigator at Princess Margaret Cancer Centre and lead author of the study, discussed the pivotal KEYNOTE-204 findings in Hodgkin lymphoma and the future of checkpoint inhibitors.

OncLive: Let’s get a pulse on the current relapsed/refractory Hodgkin lymphoma paradigm. How would you describe it?

Kuruvilla: The landscape of relapsed/refractory Hodgkin lymphoma has changed a lot in the past 5 to 10 years. Historically, novel therapy has not really [been a part of] the armamentarium for a long time, but we saw some early encouraging results with drugs, such as lenalidomide (Revlimid), mTOR inhibitors, and HDAC inhibitors, such as panobinostat (Farydak). However, it was really brentuximab vedotin that was the first novel therapy that was approved. Following that, PD-1 antibodies, such as pembrolizumab and nivolumab (Opdivo), have altered the space dramatically, so now we have a number of different active agents, we have combinations in place, and we have been moving them increasingly into the curative and potentially frontline settings. 

What were the significance of the results in the KEYNOTE-204 trial?

KEYNOTE-204 was a pivotal study designed to do a head-to-head comparison of pembrolizumab with brentuximab vedotin in patients who have relapsed after an autologous stem cell transplant or [who] were ineligible for transplant.

[Our] primary endpoint was progression free survival (PFS). Essentially, [we were] trying to show that patients who received the experimental treatment would do better for a longer period of time. The primary endpoint was met, with almost a doubling in PFS for pembrolizumab compared with brentuximab. From a safety standpoint, the treatments showed the typical toxicities that we know from earlier-phase experiences from both drugs; pembrolizumab appeared to be just as safe as we knew it would be in this setting.

Was the PFS benefit with pembrolizumab observed across all predefined subgroups?

The trial results were very consistent across the population that we wanted to look at. When you look at the forest plot of all the subgroups that were studied, all of them trended towards favoring pembrolizumab over brentuximab vedotin. The pre-planned groups of interest that were used as stratification factors [included those with] primary refractory disease and early relapse after primary treatment; both groups of patients continued to show benefit [with pembrolizumab].

The other group of interest in this trial comprised patients who had prior exposure to brentuximab vedotin. The whole trial was positive, as well as the subgroup of patients who were brentuximab-naïve, which comprised the vast majority of patients. However, even for patients [who previously received brentuximab vedotin], there was also a trend towards [improved PFS with pembrolizumab].

When you look at the study as a whole, this was the first randomized trial in relapsed/refractory Hodgkin lymphoma to test what the optimal strategy should be. Brentuximab vedotin became a standard treatment based on a pivotal, single-arm trial in patients who had relapsed or had disease correction after stem cell transplant.

Would pembrolizumab be used in all-comers, or are there biomarkers to determine which patients should receive pembrolizumab?

No biomarkers were a part of this study. [In Hodgkin lymphoma, there are not really] predictive biomarkers that have been well-defined, and there's no target that you need to demonstrate on a tissue biopsy. We know that the activity with these agents is very broad in Hodgkin lymphoma. [Pembrolizumab] broadly applies to this population that fits the inclusion criteria and had relapsed posttransplant or were ineligible for transplant.

Is there anything else about this study that you would like to highlight?

It was one of those studies where you didn't see any major surprises. The control arm performed as expected, the experimental arm performed as expected, so this is unlike a lot of the trials that we see in Hodgkin lymphoma or even in diffuse large B-cell lymphoma, in which there isn’t necessarily always a very clean signal. Things were quite clear in terms of the message around the primary endpoint.

The toxicity is important to think about because both drugs have different toxicity profiles, so we knew the issues with brentuximab vedotin, as an antibody-drug conjugate with chemotherapy, it contributes to peripheral neuropathy. That was shown in the control arm. However, patients recovered from peripheral neuropathy and still did reasonably well. In the experimental arm with pembrolizumab, we knew there were going to potentially be some toxicities. The common immune-related toxicities, which are generally mild and grade 1/2, were generally as expected.

The more worrisome toxicity [is] pneumonitis, [which] has been described with this class of agents. In general, we saw that in about 10% to 11% of patients. It was equally split between grades 1/2 and grade 3/4. The grade 3/4 rate was about 5.5%. This was successfully managed with corticosteroids, [while] a few [patients] required discontinuation, but the effect was still broad and there were no treatment-related deaths from toxicity.

Given these results, what do you think the future of checkpoint inhibitors and immunotherapy at large is in Hodgkin lymphoma?

Checkpoint inhibitors are definitely here to stay. The North American Intergroup is embarking on a randomized trial in the frontline setting that will compare a checkpoint inhibitor—in this case it will be nivolumab—with AVD [doxorubicin, vinblastine, dacarbazine] versus AVD plus brentuximab based on the ECHELON-1 study as the control treatment. That will be an interesting study to see.

Checkpoint inhibitors are being used increasingly in the replaced/refractory setting before transplant [and are] now being moved into the curative setting. There are some data from KEYNOTE-204 that speaks to that population in a subset analysis, which we'll hopefully be able to study a bit more to understand how that affects outcome in transplant and if there may be an optimal strategy in that setting.

Combinations are being used, whether that's with brentuximab vedotin or with chemotherapy, and we'll see trials play out in the next few years. An interesting question is, “With very effective salvage strategies with checkpoint inhibitors and brentuximab vedotin combination strategies, will we be able to, move away from chemotherapy as a salvage approach based on these randomized data?” Or, can we even potentially move away from stem cell transplant if we're able to show if a non–dose-intensive approach is capable of curing patients? These drugs will contribute to that sort of future for patients with Hodgkin lymphoma.

Reference

Kuruvilla J, Ramchandren R, Santoro A, et al. KEYNOTE-204: Randomized, open-label, phase III study of pembrolizumab (pembro) versus brentuximab vedotin (BV) in relapsed or refractory classic Hodgkin lymphoma (R/R cHL). J Clin Oncol. 2020;38(suppl; abstr 8005). doi:10.1200/JCO.2020.38.15_suppl.8005