John Kuruvilla, MD, on the KEYNOTE-204 Study Findings

In an interview with CancerNetwork®, John Kuruvilla, MD, of the Princess Margaret Cancer Centre, spoke about findings from the KEYNOTE-204 study.

The study, presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, evaluated the use of pembrolizumab (Keytruda) compared with brentuximab vedotin (Adcetris) in patients with relapsed or refractory classic Hodgkin Lymphoma.

CancerNetwork®: Can you explain the study design for the phase 3 KEYNOTE-204 study?

Kuruvilla: KEYNOTE- 204 is a large, randomized, international, open-label phase 3 trial in patients with relapsed and refractory Hodgkin's lymphoma that compares pembrolizumab once every 3 weeks with brentuximab vedotin given once every 3 weeks. In terms of the key inclusion, relapsed or refractory Hodgkin's lymphoma generally consisted of 2 different patient populations. The first was patients that have had autologous stem cell transplants and have had disease progression after the transplant. The second group of patients were patients that had had prior therapy for their lymphoma but had not been able to have a transplant for whatever reason.

What were the key findings from the study?

The primary endpoint of the study was progression-free survival. And so, this was met with pembrolizumab showing a statistically significant and very clinically meaningful improvement over brentuximab vedotin. So, the hazard ratio ended up being around 0.65. The median progression-free survival for [pembrolizumab] was a little over 13 months and was around 8 months for brentuximab. And so that represents, I think, a clinically meaningful benefit for the patients that got pembrolizumab in the study.

So, what would you say are the overall implications of these findings?

It's been an interesting study to think about because the population is actually both broad and focused in a way. So, the real standard in this setting for a long time had been brentuximab vedotin, and that was based on the pivotal trial that had enrolled patients that had had disease progression only following autologous stem cell transplants. And so, clinicians where possible had generalized that data to also include patients that had been ineligible for transplant due to age or comorbidity or the presence of refractory disease. And so, brentuximab was well established in that population. What these data show is in the place where brentuximab had been defined by its pivotal clinical trial, pembrolizumab has more favorable progression-free survival. And similarly, in that population that had not been in the pivotal brentuximab study, brentuximab had become the standard up until now, pembrolizumab also had superiority in those non-transplanted patients as well.

Are there any sort of next steps for this study?

Yeah, so KEYNOTE-204 was designed as the confirmatory phase 3 trial for pembrolizumab in Hodgkin's lymphoma. We have seen the activity of checkpoint inhibitors, so this includes both nivolumab, the BMS product, as well as pembrolizumab, the Merck product, in these patients that were relapsed/refractory. The goal, much like with brentuximab, has been to try and move these treatments earlier, more into the curative setting, either in pre-transplant regimens to try and improve on efficacy and toxicity in that population, as well as ultimately trying to get this into the frontline setting as well. And so, both products, and certainly brentuximab as well are, you know, now have frontline studies and hopefully, that's the goal of where this will go in the future.

Is there anything that I didn’t ask you that you think is worth mentioning in this space?

Yeah, I think, you know, so, the other thing to highlight about KEYNOTE-204 relates to the toxicity that was seen on the clinical trial. Both of the drugs, there’s certainly lots of experience in routine clinical practice using them. So, we didn't see anything particularly new or surprising, but because the drugs work with different mechanisms, we saw differential toxicity. So, with brentuximab, some of the common things that you see are things like peripheral neuropathy, largely in improving or self-limited when the drug is held or dose reduced. With pembrolizumab, we saw a lot of the immune-related adverse events that are fairly common for these types of drugs. They're generally fairly minor things like hypothyroidism or those sorts of things that are fairly common grade 1 or 2 toxicities. The one that a lot of clinicians and patients need to know a little bit about is pneumonitis. And so, this was seen in about 10% of the patients that received pembrolizumab, it was grade 3 or 4 and a little over 5% of the patients that received the drug. Again, thankfully no patient-related deaths were seen in patients with these types of toxicities. It could be successfully managed with steroids in the majority of the patients, and so is an important toxicity to highlight but certainly did not limit the effectiveness of the drug.