PD-1 inhibition has been approved for relapsed and refractory classical Hodgkin lymphoma and is highly active in this setting but durable remissions are very rare in this setting. So, given the activity of these agents in the relapsed setting, it made sense to trial them in the untreated setting in addition to combination chemotherapy. So the study that we are presenting at ASH are results of a concurrent approach of pembrolizumab plus combination chemotherapy for untreated Hodgkin lymphoma.
What was the design of the study?
There have been two other prior studies looking at PD-1 inhibitors with combination chemotherapy in untreated Hodgkin, but the prior two studies that have data available used a PD-1 inhibitor lead-in followed by combination chemotherapy. So in our study we gave all four drugs – pembrolizumab with AVD chemotherapy – concurrently, starting with cycle 1, day 1. All stages of patients were eligible and all had to receive at least two cycles of the combination therapy but could receive up to six cycles of therapy depending on baseline stage and risk factors. All patients received an interim PET scan after the two cycles as well as an end of treatment PET scan after completion of all therapy.
What were the key findings?
We found that this combination was highly active in treatment naïve classical Hodgkin lymphoma. So we did find that our interim PET CR rate was a little bit lower than we had seen previously with ABVD or other published studies at 66%. However, our one year progression free survival was excellent at 96%, owing to the fact that we only had one confirmed relapse on the study.
Interestingly, we did note that we had five patients at the end of treatment with positive PET scans, or at least FDG uptake on their end of treatment PET scan. However, only one out of those five patients ultimately developed recurrent disease with more than a year of follow-up in all of those patients.
So one of the things that will need to be looked at going forward in similar studies is the role of PET scans in the interpretation of response for classical Hodgkin lymphoma with PD-1 inhibitor-based combinations due to possible false positive PET scans. We did do some correlative testing using circulating tumour DNA with our colleagues at Stanford and we found that in our one patient with biopsy-proven recurrent disease this patient never cleared their circulating tumour DNA either on interim or end of treatment PET, despite having a negative interim PET. In contrast, we’ve also had patients with positive PETs, both on interim as well as under treatment, who never had biopsy proven recurrent disease. We found that these patients cleared their circulating tumour DNA early and this may be a possible marker for further investigation in this setting.
How can these results impact the future treatment of Hodgkin lymphoma?
There is ongoing study looking at nivolumab plus chemo versus brentuximab plus chemo, that’s ongoing here in North America. This particular study we opened a cohort of 20 additional advanced stage patients in order to better understand the activity of this combination but also to support efforts to evaluate better ways to utilise PET imaging as well as circulating tumour DNA for response assessment.
So for the time being there’s not a role for PD-1 inhibitors in the untreated Hodgkin lymphoma setting but this, in combination with other published studies, showed that these types of combinations are very promising and may very well become the standard therapies in the future with additional data.