Hodgkin lymphoma affects a little over 8,000 patients each year in the US. About half of those patients have advanced stage disease and the standard treatment for advanced stage disease for years has been combination chemotherapy. But we use different chemotherapy regimens around the globe; actually, even within North America, paediatric and adult patients receive different regimens and paediatric patients, the majority of them, actually receive consolidative radiation treatment after their chemotherapy has finished. So the treatment approaches for advanced stage Hodgkin lymphoma really have differed over the years.
About five years ago Hodgkin lymphoma patients gained a new treatment option, which is brentuximab vedotin, for the treatment of their initial disease. Brentuximab vedotin is an antibody-drug conjugate, it’s directed against CD30 on the Hodgkin lymphoma tumour cells. Several studies showed that incorporating brentuximab vedotin into the initial treatment of Hodgkin lymphoma improved outcomes. It improved overall survival in adults and event free survival in children and so the drug was approved for the initial treatment of adults and children with advanced stage Hodgkin lymphoma.
We learned that PD-1 biology played an important role in the pathogenesis of Hodgkin lymphoma. There are genetic changes in chromosome 9p24.1 which is the PD-1 ligand genes and that leads to overexpression of the PD-1 ligands on the surface of Hodgkin lymphoma tumour cells. So, nivolumab and other PD-1 blocking antibodies are a highly effective treatment for Hodgkin lymphoma that is relapsed or refractory, resistant to many lines of therapy. Then, over time, we have been marching that drug, and others like it, backwards, so using them earlier on in the course of the patients’ care. There have been early trials showing that incorporating PD-1 blockade into front-line therapy is effective.
So, with that rationale, we designed S1826 which was a randomised study. It was a collaboration between the adult and paediatric cooperative groups in North America, so trying to harmonise the treatment of advanced stage Hodgkin lymphoma to use the same. All the patients, adult and paediatric, got the same AVD chemotherapy backbone and patients were randomised to receive either nivolumab or brentuximab vedotin combined with that AVD backbone.
What were the results of this study?
We enrolled just under 1,000 patients; it was a very representative study so a quarter of the patients were under 18, 10% were over 60, a quarter of patients were black or Hispanic. There was good representation of clinically high risk patients. We found, actually, that nivolumab-AVD improved progression free survival compared to brentuximab vedotin-AVD with a hazard ratio of 0.48, so a 52% reduction in the risk of disease progression or death. This was a pretty astounding result, actually it happened at a second interim analysis. So this was a pre-planned interim analysis that actually showed that the primary PFS endpoint crossed the statistical bound and it was recommended that we consider the study question answered and we report the study results.
The one-year progression free survival after nivolumab-AVD was 94%; the one-year progression free survival after brentuximab vedotin-AVD was 86% so a significant reduction in the risk of disease progression or death. Event free survival was also improved with nivolumab-AVD. When you look at the different subgroups of patients treated on the trials, the benefit associated with nivolumab-AVD was consistent across the subgroups. So when you look at the forest plot all the squares are favouring nivolumab-AVD, so young, old, low clinical risk, high clinical risk, stage 3, stage 4 especially patients seemed to benefit, patients with or without B symptoms. So it was really an impressive result that demonstrated consistent benefit across all the subgroups.
I would say one of the most important results from this study is that, as opposed to a majority of paediatric patients receiving radiation at the end of their chemotherapy, in our study 6 out of 1,000 received radiation. So less than 1% of patients received radiotherapy which is a dramatic reduction in the amount of radiation that we’re giving the very youngest patients who are most vulnerable to the late toxic effects of the radiation and chemotherapy that we give to cure their lymphoma.
How could this research impact future treatment?
This is a tremendous advance for patients with advanced stage Hodgkin lymphoma. Of course, we’re continuing to confirm the durability of the benefit. It’s still too early to assess overall survival but, with these results, nivolumab-AVD is really poised to become a new standard of care for the treatment of advanced stage Hodgkin lymphoma.
Future important questions will be now that we have these results and in the very highest risk patients we’re seeing quite excellent outcomes, is there an opportunity to think about de-escalation of therapy? Brentuximab vedotin actually is a very good drug for the treatment of Hodgkin lymphoma so is there an opportunity to reintroduce it into the front line setting? What’s the role of brentuximab, should we be using it in second? So there are still important questions to ask and answer but this is a tremendous advance for patients to have improved outcomes, reduce the use of radiation significantly and AVD was much better tolerated than brentuximab vedotin-AVD. It really just shows the power of collaboration across the adult and paediatric cooperative groups to really drive research forward and answer questions more quickly.
Again, I just want to speak to the really tremendous collaboration between SWOG, the Children’s Oncology Group and all of the cooperative groups to really be forward thinking and try to harmonise all this complicated treatment of Hodgkin lymphoma that we do. One really exciting result that came from this study is that, because of our initial collaboration, we’ve sparked ongoing collaboration in adult and young adult patients with lymphoma. So all future studies in Hodgkin lymphoma and other relevant lymphomas are collaborations across the age spectrum, so between the adult and the paediatric cooperative groups.