ASH 2024 | A Phase II study of nivolumab plus brentuximab vedotin in early-stage classic Hodgkin lymphoma

This was a multi-center Phase II study from the North American Hodgkin Consortium, so a lot of different people participated in this study. This was in patients with stage one and two disease, A and B, including bulky patients, again with the goal of trying to avoid radiotherapy if possible by incorporating brentuximab and the PD-1 inhibitors. The nice thing about this study was patients got two cycles of ABVD and then had a PET scan and then were enrolled on the trial. So it was very pragmatic. Sometimes it’s hard to get people on trial quickly and initiate treatment. And here, they’d already started treatment. So the planning allowed for rapid enrolment after people had already started treatment. So the patients who were PET negative, and this was Deauville 1, 2, and 3 score, and had non-bulky disease, in this study was defined as a mediastinal mass of less than 7.5 centimeters, were randomized to brentuximab plus nivolumab for three cycles versus two additional cycles of ABVD followed by radiation. Patients with bulky disease got two cycles of ABVD followed by nivolumab for six doses, just like the other arm for the non-bulky patients. And then patients who were PET positive got four cycles of BVAVD, had a PET scan, and if negative, went on to receive nivolumab for six doses. So overall, there were 153 patients enrolled. About a third of patients had bulky disease. About 30% of patients had stage 2B disease. So it was a relatively high-risk population of patients. And in fact, almost 25% were PET2 positive, again reflecting enroling patients after they had had their PET scan. So I think investigators felt like, well, we need to do something more aggressive for these PET positive patients because we know the outcomes aren’t great even with escalated chemotherapy. Tolerability was as we would expect. About 8% of patients came off treatment for toxicity and there were some immune mediated toxicities, but predominantly grade one and two. So in terms of outcomes, what was really notable was the non-bulky PET2 negative patients did exceedingly well, and there were no recurrences in that group, which at two years with a median follow-up of about 27 months. For the patients who had bulky disease, outcomes were good at about 86% at two years. There’s probably some room for improvement, And I think now we’re beginning to think that perhaps incorporating PD-1 inhibitors with chemotherapy or brentuximab earlier in the course of treatment as opposed to doing consolidation with nivolumab after chemotherapy may be a better strategy. Or perhaps these patients just need more cycles of therapy. The PET-positive patients, however, didn’t do as well as we had hoped. And the two-year PFS was 77%. And I think this tells us that these folks need radiation. You know, radiation is a very good modality in Hodgkin lymphoma. It’s associated with late effects, but with modern radiation techniques, the lower doses and smaller fields that we’re using now, I think the long-term toxicity is going to look significantly better 20 to 30 years from now, which is how long it takes to see these adverse effects compared to what we’ve seen in the past. And there was a presentation at ASH, the long-term follow-up of the RAPID study, for which all the patients who were PET positive got radiation. And the late effects or deaths due to radiation looked quite good. So I think we have an early signal that this may be a good strategy. So for those PET positive patients, I think they need more therapy, probably with brentuximab, nivolumab, and radiation in hopes of really trying to get them long-term disease control with their upfront treatment.

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