ASH 2022 | Brentuximab vedotin, nivolumab, doxorubicin & dacarbazine for early stage classical Hodgkin lymphoma

So in limited stage Hodgkin lymphoma, our standard therapy for many years has been ABVD with or without radiation therapy. Most recently, we’ve been eliminating radiation therapy in the lowest-risk patients, but a number of patients will still require radiation therapy, which does still offer a modest progression-free survival benefit. We’ve also commonly been using ABVD as our backbone for decades, but ABVD of course has potential side effects, including most notably the risk of bleomycin lung injury related to, of course, the bleomycin. In advanced stage Hodgkin lymphoma, we’ve substituted brentuximab vedotin, the anti-CD30 antibody-drug conjugate for bleomycin as part of the brentuximab-AVD regimen in advanced stage disease, which now shows a progression-free and overall survival benefit over ABVD alone for stage three or four patients. But in limited stage patients, we conducted a Phase II trial of brentuximab-AVD, again, just substituting the brentuximab for bleomycin and found excellent efficacy.

But as with the ECHELON-1 trial in advanced stage disease found excess toxicity of peripheral sensory neuropathy, neutropenia and neutropenic fever, which we attribute to overlapping toxicities between brentuximab vedotin, and vinblastine, both of which target the microtubule. As a follow-up Phase II study, we therefore eliminated the vinblastine and conducted a Phase II study of brentuximab-AD in non-bulky, limited stage classical Hodgkin lymphoma. Those data recently published in Blood Advances look excellent. We see a very high complete response rate and see that 91% of patients remain progression-free with this reduced chemotherapy intensity regimen and that we see a marked reduction in the incidence of toxicities. We saw no grade four neutropenia in that trial, we saw much less peripheral sensory neuropathy with no high grade peripheral sensory neuropathy reported, and we saw no cases of neutropenic fever without the need for growth factor support.

Building upon that experience, the next question is, can we incorporate yet another novel targeted therapy without amplifying chemotherapy? And so in collaboration with the sponsor Seattle Genetics, we conducted a Phase II trial with interim analysis presented at this ASH meeting, looking at brentuximab, adriamycin, darcarbazine, plus nivolumab. These interim data continue to show benefit for reducing chemotherapy intensity and adding novel agents with high rates of complete response and very exciting rates of durable progression-free survival, though at limited follow-up. We’ll look forward to hopefully about a year from now having primary analysis of that study with a full population. And what I anticipate is that we’re going to see that reducing chemotherapy intensity and using novel agents such as brentuximab vedotin, and immune checkpoint inhibitors can amplify efficacy and reduce chemotherapy toxicities, all the while allowing elimination of the short and long-term effects of consolidative radiation therapy.