Brentuximab Vedotin in Advanced Lymphoid Malignancies

Transcript:Ian W. Flinn, MD: Let’s talk about Hodgkin’s disease. We have brentuximab vedotin. There are a lot of data out in the last few years about using it earlier in the time course, perhaps as a salvage therapy before transplant, maybe getting people to transplant. There are data now that show, that for the high-risk patient population, that it’s very effective in the posttransplant setting. Where are you using it? Are you using it in both settings?

Andre Goy, MD, MS: That’s a question that was actually addressed in a presentation at ASCO about using it as a consolidation of trying to reduce the number of cycles of ABVD (Adriamycin/bleomycin/vinblastine/dacarbazine) and reduce the need for radiation. So, very briefly, for our audience: it was approved based on phase II trial data in relapsed/refractory Hodgkin lymphoma with a very high response rate, over 80%, and it was very impressive with durable responses in patients heavily pretreated. Then afterwards, the next step was to look at other areas in the relapsed setting.

For posttransplant, the AETHERA trial was very impressive in doubling the PFS. It used a maintenance brentuximab post transplant with some neuropathy, but in high-risk patients. This is very interesting and impressive. And then for pre-transplant, there are data from Memorial and other centers using it as a first salvage line of therapy. For about one-third of the patients that can go into a CR as a single agent—outpatient—it’s easier, and it’s less chemotherapy. Although we say it’s not chemotherapy, it is a chemotherapy agent. To remind our audience, we often forget this. We use it, then we mobilize the patient’s [stem cells], and then go for the transplant. And moving into the frontline setting, there are data from the Italian group and also the United States group looking at it as a single-agent activity in patients, where the activity is 85% and there is a 50%, 60% CR rate in the elderly that can get chemotherapy. This was very impressive. And then, the next step is also to combine with ABVD. AVD versus ABVD in the ECHELON-1 trial was just completed. We are waiting for the results.

The next step is to try to develop, based on nivolumab and brentuximab, new combinations that would offer “nonchemotherapy” options in patients who are not chemotherapy candidates, and I think that’s across the board. My impression is that it’s maybe more interesting to use it as a combination in high-risk patients rather than as a durable maintenance. Because if you talk about early-stage Hodgkin lymphoma, the standard is combined therapy, wait if you have PET-negativity after three cycles, and you don’t need radiation unless you’re bulky, etc. But committing patients to an additional six cycles of brentuximab, and maybe more toxicity, versus seeing if you are PET-negative after three cycles of ABVD, you don’t need radiation, you do very well, and you can always be salvaged later. And so, I think this is something we need more mature data on to really say how this is going to be in the early stage, but definitely in combination with ABVD in aggressive presentation.

Ian W. Flinn, MD: I was interested that there was the pulmonary toxicity. I’m looking forward to the results of the large randomized trial replacing bleomycin with brentuximab vedotin. But I was impressed that the toxicity was bleomycin. I would have thought it would have been a problem with the vinca alkaloids, that you needed to take the vinblastine out. Though a colleague reminded me that there were actually some data with naked CD30 in combination with ABVD and they had seen pulmonary toxicity with that. So, perhaps it’s the targeting of the CD30 rather than the delivery of the antibody drug conjugate.

Andre Goy, MD, MS: It’s interesting, because I don’t think we have a clear definition, but in the original data, they actually had to stop the trial and stop the bleomycin as you mentioned. But when you think of bleomycin, it’s an antibiotic cytotoxic that does not get cleared because we don’t have the enzyme to break it in the skin. That’s why you get the markings or enzymes in the lungs. It accumulates in the lungs and creates an inflammatory environment. So, there might be more CD30-positive cells hanging around in the lungs once you’re receiving bleomycin subclinically, and potentially you have more toxicity this way. That’s a way of thinking about it.

Ian W. Flinn, MD: What about combining it with checkpoint inhibitors or other immunotherapeutics? We’ve seen pneumonitis with the checkpoint inhibitors. Do you think there’s going to be a potential issue if we combine a checkpoint inhibitor with brentuximab vedotin?

Frederick L. Locke, MD: Well, I think conducting clinical trials in that regard will help answer that question. As always, we have to determine the safety and then see if it affects efficacy. But, there’s clearly room for improvement in Hodgkin’s lymphoma and peripheral T-cell lymphomas, where brentuximab is utilized, so a combination with checkpoint inhibitors make sense. I think the landscape of immunotherapy for hematologic malignancies is such that each of these different types of therapy is likely to provide something slightly different. So, if we’re going to talk about checkpoint inhibitors, they’re going to release the inhibition of the native immune system and help the immune system of the patient overcome the malignancy. If we talk about adoptive transfer, gene modified T cells, or other immune system cells, like NK cells, that’s likely to provide something above and beyond possibly the native immune system, but has its own limitations in terms of logistics and toxicities. And then, if we talk about monoclonal antibodies, it’s just a perfect way to target something that’s on the surface of a cell, deliver a chemotherapeutic agent to the surface or to the cell, or to turn on those immune system mechanisms that we’ve been talking about.

Transcript Edited for Clarity