iwNHL 2023 | Novel therapies in NHL: antibody-drug conjugates

John Gribben: Okay. Welcome again to the 20th International Workshop for Non-Hodgkin’s Lymphoma here in Miami. Again, this afternoon, we’ve had, what’s very traditional at these meetings, is a session looking at novel agents. And this afternoon, in a session put together by my colleague, Laurie Sehn, we focus initially on antibody-drug conjugates, which we’re going to talk a little bit about here. I’m joined today by three of the presenters, Sven de Vos from UCLA who is going to talk about one of the compounds this afternoon. Laurie Sehn, of course, who’s on the organizing committee from Vancouver and needs no introduction. And Andy Davies from Southampton in England. So, we heard a whole variety of talks, one after the other, all looking at different antibody-targeted therapies, all often carrying different payloads but with the same kind of approach of delivering the agent in. Some of these, of course, are already established and already part of an algorithm and part of established multi-drug compounds. And I’ll come back and talk about that in a moment, Laurie’s an obvious place to start. All the way through to agents which are in early phase, drug one development to compounds, Andy, that were in development, what looked like pauses have been held for a whole variety of different reasons. Let me start with you then, Laurie, in terms of polatuzumab vedotin, which of course, as you very rightly put out, is the first compound we’ve seen actually moving the algorithmic approach to be talking about moving beyond R-CHOP in diffuse large B cell lymphoma. So, what’s your take of where we are now? And you can just comment also on the question you made about, is R-Pola-CHP now the standard of care for diffuse large B-cell lymphoma?

Laurie Sehn: Yeah. So, POLARIX is the first clinical trial in DLBCL that really has met its primary endpoint, I should say, the first large randomized Phase III, introducing a novel agent into the frontline setting for DLBCL. And it did meet its primary endpoint, which was progression-free survival. But there’s been a lot of controversy around that, I think, because, number one, there was no overall survival advantage and we historically have seen PFS and OS very much linked in DLBCL. So, there was that expectation that PFS should lead to OS.

I think we’d all admit now that there are so many downstream opportunities for these patients, many of which have durable benefit and maybe even secondary chance of cure that the days of having the close link between PFS and OS are not there. But I would argue that, as a clinician, I still think our goal is to increase the cure rate in the frontline setting. And I think the data shows now with three-year follow-up most recently at ASH that those curves showing the difference in progression-free survival is sustained for at least up to three years. So, that, to me, is an improvement in the cure rate with the addition of the polatuzumab.

The controversial aspect, I think, is the forest plot that looked at a number of subgroups, many of which were not stratified within the clinical trial. So, it really is just a univariate look, and people are trying to pull out maybe subgroups that might preferentially benefit. Maybe we can ration what we know is an expensive drug compared to just giving people R-CHOP. But I think the difference is that, in this scenario, the toxicity is really quite comparable between the arms. And I think that it’s hard to put too much weight on those underpowered subgroup analyses that certainly aren’t controlled for the multitude of factors that could impact outcome.

John Gribben: On that, you highlighted one of those subgroup analyses, which is that elderly patient group in which there did appear to be a particular advantage. Now, we got questions from the audience about, was that associated with additional increased toxicity? I would argue that it’s in the elderly group that you have less ways to be able to salvage those patients back, and that maybe that is the subgroup analysis in whom getting to a curative approach is actually more important. And to my mind, that would be worth, and it’s some additional short-term pain to get that longer term gain.

Laurie Sehn: I fully agree. So, there was a suggestion actually from the forest plot that the elderly were not disadvantaged. If anything, might actually preferentially benefit. So, I thought it was an important subgroup for further analysis. And now, we have a subgroup analysis that’s been presented formally and we’ll see a manuscript soon. But it certainly appears the elderly population definitely benefits as well, if not even somewhat better. And I think that the toxicities, again, even in that group are fairly comparable.

What we pointed out is that across the whole group and within the elderly group, there’s a higher rate of febrile neutropenia, maybe a higher rate of low-grade infection. Those are short-term toxicities that, in general, we can manage, but there wasn’t a heightened risk of mortality because of the treatment and certainly not that was offsetting the outcome.

John Gribben: Sure. Now, of course, the other question you raised, and I’m going to come back to you on this one because you raised some issues here at the panel discussion about, is R-Pola-CHP the new standard of care? And of course, it isn’t. It’s the standard of care for a subgroup of the patients really at the moment; isn’t it? But the question then becomes, if we’re going to be doing randomized clinical trials, is our new benchmark against R-Pola-CHP or should it be still against R-CHOP? And Andy, you raised some interesting concepts in terms of the ethical issues about how you randomize a patient to receive R-CHOP when R-Pola-CHP would be an approved indication for that patient.

Andrew Davies: I think this is really important that we try and have this discussion because we’ve got many frontline trials that are either already open or in development asking the question about a novel intervention with a CHOP-like combination against R-CHOP chemotherapy. And so, of course, many territories have really adopted, at a very high penetration level, Pola-R-CHP in frontline DLBCL. And I think trying to randomize a patient into a study where R-CHOP is the standard of care then raises some significant dilemmas for the investigator and a difficult conversation with the patient. I’m not saying that R-CHOP chemotherapy is no longer an acceptable standard of care and I think Pola-R-CHP is just another choice as a standard of care, but it does make it very difficult when we’re thinking about what our control arm is going to be. And I think that’s also really important in terms of future-proofing the studies as we see perhaps even greater penetration of Pola-R-CHP in the years to come in very many territories where they’re struggling a little bit with the funding approvals. I think it’s going to be very difficult to have some studies that have compared with R-CHOP chemotherapy when they get their readouts and some studies that compared with Pola-R-CHP. It makes the landscape really quite difficult for us.

John Gribben: Sure. Sven, moving on to, you talked about an agent targeting ROR1, which of course, we’ve seen a lot of interest in as a potential compound, particularly sought first in CLL, but now across B-cell malignancies. Also, raised an issue that came across lots of the discussions we’re having today about levels of expression on the target and is it something that we look at, and is that a requirement to come into the study? And we saw in many of your studies, certainly across different histologies, that it was all-comers and then potentially a retrospective look. Is that the right way for us to go forward, or is it by looking at it in this way that we begin to understand they don’t always work in exactly the way that we thought? What are your thoughts?

Sven de Vos: Well, one is a new target to go after in oncology. It’s a very interesting target which is only expressed in normal life during embryogenesis and not anymore. So, it is expressed in the vast majority of malignancies, including hematological malignancies. And the more aggressive and faster-growing these are, the higher the expression is. So, I think it’s important initially to allow all-comers to come into a trial and then learn what the level of expression in relation to response might be. There is an indirect link right now in a more aggressive, more fast-growing lymphomas responding better and longer lymphomas are responding poorly. But I also would like to see the correlation with expression, and if you learn something from that too on select patients.

John Gribben: What was quite common in that whole variety of compounds we heard this afternoon was that there was a level… So, there were responders and non-responders, which of course, raises interesting concepts, but the response rate was often quite similar from compound to compound. Working the premise that many of these compounds are or will be in the future approved, how do you think we’re going to algorithmically think about the series in which we offer these? Or do you think almost all of them, as we’ve done for polatuzumab, are going to land up being used as part of a combination and moving more and more frontline? I think, Laurie, you raised the issue, we can’t have R-Pola-Zolo something-CHP. We can’t just keep adding and adding and adding to our algorithm. So, how do you think we’re going to be thinking about where these compounds fit into our algorithm?

Laurie Sehn: Yeah, it’s a real challenge. I mean we heard, I guess, a lot of individual compounds, lots of great science behind them. The one thing that I am being challenged by right now is that also, if you’re doing single arm studies of these single arm drugs, the bar has changed. The kinds of patients we’re putting on these trials are not the kinds of patients we put on even five years ago. So, I have many trials or proposed and they say, “We’re trying to test this in the unmet need of third line DLBCL.” And you could argue that most third line DLBCL patients are not going on trials of novel compounds anymore. They have a series of options and now, we’re enrolling patients in their fifth line and beyond. So, what is the bar now that gives you that signal of activity in those fifth line and sixth line patients that makes you want to move a drug forward? And it’s unlikely that any of these drugs are going to have a high level of success as single agents. So, we’re going to want to combine them, but it does get complicated when you think about the permutations and combinations and the number of options that we have. I think it’s going to be very challenging moving forward.

Andrew Davies: And John, I think part of this is also about how the target antigen is going to be modulated through the clinical course of the disease and perhaps how prior therapies that you may have been exposed to may modify that. We already know the story about loss in CD19 in patients who had previous CAR-T exposure. It doesn’t look from the preliminary data that patients who had lonca-T, which is an ADC target, CD19, a different epitope may not lose the CD19 expression in progression.

John Gribben: Yeah, it’s an interesting concept as to why that should be; isn’t it?

Andrew Davies: Absolutely. So, I think this is going to be a really important story in terms of our evolution of sequencing.

John Gribben: Now, the other session we had within the session this afternoon was this industry perspective on some of the things that are happening. And of course, what we heard from our industry panel this afternoon is, of course, the FDA’s moving the goalposts here in terms of exactly how we get it. And I didn’t hear anything today that made me comfortable to think that there’s going to be an easier path to approval for many of these compounds.

And in fact, what we did hear was that the move towards looking for overall survival advantage, which of course, is the goal of what we all want to do in our clinical trial developments, but particularly in hem malignancies where we’ve got multiple lines of therapy being able to be offered, it’s very difficult to see – if that’s going to become a goal that needs to be required for registration, is that too high a goal for us to see any of these compounds ever make it through in the future? Sven, let’s come to you.

John Gribben: As the American on the panel.

Sven de Vos: Thank you very much. Recognizable by my accent. Clearly, in trials that are randomized where crossovers are allowed, you basically design the trial against actually necessarily seeing survival advantage. Therefore, I think that that should not, I think, be over-emphasized in these aggressive lymphoma trials.

John Gribben: The trouble is, of course, that’s what the FDA is looking for. It was interesting to see the industry perspectives on the panel, look at how they are creatively trying to come up with ways. But in the end, they’re going to have to sit down with the regulators and find out whether their approaches are going to be acceptable to the agency. But there is the potential that with all the best intentions in the world, that we may have actually shot ourself in the foot here in terms of what it is we are looking to achieve for our patients. Andy?

Andrew Davies: Yeah, I think you’re absolutely right. I think we should be concerned that perhaps we may slow the pace of development down. We’ve had this excess of accelerated approvals. And now, we’ve seen some backward stepping on that because some of these agents that were approved under this process actually haven’t proven themselves in the Phase III setting, or the safety signal hasn’t really been confirmed. And we’re seeing a decrease in the number of agents that are getting accelerated approval. So, I think that we’ll see as a result of this perhaps some slowing of the pace of drugs and therefore, access to our patients, which I think we’re going to have to be really mindful. I think one of the commentators said, “Look, there’s this big focus now from the agency towards overall survival. The pendulum has really swung from one to the other, and we hope that that may well move back in the future to somewhere that really gives us a proof of efficacy and safety, but actually is able to deliver these new agents in a timely way for our patients.”

John Gribben: Okay. So, there you have it. That’s the end of day one from iwNHL today. We look forward to being able to see all of you tomorrow for what, I think, looks like a very exciting day two. We’ll be posting more on what we find from the sessions following this one. So, thank you very much for your attention, and thank you very much to the panel for joining me today.