Toby Eyre

It’s great to be here at EHA 2024. My name is Toby Eyre. I’m a consultant hematologist in Oxford in the UK, and I’m joined by Lydia Scarfò, who is a consultant in Milan, and we’re going to be talking about some of the highlights we’ve seen at EHA, with a focus on CLL and Richter’s.

So, Lydia, we saw some really interesting data with combinations of BTK inhibitor and BCL2 inhibitor, both in first-line treated patients and also in the relapsed/refractory setting. What were your highlights from those abstracts?

Lydia Scarfò

Very interesting data because during this meeting we have the first look at the data of the arm D of the SEQUOIA trial, where zanubrutinib was combined with venetoclax in a particularly high-risk population of patients carrying 17p deletion or TP53 aberrations, and we see a very high efficacy in this hard to treat patient population. So I’d say probably the follow-up is still short. And we need to see only three patients discontinue treatment. And we need to see in the long run, if even in this high risk population, we are able to achieve deep responses based on CR and undetectable MRD, allowing us to discontinue treatment. What about the combination of zanubrutinib and sonrotoclax in the relapsed/refractory setting from your side, Toby?

Toby Eyre

Yeah. Thank you. So I mean, sonrotoclax is a new BCL2 inhibitor. It’s being studied. It’s got a shorter half life, and it looks like a very potent agent. And it’s being studied, as monotherapy in some diseases, but also in combination. And here we saw data, reasonably mature data, and quite a large number of patients treated with sonrotoclax plus zanubrutinib in patients with relapsed CLL. You could have had a prior BTK inhibitor, but you had to be intolerant rather than resistant to it. And nearly 50 patients were studied here and the response rates were excellent. And very few patients had progressed through therapy up until now. In fact, only I think one patient hadn’t maintained a response. So it looks like a very active combination, well-tolerated, fairly low rates of, for example, GI toxicity, cytopenias and so forth. So it looks a promising combination. And we know this is moving forward into a randomized clinical trial going forward. So, the combination of zanubrutinib plus sonrotoclax as fixed duration therapy is being compared with venetoclax rituximab in a large international randomized clinical trial. So that’s currently enrolling. And we look forward certainly to seeing the results of that in the future. So what do you think of those other combinations of BCL2 BTK inhibitors? I think Nitin Jain presented data with venetoclax obinutuzumab and the non-covalent BTK inhibitor pirtobrutinib. And what were your thoughts about that first-line trial?

Lydia Scarfò

Absolutely right. Very impressive data, meaning that they reach very deep responses up to 100% undetectable MRD as assessed by NGS analysis. So the level is ten to the minus six. So very favorable responses. But this is associated in my opinion with a sort of trade off in terms of toxicity, because you have 30% of patients who had to dose reduce both pirtobrutinib and venetoclax because of cytopenia. So I’m wondering if the addition of obinutuzumab is still really needed in this patient population. What’s your opinion on that Toby?

Toby Eyre

Yeah, I think we’re sort of at a bit of a crossroads in CLL where we’re not quite sure where the triplets have a role versus doublets in terms of CD20, BTK, BCL2 versus perhaps, well, either BCL2 and CD20 or BTK, BCL2. And you’re right, there’s this trade off of toxicity and efficacy. I think clearly that study had very high rates of undetectable MRD. Probably obinutuzumab adding quite a lot to that. But it was a very fit young group of patients. And you always need to think about the broader applicability of a combination and a triplet regime. And we haven’t seen that sort of make its way into our routine clinical practice, have we. So we’ll need randomized clinical trial data and long follow-up before I think we make that decision and move towards triplet therapy in my opinion.

Lydia Scarfò

While for the combination of pirtobrutinib plus venetoclax in first-line, we are eagerly awaiting the start of the CLL18 trial where pirtobrutinib plus venetoclax fixed duration or based on MRD driven approach will be compared with the standard of care venetoclax plus obinutuzumab. So this would probably provide some additional insights on this combination.

Toby Eyre

That will provide some really interesting results. Answering a number of questions actually. MRD driven strategy versus fixed duration. And then also the question about how those regimes fare with a standard of care that we have at the moment, venetoclax obinutuzumab. So yes, I think a doublet, particularly with venetoclax and pirtobrutinib, which we know to be a very well tolerated BTK inhibitor, certainly looks attractive to study, so we’ll be waiting the results of that with interest.

Lydia Scarfò

What about relapsed/refractory patients? Are there any new agents that you found interesting during this meeting?

Toby Eyre

Yeah. So, I mean, we’ve seen just new agent after new agent in the last ten years. We’ve been very spoiled. And it’s been fantastic to see the developments. And I think we have a new class of drug that we’ve seen very interesting data from this congress. So the BTK degraders have been assessed and are ongoing in in early phase clinical trials. These agents are specifically designed proteins that bind to BTK and lead to ubiquitisation and degradation by the proteasome. So you degrade the whole of BTK, including scaffolding around BTK. So they work differently to both covalent and non-covalent BTK inhibitors. And we’ve seen data from two companies, from the Nurix company and also from Biogen, from early data from their phase one studies. The groups of patients studied with these oral molecules are very heavily pretreated. Lots of patients have had multiple prior lines of therapy, high risk genomic characteristics, including BTK mutations, and nearly all patients have been exposed to a prior covalent BTK inhibitor. And there are, in fact, some patients in these studies that have been exposed to BCL2 inhibitors, covalent BTK inhibitors, and indeed non-covalent BTK inhibitors. So very heavily pretreated patients. Both the agents look pretty well tolerated, I think, in the two studies. No hugely concerning toxicities. You do see BTK related toxicities that we’re sort of used to from covalent BTK inhibitor and non-covalent BTK inhibitor data. But I would say their response rates look pretty equivalent with the two agents in the post-covalent BTK treated patients, response rates are about 70%. Very encouraging early data. We, of course need long follow up and a good understanding about the different subgroups and how the treatment fares and how durable these responses are. But I personally thought very interesting data and look forward to seeing more with the development of these two agents.

Lydia Scarfò

I totally agree, if I may. And due to the shorter of follow-up it is still difficult to assess the long term disease control. And the interesting and potential great advantage is they seem to work even in the presence of different BTK mutations, and they lead to BTK degradation in more than 100% of molecules. So it’s a very effective potential mechanism of action. So as you said, we need long-term follow-up and probably larger patient cohort.

Toby Eyre

And I think a really key question is about the sort of strategic development of these molecules moving forward. The nature of their activity and their actions suggests that probably you would want to use them sort of after covalent BTK inhibitors certainly have stopped working. Who knows, maybe after non-covalent BTK inhibitors, or maybe they’ll compete with non-covalent BTK inhibitors. I don’t know what your thoughts are in that regard.

Lydia Scarfò

That’s the $1 million question, I must say. I mean, so far we have data on a sequence starting from covalent BTK inhibitor, then going to non-covalent. And then we have preliminary efficacy and safety data on BTK degrader. But generally very effective drugs should be used earlier. So if the promising efficacy results are confirmed in the long run, probably we should design trials where we consider the use of this drug earlier, probably combined with something else in order to use fixed duration combinations, anyhow.

Toby Eyre

Very interesting, so watch this space with these agents. And Lydia, just to finish, I think there was some very interesting data just switching tact on Richter’s transformation. This is clearly a very feared complication of CLL, a disease that we struggle with in our clinical practice. And clearly we need newer agents in this setting. But we saw some interesting data with the CD3-CD20 bispecific epcoritamab. We’d seen some previous data with this agent before, but there was a much larger cohort presented here. What did you make of that data?

Lydia Scarfò

Yeah, actually this meeting, they presented the fully recruited cohort of patients with Richter’s transformation and confirmed an overall response rate of around 60%. That is very impressive in this highly refractory patient population. The efficacy was actually associated with a tolerable safety profile, meaning that as expected, patients experienced CRS and in small percentage also neurotoxicity. But they were manageable. Again, probably we should better understand with the longer follow-up the duration of response. As mentioned, this was a very heavily pretreated patient population previously exposed to treatment for both CLL and Richter’s transformation. And we have also to consider that in the future cohort of the study epcoritamab will be explored in combination with other treatments. On one side, there is a cohort recruiting patients who will be treated with epcoritamab and R-CHOP. And a second cohort I found very interesting is the combination of epcoritamab and the immune modulator lenalidomide. So I’m looking forward also to these additional cohorts in order to better understand if we can achieve long term disease control in Ricter’s.

Toby Eyre

I completely agree, and I think one of the really interesting things here about these monotherapy data is that these are the highest complete remission rates we’ve really seen with a monotherapy in in Ricter’s transformation. The question would be how strategically do you combine these agents. What’s the best treatment? Should you go completely chemotherapy free, or does chemotherapy still have a role in these patients? Lots of interesting questions. But certainly bispecific antibodies look very active here. Excellent.

Well thank you for joining me Lydia. And I hope that was of interest. And thank you for listening.