ASH 2024 | The potential of combining BTKis with immunotherapies to treat R/R MCL

So, BTK inhibitors are a highly effective treatment option for mantle cell lymphoma. In the past, we’ve typically used these as monotherapy in relapsed/refractory settings. And they are, most patients respond to these agents, but it tends to be in a time-limited fashion. So combination therapies with BTK inhibitors are a highly promising way of trying to get more out of these agents. Furthermore, there’s a global push towards the earlier utilization of BTK inhibitors in the frontline setting. And we’ve seen a number of studies published showing high rates of efficacy and improvements in progression-free survival when we incorporate BTK inhibitors earlier in the treatment paradigm. So I think the landscape of BTK inhibitor use in mantle cell lymphoma is constantly evolving. We tested a combination of BTK inhibitors and CAR T-cells in relapsed/refractory mantle cell lymphoma and we presented the results of this at ASH 2022 in the TARMAC study, which was a small investigator-initiated study that used ibrutinib together with tisa-cel CAR T-cells in relapsed/refractory mantle cell lymphoma. And we found very high rates of efficacy using that combination and great durability of responses. And we hope to present some long-term follow-up in the coming years. But this really showed to us that incorporating BTK inhibitors with active immunotherapies may be a paradigm that’s worthwhile continuing to pursue. I think it’s also important to recognize that with the earlier use of BTK inhibitors, particularly in the frontline, and we saw further results of the TRIANGLE study, again showing that the addition of BTK inhibitors in the first treatment line can improve outcomes and potentially mitigate the requirement for autologous stem cell transplant, that the future of mantle cell lymphoma may mean that many patients have already been exposed to a BTK inhibitor when they come to their first or subsequent relapse. So we need to have strategies to address this patient population because we know that patients whose mantle cell lymphoma has become resistant to a BTK inhibitor can often be hard to treat. We’ve taken the lessons from the TARMAC study, as well as this evolving landscape, to develop an ongoing study run by the Australian Lymphoma and Leukemia Group called Goldilocks, where we incorporate the non-covalent BTK inhibitor pirtobrutinib with the bispecific antibody glofitamab. And we think that in the future, potentially the lessons that we’ve learned from the past can inform our future study designs to really address this patient population at need and try to get the most out of BTK inhibition with novel cellular and other immunotherapies.

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