ASH 2024 | Strategies to overcome resistance to BTKis in R/R MCL

In terms of BTK inhibitor resistance, that’s a challenge for relapsed mantle cell lymphoma, as we just mentioned. So the good thing is if a patient progresses through a BTK inhibitor, now the standard care, we have CAR T-cell therapy, which is pretty effective in a lot of the patients, and we have exciting trials right now exploring other strategies in treating post-BTK relapses in mantle cell lymphoma, for example, the BTK degrader, which can be used after covalent BTK inhibitor failure or even after non-covalent BTK inhibitor failure. The idea is, when patient disease relapses on a BTK inhibitor, the kinase activity may no longer be very important sustaining the disease growth, but the BTK protein may still be important as a scaffold protein to recruit other proteins to activate alternative signals. So in this setting, if you use a degrader to destroy the BTK protein, you kind of abolish your other alternative signaling pathway that depends on BTK protein as well. So that’s one great strategy. Other strategies in post-BTK failure, like we mentioned before, bispecific antibody therapy, there are other targets that are being explored like ROR1 protein. Some other strategies for CAR-T, like BAFFR targeting and the CD22 targeting or dual CARs. So those are the strategies, many, many things either already available or in trials as a single agent. But building upon BTK, we do have a combination strategies that we can explore maybe upfront to combine with BTK inhibitor to reduce their resistance prolong the duration of remission, for example, I can use BTK and a venetoclax or other BCL2 inhibitor combination, as shown in the ZUMA trial, where the PFS is better than single agent ibrutinib. Or we can explore other combinations like in combination with lenalidomide-based therapy. Like we see with acalabrutinib-R-squared or ibrutinib-R-squared. And also, other exciting agents can be combined in the setting as well, like Bruton’s tyrosine kinase inhibitor in combination with bispecific antibodies. There are even trials combining BTK inhibitors with CAR-Ts. I think those are all exciting combination strategies to reduce the development of resistance and also prolong the duration of remission with BTK inhibitors.

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