ERIC CLL 2026 | CaDAnCe-101 trial: exploring the potential of tacabrutideg, a novel BTK degrader, in R/R CLL/SLL

CaDAnCe-101 trial is a Phase I trial evaluating tacabrutideg, or formerly known as BGB-16673, a totally novel agent, a BTK degrader in patients with relapsed refractory B-cell malignancies. Now this treatment principle of these degraders is totally different as compared to the classical BTK inhibitors because with these drugs you target the protein and direct it specifically through degradation by ubiquitination and the proteasomal pathway. The metaphor that somebody has coined is that with BTK inhibitor, you lock the tiger in a cage to prevent them from doing any harm. But from that cage, they can escape because they are still alive. And with a BTK degrader, you shoot the tiger and a dead tiger cannot do any harm anymore. So it’s truly a different thing to become more scientific again. You can say a BTK inhibitor is just inhibiting the function, the BTK kinase function, but not the scaffolding function. And there is resistance based on various mutations to BTK inhibitors. Now with this degradation principle, we also take away the scaffolding function that works independently of the kinase function of BTK. And it has been shown that BTK degraders are active also against a range of BTK resistance mutations. So mutations that make the disease resistant towards classical BTK inhibitors. So great potential. What was reported now is the segment of 67 patients with CLL, heavy prior therapy, who have been treated on that trial with BTK, a degrader tacabrutideg monotherapy to evaluate the safety firstly of this agent, but also to detect preliminary signals for efficacy. Now, CaDAnCe-101, the phase one single arm monotherapy trial, has shown that in a population with heavy prior therapy median number of prior lines was four and characterized by very high risk disease biology very high rate of unmutated IGHV high rate of 17p deletion and also a high rate of BTK resistance mutations in this population tacabrutideg a high response rate, 85 to 90 percent in the overall population and produced very good durability of these responses and very good progression-free survival with a median around two years and also very good overall survival with about an 80 percent overall survival rate at two years. So very, very good tolerability also coming with this. So a very promising new agent. Now obviously a role for this agent once licensed could come in a very late stage refractory population who have failed all available prior therapies, prior licensed therapies. But to move this agent more into earlier lines of treatment, obviously, randomized comparisons against standard of care are available. Trials are underway, evaluating tacabrutideg head-to-head against pirtobrutinib, so the non-covalent BTK inhibitor, to move it into an earlier treatment scenario. One could foresee also trials in even earlier lines of treatment, for instance, also when combined with other novel agents such as BCL2 inhibitors, potentially experimental BCL2 inhibitors such as sonrotoclax, where we could foresee very, very efficacious and very well tolerated, also finite duration treatment principles. So as the first important adjunct to our treatment armamentarium, it would be great if tacabrutideg be licensed in these late stage patients who have failed established treatment options, because for them, we know from clinical trial data, this agent offers a great, you know, avenue of new hope. As a monotherapy, I think we know that it can be very efficacious, but I think its true future lies in combinations, possibly with BCL2 inhibitors such as sonrotoclax, a very good second generation BCL2 inhibitor and a combination of a BTK degrader plus a BCL2 inhibitor could offer also obviously the option of finite duration treatment based on the deep responses that we presume to see in such a combination. On the other hand, this is obviously at the moment hypothesis and we need clinical trial data proving the benefit of such combination treatments to make this agent available in earlier lines of treatment and also in a finite duration treatment paradigm.

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