Overcoming BTK Resistance in CLL With Noncovalent BTK Inhibitors—Where We Are

Treatment of chronic lymphocytic leukemia (CLL) with irreversible covalent BTK inhibitors ibrutinib and acalabrutinib has led to a dramatic improvement in patient outcomes. However, treatment over time has led to resistance with development of a C481S mutation. This occurs because covalent BTK inhibitors—the 2 above and zanubrutinib—bind BTK at cysteine 481, and when that cysteine changes to a serine, these inhibitors are no longer able to maintain a strong covalent bond to the molecule, leading to resistance, something we are starting to see in some of our patients treated with ibrutinib and acalabrutinib.

To address this, investigators are exploring a group of reversible, noncovalent BTK inhibitors that do not bond to cysteine 481 and consequently retain the ability to inhibit BTK even in the presence of the C481S mutation. One of these inhibitors is LOXO-305, a next-generation, highly selective, noncovalent BTK inhibitor that promotes apoptosis and inhibits BCR signaling in CLL cells both with wild-type BTK and those harboring the BTK C481S mutation.

The dose-escalation phase of the phase I/II BRUIN study of LOXO-305 in B-cell malignancies (N = 28) included 16 patients with CLL, with a median of 4 previous therapies; 75% had discontinued treatment with a previous BTK inhibitor (6 relapse, 3 refractory, 3 discontinued due to other causes). Results reported at ASH 2019 showed that patients treated with LOXO-305 responded at all 6 dose levels, from 25 mg QD to 200 mg QD. In the CLL group, 77% (10/13) of evaluable patients responded, including patients with the C481S mutation; 62% with PR and 15% PR with lymphocytosis, with the remaining 23% with stable disease. LOXO-305 was well tolerated, with fatigue and diarrhea being the most common adverse events at 25% and 18%, respectively. There were only 2 grade 3 treatment-emergent adverse events—1 leukocytosis and 1 neutropenia—with no dose-limiting toxicities, and the maximum tolerated dose was not reached. Recruitment for this study is ongoing.

ARQ 531 is another interesting noncovalent BTK inhibitor; like LOXO-305, it’s reversible and targets both wild-type and C481S-mutated BTK. In a preliminary dose-escalation phase I trial, also reported at ASH 2019, in relapsed/refractory patients with B-cell malignancies and a median of 4 previous therapies (N = 47; 29 with CLL/small lymphocytic lymphoma), 30% of all patients had PRs and 21% had stable disease. What was particularly interesting is that 89% of patients with C481S-mutated CLL treated at the 65-mg dose had PRs, and 50% with very difficult to treat Richter’s transformation did as well.

One of the goals of treating CLL with BTK inhibitors is to maximize the duration of time that a patient can benefit from a BTK-targeted agent, including in the relapsed/refractory setting, whether that is by dose reduction, substitution with a similar BTK inhibitor, or addressing mutation resistance. Promising early trials give reason to look forward to further study of noncovalent, reversible BTK inhibitors as a potential response to ibrutinib and acalabrutinib resistance seen in many of our patients with CLL.

Your Thoughts
How do you address ibrutinib resistance in patients with CLL at your institution? Join the conversation by answering the poll question or leaving a comment. I also invite you to view an on-demand Webcast where I discuss CLL management in more depth with my colleagues, Danielle Brander, MD, and Nicole Lamanna, MD.