Expert Highlights Role of BTK Inhibition in Treatment Landscape for CLL

Jennifer Woyach, MD

The current treatment landscape for patients with chronic lymphocytic leukemia (CLL) has a number of available treatment options, both in the frontline setting and beyond. In particular, Bruton’s tyrosine kinase (BTK) inhibitors, like ibrutinib (Imbruvica) and acalabrutinib (Calquence), have been promising therapeutic options.

Acalabrutinib received its approval from the FDA as treatment of patients with CLL in November 2019. The approval of ibrutinib was expanded by the FDA to include the frontline treatment of all adult patients with CLL in April 2020. Clinical trials are now reviewing ways to incorporate venetoclax (Venclexta) into the treatment with BTK inhibitors, but it still remains an unanswered question of in which setting this strategy would work best.

One concern with the BTK inhibitors are the toxicities. However, acalabrutinib appears to have a more favorable toxicity profile compared with ibrutinib, making it a particularly interesting agent in current research for the treatment of patients with CLL.

In an interview with Targeted Oncology, Jennifer Woyach, MD, associate professor, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center–James, discussed the current treatment landscape for patients with CLL and some of the latest research regarding the BTK inhibitors.

TARGETED ONCOLOGY: What do you find the most interesting in the current treatment landscape of CLL?

Woyach: It's always interesting to discuss frontline therapy because there are so many phase 3 studies now that are positive and have investigated different novel agents versus chemo-immunotherapy. Just to hear how people approach the discussion with patients [is interesting] because now that's probably the longest conversation I have with patients in the clinic for somebody who needs new needs treatment for the first time. We go over the benefits and risks of chemo-immunotherapy, BTK inhibitors, BCL2 inhibitors, etc. That’s always an interesting discussion.

The 1 thing I thought was particularly interesting is even though there probably are still groups of patients where fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR) chemo-immunotherapy is still relevant, so those patients who are previously untreated young, fit, have mutated IGHV, and no concerning genomic abnormalities, even in those patients where the textbook answer is still that FCR is very appropriate, most experts are not using chemo-immunotherapy, and most patients are preferring not to receive chemo-immunotherapy in that situation.

TARGETED ONCOLOGY: What are the latest updates in the field of CLL?

Woyach: Things that have come out in recent meetings have in frontline therapy are mostly updates of trials where we had shorter follow up before, such as updates from the CLL14 study of venetoclax (Venclexta) plus obinutuzumab (Gazyva), updates to the acalabrutinib studies, and even updates of ibrutinib studies where the most long-term data exists.

One thing that has come out of recent meetings and has been a question for many patients and practitioners is, does it matter how you sequence those novel therapies? Most of the trial data we have is for patients who are on a BTK inhibitor, come off of it, and move to venetoclax. It's always been a question of whether you could successfully transition a patient from venetoclax to a BTK inhibitor. We still don't have prospective data in that setting, but we have accumulating data from retrospective studies where it looks like that is a very successful strategy, and most patients who are treated with venetoclax really in any line of therapy, but most data's for the relapse setting, and then relapse either on or after venetoclax, almost all of them can successfully be treated with a BTK inhibitor.

TARGETED ONCOLOGY: Could you also speak to small molecule inhibition in this space?

Woyach: Most patients with CLL will be treated through the entire course of their disease. Now with small molecule inhibitors, we have FDA-approved inhibitors of BTK, ibrutinib, and acalabrutinib, as well as another, zanubrutinib which is in large scale clinical trials currently. We have the BCL2 inhibitor venetoclax, which is given with either obinutuzumab or rituximab. Those are primarily the agents that people are using for standard treatment of CLL.

We also have a number of small molecules that are currently in development. There are reversible BTK inhibitors, which are designed to inhibit BTK even when the irreversible inhibitors, which is ibrutinib, acalabrutinib, and zanubrutinib, even if those stop working this class of reversible BTK inhibitors have a lot of preliminary efficacy so far in that setting, which is very nice. There are also a lot of new antibodies and a lot of new small molecule targets that are in development too.

TARGETED ONCOLOGY: What was the rationale for evaluating acalabrutinib in this patient population?

Woyach: Acalabrutinib is an inhibitor of BTK, and it's a second-generation covalent inhibitor so like ibrutinib, it binds irreversibly to BTK. It's actually a much more selective inhibitor than ibrutinib is, so while ibrutinib does also inhibit a lot of structurally similar proteins, acalabrutinib inhibits less of those, and that's important primarily for toxicity. We think that some of the toxicity we see with ibrutinib is because of those alternative targets. some of those toxicities may be lessened by treatment with acalabrutinib. In the treatment-naïve setting, as well as relapsed and refractory disease, the data has looked very promising with this agent. In 1 particular study, which was 53 months of follow-up for 99 patients with treatment-naïve CLL. At that time, about 86% of the patients were still on treatment, which is very impressive. The event-free survival at 48 months, so 4-year event-free survival, was 90%. This is certainly looking very promising with this agent, which is similar to what we've seen with ibrutinib in this patient population. You can't really compare trial to trial, but it's very comforting to see that it looks fairly similar to where ibrutinib was looking in that situation.

TARGETED ONCOLOGY: What does the safety profile of the agent look like?

Woyach: The safety profile acalabrutinib looks very promising. The rates of some of the toxicities that we associate with BTK inhibitors, such as atrial fibrillation, are seen relatively infrequently with acalabrutinib, although it is seen probably a little bit more than the general population. Hypertension seems to be a little bit less, although with the caveat that it has taken a lot of clinical trials, a lot of patience, and a lot of time to identify hypertension as toxicity with ibrutinib, but it does look like it may be less with acalabrutinib. Some of the milder toxicities, like arthralgias and bruising, appear a little bit less significantly; bleeding is also very rare, really with both agents, but it doesn't look like it's more with acalabrutinib than we see with ibrutinib.

TARGETED ONCOLOGY: Are there any current ongoing studies in CLL that you wanted to discuss or highlight?

Woyach: I would love to take a moment to highlight the cooperative group studies that are going on right now. These are the NCTN trials that are designed for frontline CLL and similar to the previous ones, which are the E1912 study for younger patients and AO41202 for older patients. These new studies, EA9161 and AO41702, are designed to look at frontline treatment in younger and older patients with CLL. Both studies are comparing ibrutinib plus obinutuzumab to ibrutinib plus obinutuzumab plus venetoclax to see whether the strategy of adding venetoclax to an ibrutinib-based regimen improves progression-free survival. The studies are a little bit different in how they then discontinue therapy in that triplet group, so this is looking at a triplet versus a doublet in CLL. It will also be very helpful to see if those benefits we might see for a triple versus a doublet extend to both the older and the younger patient population.

TARGETED ONCOLOGY: What is your take home message?

Woyach: I would just say that CLL is advancing very rapidly. We have a lot of drugs that are very effective, and I think the most important thing is that we shouldn't become complacent with the success that we've had so far. We should continue to work to develop new trials to put patients on track and to continue to optimize therapy for patients with CLL.