The State of the Targeted Therapy Landscape for CLL

Cyrus M. Khan, MD

An array of Bruton’s tyrosine kinase (BTK) inhibitors are available for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). According to Cyrus M. Khan, MD, the current drug pipeline is also abundant with promising prospects.

Regarding prospective agents, there have been continuous reports of positive efficacy in clinical trials of patients with CLL/SLL, but safety has been of concern for some therapies. Khan, a hematologist in the Division of Hematology and Cellular Therapy at West Penn Hospital of Allegheny Health Network, explained that it would be the best interest of investigators to limit the amount of time a patient is on certain drugs, in the future. This tactic may improve outcomes overall.

“We use all these novel agents in the same fashion where we continue them until progression or toxicity. I think, in the future, if some of these drugs come out, probably a more time-limited treatment would be better. We won’t expose the patients to the long-term toxicity of these drugs. Instead, we might expose patients for 6 to 12 months. Then, perhaps we can put them on another drug for some time to slightly reduce the toxicity,” Khan told Targeted OncologyTM, in an interview.

In the interview, Khan reviewed the recent FDA approvals is the CLL space and discussed other FDA decisions that have recently altered the landscape for the better.

TARGETED ONCOLOGY: Can you discuss the approval of zanubrutinib [Brukinsa] for CLL and SLL? What is the potential impact of this approval?

Zanubrutinib is the third BTK inhibitor that was approved recently for CLL and SLL in the frontline setting, and of course, the relapsed setting was there already. We can use it frontline now. It's a welcome addition. It's the second-generation BTK inhibitor, [and] we previously had ibrutinib [Imbruvica] and acalabrutinib [Calquence].

The data for zanubrutinib were positive. It has a slightly different [adverse] effect profile than other BTK inhibitors. It is always good to have some options available to us, in case patients need it. All in all, it is a good addition and it has good data behind it.

What are your key takeaways from the ALPINE [NCT03734016] and SEQUOIA [NCT03336333] studies?

The ALPINE study compares zanubrutinib with ibrutinib in relapsed/refractory CLL patients in the second-line setting. This was a superiority trial and it set off to show that is zanubrutinib is superior to ibrutinib, and it showed that the PFS was better. We don't have data yet about [overall survival] since that takes many years, but it also showed that in some respects, the [adverse] effect profile was keener as well, particularly in cardiovascular areas. There were fewer cases of overall cardiac disease.

The key point is that we have to start a patient on a BTK inhibitor for CLL/SLL, probably using a second-generation BTK inhibitor like zanubrutinib or acalabrutinib because these are the best choices.

Then, SEQUOIA was a frontline study zanubrutinib with bendamustine and rituximab [Rituxan; BR]. It was 6 months of BR vs continuous zanubrutinib, and that also showed at 2 years, BTK inhibition was better. The PFS was almost 85% with zanubrutinib, and it was almost the same for patients with 17p deletion, which is a high-risk disease, [which] certainly beat out frontline chemotherapy.

Last year, there was an important meeting with the Oncologic Drugs Advisory Committee [ODAC] discussing the future of PI3K inhibitors. How did the actions that followed this meeting impact the CLL treatment landscape?

We've had PI3K inhibitors for about as long as we’ve had the BTK inhibitors, which is about 7 years. The first PI3K inhibitor was idelalisib [Zydelig], then copanlisib [Aliqopa], then duvelisib [Copiktra]. Then, more recently, we had umbraslisib [Ukoniq] come out, but the developer withdrew their application, so it's no longer available.

The problem with these drugs has been the [adverse] effect profile. We've had a lot of autoimmune problems come up like pneumonitis, transaminitis, colitis, infectious complications, and other adverse effects. In some of the studies, the overall survival has even been poor on PI3K inhibitors rather than the standard of care. The ODAC sort of went back, reviewed the data, and decided what we should do about this. The decision was that any new PI3K inhibitor that have to be approved must show phase 3 data competitively rather than have an accelerated approval. That means we can no longer have accelerated approvals of PI3K inhibitors.

Companies have to do a longer study that shows an overall survival benefit over the standard of care and that may weed out any potential problems that come up with using PI3K inhibitors. The impact of this decision is that future approvals might be slower. It may not have a big impact in CLL because there is limited use of PI3K inhibitors.

The application for duvelisib in CLL/SLL was also withdrawn after the ODAC’s decision. Can you discuss the phase 3 DUO study [NCT02004522] and why the data were not sufficient to support approval?

The phase 3 DUO study compared duvelisib with ofatumumab [Kesimpta], and, once again, that main reason for the withdrawal were the issues that I described with the toxicity profile. That is why they could not improve overall survival.

We use all these novel agents in the same fashion where we continue them until progression or toxicity. I think, in the future, if some of these drugs come out, a more time-limited treatment would be better. We won’t expose the patients to the long-term toxicity of these drugs. Instead, we might expose patients for 6 to 12 months. Then, perhaps we can put them on another drug for some time to slightly reduce the toxicity.

An oral acalabrutinib formulation was also approved. What is the importance of this new formulation for patients with CLL?

Acalabrutinib was always oral, it was just in capsule form before. The capsule form had issues with absorption, so you couldn't take any proton pump inhibitors, h2 blockers, or antacids with it. Of course, if patients have bad gastroesophageal reflux disease or bad ulcer disease, they couldn't be on the drug.

Now, it's a tablet formulation. It's a different formulation and there's no problems with absorption. Even patients on a proton pump inhibitor, h2 blocker antacids can easily take the drug. That's pretty much the only difference, it just expands on the kind of patients that can take the drug.

There are several novel agents getting the attention of the FDA. Which agents do you think could be important for CLL in the future?

There’s been a lot of activity. One I’m really excited about is pirtobrutinib [Jaypirca]. Patients do progress on the current group of BTK inhibitors because of a certain mutation. The BRUIN study [NCT03740529] of pirtobrutinib for B-cell malignancies also looked at patients with CLL. I'm hoping that drug gets approved for patients who progress on the current crop of BTK inhibitors.

The bispecific T-cell engagers look promising in CLL also, as does [chimeric antigen receptor] T-cell therapy. So, there’s a good pipeline ahead of us.