Mazyar Shadman, MD, MPH, discusses the evolution of BTK inhibitors in CLL, highlights how treatment patterns have evolved with the continued emergence of data on ibrutinib, acalabrutinib, and zanubrutinib, and expands on how pirtobrutinib and liso-cel could address unmet needs for this patient population.
Although the covalent BTK inhibitors ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa), as well as the BCL-2 inhibitor venetoclax (Venclexta), represent staples in the treatment of patients with chronic lymphocytic leukemia (CLL), the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) and the CAR T-cell therapy lisocabtagene maraleucel (liso-cel; Breyanzi) represent therapies that could expand treatment options for patients in the relapsed/refractory setting, according to Mazyar Shadman, MD, MPH.
“Despite all the advancements, we are not curing patients, and that's an unmet need. We are, unfortunately, still dealing with patients who have tried the two main classes of drugs we [currently] have: covalent BTK inhibitors and BCL-2 inhibitors. We do need new drugs, and we will continue to work to make the outcomes better,” Shadman said. Shadman is an associate professor in the Medical Oncology Division at the University of Washington School of Medicine in Seattle.
In an interview with OncLive®, Shadman discussed the evolution of BTK inhibitors in CLL, highlighted how treatment patterns have evolved with the continued emergence of data on ibrutinib, acalabrutinib, and zanubrutinib, and expanded on how pirtobrutinib and liso-cel could address unmet needs for this patient population. Shadman also serves as an associate professor in the Clinical Research Division and an attending physician of Hematologic Malignancies at Fred Hutchinson Cancer Center.
Shadman: Ibrutinib changed the treatment landscape for CLL. In several head-to-head trials, it showed that it was not only superior to chemoimmunotherapy in terms of progression-free survival [PFS], but we also have data from the [phase 3] E1912 trial [NCT02048813] showing that ibrutinib [plus rituximab (Rituxan)] was superior to fludarabine, cyclophosphamide, and rituximab [FCR] from an overall survival standpoint. Ibrutinib not only changed the treatment landscape for patients with high-risk CLL, including those with p53 aberrations, but over time, it also showed that in patients with standard-risk CLL, it should be one of the treatments of choice.
Ibrutinib started being used widely. However, being a first generation BTK inhibitor, tolerance has been an issue for some patients in terms of developing adverse effects [AEs] while still responding to treatment. It should be noted that many patients can still remain on ibrutinib after dose adjustments are done, and we try to utilize those changes per label as much as possible to keep patients on ibrutinib. However, there are patients who don't tolerate even the reduced doses or dose interruptions. There are some AEs that you wouldn’t want to take a chance on by keeping a patient on the drug.
Over time, we started heving access to second-generation covalent BTK inhibitors: acalabrutinib and zanubrutinib. These were later introduced to our treatment landscape, first in the form of clinical trials. Acalabrutinib received [FDA] approval for the first-line and relapse setting.1 Later on, [the FDA approved] zanubrutinib. We now have these 2 drugs that are next-generation, covalent BTK inhibitors. Both drugs come with a much better safety profile [compared with ibrutinib], and there were prospective studies with both drugs showing that in patients who don't tolerate ibrutinib, you can use acalabrutinib or zanubrutinib. These patients still benefit from this important class of drugs.
[Prospective trials have shown that] the next-generation BTK inhibitors [displayed] safety profiles that were in favor of both acalabrutinib and zanubrutinib vs ibrutinib. Looking at the phase 3 ALPINE study [NCT03734016], which looked at zanubrutinib vs ibrutinib, there was also a superiority of PFS in [all-comer] patients who were enrolled in that study, and also in patients with 17p deletions.
In the phase 3 ELEVATE-RR study [NCT02477696], the primary end point [of PFS] was [examined for] non-inferiority and that was reached, meaning that acalabrutinib was not inferior to ibrutinib; however, in that study, we have not seen a PFS advantage with acalabrutinib. Now, we have two second-generation covalent BTK inhibitors that should be preferred over ibrutinib, mainly for the safety profile, and in the case of zanubrutinib, for the efficacy advantage.
While it is not currently approved for CLL, pirtobrutinib is the first noncovalent BTK inhibitor that has shown [a potential] benefit patients who have been previously exposed and treated with covalent BTK inhibitors. It has shown promising efficacy for that patient population. The drug is currently approved for [the treatment of select patients with] mantle cell lymphoma [MCL]. However, in selected patients, you could use it for CLL as an off-label use.
We have gone from having 1 BTK inhibitor to now having three approved and one approved for a different indication [in MCL] that is potentially an option for patients with CLL. [BTK] is an important pathway for CLL. Overall, it's good to have several options to attack that pathway and benefit our patients.
Zanubrutinib was designed to be selective to BTK, meaning that some of the off-target effects that we used to see with ibrutinib are not seen with zanubrutinib. That translates into being a better-tolerated drug. There is a hypothesis that the drug also has, in terms of the exposure coverage and the drug levels, some efficacy advantage.
In terms of studies that led to the approval of zanubrutinib for CLL in the first-line setting, the phase 3 SEQUOIA trial [NCT03336333] evaluated patients who were not suitable for FCR because of age or comorbidities. Patients who did not have 17p deletions were randomly assigned to receive either zanubrutinib as monotherapy until progression or intolerance, or bendamustine plus rituximab in the standard arm. This study showed advantage in terms of PFS for zanubrutinib in the primary analysis.
Updated that data have shown that zanubrutinib is superior, not only in patients with IGHV-unmutated disease, but we had also shown that in the primary analysis and now with the extended follow-up the superiority of zanubrutinib even in patients with IGHV mutations.
These were patients who historically benefit from chemotherapy, and showing that zanubrutinib is even better than chemotherapy in that patient population was an important finding. The study also included patients with 17p deletions, and they were all treated on zanubrutinib monotherapy. This is the largest prospective study in patients with first-line CLL harboring 17p deletions, and data continue to show [beneficial] PFS.
In the first-line setting, zanubrutinib has shown very promising efficacy. In the relapse setting, ALPINE was a head-to-head trial comparing zanubrutinib vs ibrutinib in patients—regardless of cytogenetic markers—who were previously treated. The study had a primary end point of non-inferiority of overall response rate. PFS superiority was also observed. A predefined analysis showed that patients with 17p deletions had a significant [benefit] with zanubrutinib.
Other studies showed that zanubrutinib was well tolerated and remained effective in patients who didn't tolerate ibrutinib or acalabrutinib. Overall, these studies not only led to the approval of zanubrutinib, but also show that this is a reliable drug for patients with CLL and one of the important options preferred for patients with CLL today.
Historically, the 2 main classes of drugs that we had were covalent BTK inhibitors and the BCL-2 inhibitor venetoclax. When we have patients who had progression on a covalent BTK inhibitor, the natural next option would have been a venetoclax-based therapy with or without the CD20 antibody. The study that led to the approval of venetoclax in the relapse setting was the phase 3 MURANO trial [NCT02005471]. However, it did not include many patients who were previously exposed to or progressed on covenant BTK inhibitors. We do have some studies that [evaluated] venetoclax in patients who received a prior BTK inhibitor. Whether the patients should have had a time-limited therapy [with venetoclax] in that setting is something that varies in clinical practice, and most of us would probably continue venetoclax indefinitely.
We have PI3K inhibitors as another option. These drugs have not been studied in the post–BTK inhibitor setting, and the safety profile with PI3K inhibitors is not great enough to use them as long-term therapy.
The new [drug] that is not approved for patients with CLL, but could be used in selected patients, is pirtobrutinib, a noncovalent BTK inhibitor. In the phase 1/2 BRUIN study [NCT03740529], we saw that a majority of patients were exposed to a prior covalent BTK inhibitor and had either intolerance or progressed on those drugs. However, these patients benefited from pirtobrutinib. The drug is currently only approved for MCL, but we are hoping that if it passes the regulatory steps, it will become available for patients with CLL. It is now part of the National Comprehensive Cancer Network guidelines for use in select patients.
[If pirtobrutinib is] approved, the question of a noncovalent BTK inhibitor vs venetoclax [will need to be addressed]. We would need longer follow-up data with both drugs; we need published literature looking at venetoclax in patients after progression on a covalent BTK inhibitor. This will be a topic of discussion, looking at the logistics and whether a patient could be switched to a different class of drugs. At the moment, these are the 2 options that will be discussed if pirtobrutinib is approved for patients with CLL.
[Data for] the CD19-directed autologous CAR T-cell therapy liso-cel [from the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198)] have been published; we still don't have it approved by the FDA or other regulatory bodies. If liso-cel becomes available, that would be another very important option for our patients. We will need to discuss the right sequence of therapy, such as whether pirtobrutinib should be used as a bridging therapy to CAR T-cell therapy or in sequence.
Next-generation BCL-2 inhibitors are in development in clinical trials. Some are showing high efficacy in terms of the pharmacology. Compared to venetoclax, some of them have higher potency, so we're hoping that translates to better clinical outcomes.
Staying in the BTK pathway, we have a number of BTK degraders that are in development, and maybe that will be another class initially for patients in the relapse setting after covalent BTK inhibitors. Depending on safety and efficacy, we may see those drugs moving up to earlier lines of therapy. We have studies looking at bispecific antibodies in CLL, either as monotherapy or in combination with other drugs. The list goes on.
CLL remains an active area of research. We need a time-limited, safe, and effective treatment for patients at the time of diagnosis for a short period of time so we then can stop and tell them that they’re cured; that is the goal. In the meantime, we need effective treatments that can control patients’ disease.
We have many effective treatments for the first-line setting. Combination studies are going to be the future of CLL, and I would highly encourage my colleagues to consider clinical trials. When we have effective and safe drugs available, there is this tendency of straying from clinical trial participation. However, the treatments are becoming more effective and better tolerated. There are several interesting and practical combinations that are being studied in the frontline setting.
The sequence is important. For patients, especially with high-risk disease, we need to ensure that we use the right sequence, we need to be updated on the ongoing and updated outcomes from major clinical trials. Every meeting we learn something new, such as the variables that could predict response to time-limited venetoclax-based therapy. A lot of these treatments could then be delivered in the community or with the primary oncologist or hematologist of the patient. It's nice to have a have a long-term plan, and we need to ensure we take advantage of all these new drugs that are becoming available in clinical trials to help potentially move them to clinical practice.