Bruton Tyrosine Kinase Inhibitors Signal Promise in the Treatment of Chronic Lymphocytic Leukemia

Recently reported data on Bruton tyrosine kinase (BTK) inhibitors for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) may herald a shift in the standard of care, reducing the need for chemoimmunotherapy in certain patient sets and promoting the most efficacious treatments to earlier lines of therapy.

The use of agents targeting BTK have moved into the standard of care for the treatment of CLL/SLL in recent years. New data have indicated that more effective therapy by way of combination regimens and newly approved agents may further improve the prognosis of this disease.

In a relatively short time, BTK inhibitors for CLL have shown drastic improvements in patient response to therapy. "It's amazing to see how quickly the field has developed," Michael Choi, MD, associate clinical professor of medicine at the University of California, San Diego, said in an interview with Targeted Therapies in Oncology (TTO). "A year ago, we had data showing BTK inhibitor therapy, ibrutinib [Imbruvica], was superior to chemoimmunotherapy. Now, we're already improving on that with combination therapies. It's exciting and promising for our patients. We're close to the point where patients with CLL will have full lives [in which they are] not necessarily on continuous therapy."

BTK is a crucial component of B-cell receptor signaling and is overexpressed in CLL, making its inhibition an attractive therapeutic target.¹ Ibrutinib was the first BTK inhibitor to receive FDA approval in 2013 for mantle cell lymphoma, with an expanded indication for patients with CLL who received at least 1 prior therapy granted in 2014.² Since then, next-generation BTK inhibitors have been developed for the treatment of hematologic malignancies, including zanubrutinib (Brukinsa) and acalabrutinib (Calquence; TABLE). To date, the only FDA-indicated use for zanubrutinib is in patients with mantle cell lymphoma.³

Acalabrutinib Moves to Frontline

In November 2019, acalabrutinib received FDA approval for use in patients with CLL or SLL based on results of the ELEVATE-CLL TN and ASCEND trials.⁴

ELEVATE-CLL TN was an open-label phase III trial in 535 treatment-naive patients with CLL that evaluated acalabrutinib as a single agent, acalabrutinib in combination with the CD20 inhibitor obinutuzumab (Gazyva), or obinutuzumab plus chlorambucil. Prior to the approval of ibrutinib, obinutuzumab plus chlorambucil was considered the standard of care for CLL. Baseline characteristics were similar across all 3 treatment arms.⁵

Median progression-free survival (PFS) was superior for acalabrutinib plus obinutuzumab (HR, 0.10; 95% CI, 0.06-0.17; P<.0001) and acalabrutinib alone (HR, 0.20; 95% CI, 0.13- 0.31; P<.0001) compared with chlorambucil plus obinutuzumab. Adverse events (AEs) led to discontinuation in 11.2%, 8.9%, and 14.1% of patients receiving acalabrutinib plus obinutuzumab, acalabrutinib monotherapy, and obinutuzumab plus chlorambucil, respectively.⁵

ASCEND was a randomized, multicenter, open-label phase III trial investigating the efficacy and safety of single-agent acalabrutinib versus idelalisib (Zydelig) plus the CD20 inhibitor rituximab (Rituxan; IdR) or bendamustine plus rituximab (BR) in 310 patients with relapsed/ refractory (R/R) CLL. At a median follow-up of 16.1 months, median PFS was not reached in the acalabrutinib monotherapy group compared with 16.5 months for the combined IdR/BR group (HR, 0.31; 95% CI, 0.20-0.49;P<.0001).⁶

Data presented at the 2019 American Society of Hematology Annual Meeting & Exposition (ASH) demonstrated that acalabrutinib continued to show long-term efficacy and a tolerable safety profile at 42 months in the phase I/II ACE-CL-001 trial.⁷

"Acalabrutinib in relapsed or refractory disease in 134 patients [demonstrated promising results with about 4 years of follow-up], with a 45-month PFS of 62%, showing similar results to ibrutinib." Jennifer A. Woyach, MD, associate professor in the Division of Hematology at The Ohio State University Comprehensive Cancer Center in Columbus, said in an interview with TTO. Efficacy end points assessed in the ACE-CL-001 study included median duration of response, event-free survival, and PFS; these had not yet been reached at the time of assessment.^{7 "}The data we have for acalabrutinib in a fairly similar patient population to that of ibrutinib-treated patients show durable responses," said Woymach.

Commonly reported AEs with acalabrutinib included headache, neutropenia, diarrhea, anemia, and upper respiratory tract infection.^{5-7 "}Compared with data [that have] been shown with ibrutinib, [there have been] less hypertension and atrial fibrillation with acalabrutinib, with a caveat [of fewer] patients treated with acalabrutinib and shorter follow-up. Some of those [data] might get closer together with longer follow-up," said Woyach.

Investigators also evaluated acalabrutinib as part of a triplet regimen in combination with the BCL2 inhibitor venetoclax (Venclexta) plus obinutuzumab. In an open-label, single-arm, phase II trial, they treated patients with CLL by sequentially starting the 3 agents: After a lead-in cycle with acalabrutinib, they added obinutuzumab to the regimen, followed by venetoclax ramp-up. Patients discontinued obinutuzumab after 6 months but continued on acalabrutinib plus venetoclax. After cycles 15 and 24, patients could discontinue therapy if they achieved complete response (CR) with bone marrow undetectable minimal residual disease (MRD); the rest remained on acalabrutinib plus venetoclax.⁸

At cycle 8 restaging, among patients withTP53-aberrant disease, investigators found undetectable MRD in the peripheral blood of 78% of patients and in the bone marrow of 33%. With a median follow-up of 11 cycles, the overall response rate (ORR) was 100% after cycles 8 and 16. Furthermore, 12.5% of patients had achieved a CR with undetectable MRD in the bone marrow after cycle 16.⁸

Common AEs included fatigue (81%), headache (76%), neutropenia (68%), and bruising (43%). At baseline, 97% of patients were at medium to high risk for tumor lysis syndrome (TLS), which was reduced to 9% at the start of venetoclax therapy. Having unfavorable disease characteristics, such as unmutated IGHV or TP53-aberrant disease, did not diminish the efficacy of acalabrutinib in combination with obinutuzumab and venetoclax.⁸

BTK combination therapy is still under investigation, with the goal of further extending patient survival outcomes. "Combination [therapy data in studies presented thus far] appear tolerable. What we don't know yet is PFS with this limited duration of therapy [with] BTK inhibitor plus BCL2 inhibitor with or without an antibody, or whether the time off treatment is enough to justify the up-front toxicity and cost," said Woyach.

Working Zanubrutinib Into Care

Zanubrutinib demonstrated high response rates in patients with CLL/SLL, regardless of deletion of chromosome 17p13.1 (del[17p]) status, in both the SEQUOIA and AU-003 trials.

SEQUOIA is an ongoing open-label, multi-center, phase III trial that includes a nonrandomized cohort of 109 patients with del(17p) CLL/SLL who have not received prior treatments (arm C). In preliminary data for arm C, the ORR was 92.7% (95% CI, 86.0%-96.8%). This high response rate was particularly impressive given the unfavorable prognosis associated with del(17p). With a median follow-up of 10.0 months, the majority of patients (78.9%) achieved a partial response (PR), and 2 (1.9%) achieved CR. Additionally, the vast majority (95%) of patients across all subgroups had a duration of response lasting at least 6 months. The most common grade >3 AEs included neutropenia (10.1%), pneumonia (3.7%), and hypertension (2.8%).⁹

AU-003 was an open-label, multicenter, phase I/II trial in patients with various B-cell malignancies with indication-specific expansion cohorts. Patients with CLL/SLL (n = 123) demonstrated efficacy results similar to those in the SEQUOIA trial, with an ORR of 96% at a median follow-up of 29.5 months. The study included patients with both treatment-naive and R/R CLL/SLL. In treatment-naive patients, the PFS rate was 95% at 1 year and 97% at 2 years, indicating potential durable responses; these rates compared with 97% and 91%, respectively, in the R/R group. Common AEs included contusion, upper respiratory tract infection, diarrhea, cough, headache, and fatigue.¹⁰

Updated Data for Ibrutinib

Investigators recently presented an integrated analysis of the RESONATE and RESONATE-2 trials at 2019 ASH, with 271 patients stratified by number of prior therapies.¹¹

"RESONATE and RESONATE-2 were both phase III studies of ibrutinib [that] led to the FDA approval of the agent in CLL. RESONATE compared ibrutinib alone with ofatumumab [Arzerra; a CD20 inhibitor] in relapsed or refractory CLL. RESONATE-2 was a frontline study [that] included patients aged 65 and older, randomized to either chlorambucil or ibrutinib," said Woyach.

With long-term follow-up of 5 and 6 years for RESONATE-2 and RESONATE, respectively, the risk of disease progression or death was reduced by 68% with first-line treatment compared with treatment after >3 prior lines (HR, 0.32; 95% CI, 0.21-0.49). The CR rate was 30% in the first-line treatment group compared with 12% and 10% for 1 to 2 and >3 prior lines of therapy, respectively.¹¹

"[Results continue to demonstrate] superiority of ibrutinib over previous standard-of-care regimens and that patients can do well for many years on ibrutinib," said Woyach.

Treatment discontinuation because of AEs occurred in 19% of all patients randomized to ibrutinib.^{11 "}Besides hypertension, a cumulative toxicity, and atrial fibrillation, which can occur at any time, no other toxicities have come out as cumulative and concerning for long-term administration [of ibrutinib]," said Woyach.

In Combinations

Investigators also explore ibrutinib as part of a combination regimen in the phase III E1912 trial, which randomized 529 treatment-naive patients >70 years in a 2:1 ratio to receive ibrutinib plus rituximab (IR) or chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR). Patients with del(17p) were excluded because this group is known to have a poor response to FCR. The median follow-up was 33.6 months, with significantly longer median PFS and overall survival (OS) in the IR group compared with the FCR group.¹²

Updated results presented at 2019 ASH showed that, with a median follow-up of 48 months, IR demonstrated a consistent benefit over FCR in terms of both PFS (HR, 0.39; 95% CI, 0.26-0.57; P<.0001) and OS (HR, 0.34; 95% CI, 0.15-0.79; P= .009).¹³ Grade >3 treatment-related AEs occurred in 70% of patients receiving IR versus 80% for those receiving FCR (OR, 0.56; 95% CI, 0.34-0.90; P= .013).¹³

Another noteworthy BTK combination trial, CAPTIVATE, is exploring the frontline combination of ibrutinib and venetoclax. "I think [there have] been a couple of well-done trials with BTK inhibitors and BCL2 inhibitors, the CAPTIVATE trial being one," said Choi.

In the multicenter phase II study, 164 treatment-naive patients >70 years received single-agent ibrutinib in a 3-cycle lead-in phase, followed by ibrutinib plus venetoclax for 12 cycles. The median age was 58 years, and 16% of patients had del(17p). At the end of 12 cycles of ibrutinib plus venetoclax, 74% of patients had achieved undetectable MRD in peripheral blood and 68% in bone marrow, with similarly high rates in high-risk patient subgroups. Response, as measured by the International Workshop on CLL (iwCLL) criteria, was achieved in 97% of patients, with a median follow-up of 14.7 months.¹⁴

&ldquo;[Ibrutinib therapy] does appear to be a way that most patients can get good remission and do so with a convenient all-oral regimen,&rdquo; said Choi.

High risk for TLS was reduced from 24% at baseline to 2% after the ibrutinib lead-in period. Common AEs during the ibrutinib lead-in period included diarrhea and arthralgia, with the combination therapy resulting in AEs such as diarrhea, neutropenia, nausea, upper respiratory tract infection, and fatigue. Dose reductions and treatment discontinuation attributed to AEs occurred at rates of 20% and 7%, respectively. Combination therapy with ibrutinib and venetoclax in the frontline setting for CLL/SLL proved to have high rates of response, as measured by undetectable MRD in both the peripheral blood and bone marrow, with AEs consistent with those reported for both single agents.¹⁴

"I am anxious and curious to see long-term outcomes for how long patients remain in remission. The CAPTIVATE study has this additional portion, which will randomize patients after achieving a remission [to continue] ibrutinib or [discontinue] therapy altogether. We&rsquo;ll [learn more] about that approach [as the CAPTIVATE study results are presented] and what to do when patients are already in remission," commented Choi.

Data for BTK inhibitors as doublet and triplet therapy are not yet fully mature, although preliminary results appear promising. "We're still learning how to do this optimally. It does appear that the 2-drug and 3-drug combinations are safe, although there is a slight increase in neutropenia and [risk of] TLS with [the addition of] BC12 inhibitors or CD20 inhibitors," said Choi.

With Investigational Agents

Not only have BTK inhibitors been used in combination with current standards of care, but ibrutinib has also been investigated in combination with cirmtuzumab, an ROR1 inhibitor, in patients with treatment-na&iuml;ve or R/R CLL/ SLL.¹⁵

"The background and rationale for [ibrutinib in combination with cirmtuzumab] is along the same line as [that of] other combination therapies. We know that ibrutinib is an active and effective drug that is largely well tolerated. We added another agent [with the goal of maintaining the same] safety profile. Cirmtuzumab is a monoclonal antibody that inhibits ROR1, which we think is a specific target expressed on CLL cells...and [cirmtuzumab] does not bind to adult tissue. We think inhibiting ROR1 inhibits another signaling pathway that contributes to CLL cell survival and proliferation that is not inhibited by ibrutinib or other small-molecule inhibitors," explained Choi.

Choi and colleagues designed a 3-part phase Ib/II trial.^{15 "}We completed a dose-finding and a dose-expansion portion of the study. Now we are recruiting for the randomized phase II portion of the study, where patients receive cirmtuzumab and ibrutinib or ibrutinib alone. I think this will be the true test of the value of the combination [to see whether there is an improvement] in CR rates or survival," commented Choi.

In the first 2 parts of the study, the median age was 68 years for 34 patients with CLL/SLL. The ORR was 85.3%, with the majority of patients having a PR (82%).^{15 "}We found a high response rate, [even at an early point with a short median follow-up period, and] we had 1 patient who met iwCLL criteria for complete response," said Choi.

Choi also noted "We did not change the safety profile of ibrutinib and have not seen new adverse effects [not previously observed with ibrutinib]. True to the hypothesis, cirmtuzumab is a specific and safe drug; there weren't new safety signals or complications." Cirmtuzumab- or cirmtuzumab-plus-ibrutinib related AEs for CLL/SLL were primarily transient and grade 1 or 2 in severity. The most commonly reported grade 1 or 2 AEs related to the combination therapy included fatigue (17.6%), diarrhea (5.9%), and contusion (5.9%).¹⁵

Choosing for Patients

Reflecting on different BTK inhibitors, Choi commented, "The efficacy data for [acalabrutinib, zanubrutinib, and ibrutinib] for CLL are similar. The majority of patients have partial responses, and patients should generally be continued on therapy to maintain those remissions."

Regarding patient adherence to therapy, Woyach said that "ibrutinib does have the advantage that it's given [only] once a day."

Choi expanded on the different toxicity profiles of each of the therapies reviewed. "There may be less cardiovascular risk with acalabrutinib [and zanubrutinib in their respective CLL trials]. It&rsquo;s still early for those patients treated on trial [with the initial follow-up time], so I think we should remain vigilant as clinicians and investigators to monitor patients for those potential adverse effects of BTK inhibitors. At least right now, it gives us options for patients who perhaps have recent cardiovascular problems to try acalabrutinib."

Looking to the future, both Choi and Woyach also expressed optimism about noncovalent BTK inhibitors currently in early-phase trials. "I think this is an exciting time in CLL therapeutics. There are so many good standard-of-care options available and a lot of clinical trials looking to take the next step forward. It remains important that we focus on doing studies in this group of patients and not rest on successes we&rsquo;ve had so far," Woyach concluded.

References

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