Bruton Tyrosine Kinase Inhibitors in B-Cell Lymphomas

Bruton tyrosine kinase (BTK) inhibitors play an important role in the therapeutic spectrum of B-cell lymphomas. As agents such as ibrutinib have arguably reshaped the spectrum of chronic lymphocytic leukemia (CLL) in particular, emerging data suggest that second-generation BTK inhibitors offer benefits to patients with various other B-cell lymphomas.¹

Recently, a select group of oncologists who specialize in the treatment of hematologic malignancies participated in a series of virtual workshops to discuss the treatment landscape and management of patients with B-cell lymphomas. Stakeholders discussed key efficacy and safety data pertaining to the use of BTK inhibitors, reviewing both current and emerging therapies. This article summarizes key points from the data as well as from the stakeholder discussion.

Review of Recent Data for BTK Inhibitors

Ibrutinib

Ibrutinib is a first-generation BTK inhibitor that covalently binds to Cys481 in the active site of the ATP-binding domain of BTK.^2,3 Taken once daily, it currently has indications in patients with CLL/small lymphocytic leukemia (SLL), CLL/SLL with a 17p deletion, mantle cell lymphoma (MCL) in those with a prior therapy, and Waldenström macroglobulinemia (WM).⁴

Clinical studies leading to the approval of ibrutinib in CLL saw promise with ibrutinib in older populations. In RESONATE-2 (NCT01722487), an international, open-label, randomized, phase 3 trial, investigators compared ibrutinib with chlorambucil
in 269 treatment-naïve patients 65 years or older with CLL/SLL. Twenty percent of patients had chromosome 11q22.3 deletion. Patients were randomly assigned 1:1 to either 420 mg/day ibrutinib until progression or 12 cycles of chlorambucil. Ibrutinib showed superiority, with an estimated prolonged survival rate of 98% vs 85% with chlorambucil at 24 months.⁵ In a 5-year efficacy and safety follow-up, the investigator-assessed overall response rate (ORR) for ibrutinib was 92%.⁶

Because single-agent ibrutinib and the combination of chlorambucil and obinutuzumab both showed better efficacy against single-agent chlorambucil, the iLLUMINATE trial (NCT02264574) tested the efficacy of ibrutinib plus obinutuzumab vs obinutuzumab plus chlorambucil. Treatment-naïve patients (N = 212) who were 65 years or older, or younger than 65 years with coexisting conditions, were randomized to receive one combination or the other.⁷

he overall survival (OS) rate at 30 months was 86% in the ibrutinib/obinutuzumab arm and 85% in the chlorambucil/ obinutuzumab arm. The ORR for ibrutinib/ obinutuzumab was 88%; it was 73% in the obinutuzumab/chlorambucil group. Nineteen percent of patients receiving obinutuzumab/ibrutinib achieved a complete response (CR). The iLLUMINATE trial showed particularly promising results in progression-free survival (PFS) for high-risk CLL patients with del17p, TP53 mutation, del11q, or unmutated IGHV; those who took the ibrutinib/obinutuzumab regimen had similar PFS rates at 30 months as the overall CLL population.⁷

Ibrutinib as second-line therapy for MCL has also been shown to be favorable, according to a 3.5-year follow-up study in which approximately one-third of 370 patients had high-risk disease, as defined by the Mantle Cell Lymphoma International Prognostic Index: 48.9% had bulky MCL, 11.9% had blastoid variant disease, and 73.2% had 2 or more previous lines of treatment. Overall, patients who received ibrutinib as a second-line therapy experienced better outcomes than those who were given it as a later line of therapy. Investigators also assessed ibrutinib further in subgroups of this patient population, particularly those with chemosensitive disease or mutated TP53. Of the pooled dataset, 144 patients had known TP53 mutation status, and 20 had mutated TP53. In patients with wild-type and mutated TP53 who were treated with ibrutinib, the median PFS was 4 months and the median OS was 33.6 and 10.3 months, respectively. The ORR was 55.0% and 70.2% in mutated patients and wild-type patients, respectively.⁸

Ibrutinib resistance and safety. Although ibrutinib has yielded positive response in patients, the toxicity profiles and known resistance associated with treatment raise concerns. Patients with primary refractory disease or early progression may present with histologic transformation, for instance. Additionally, BTK Cys481 mutations and PLCG2 mutations have been found in patients who have progressed with CLL. Del(8p) leading toward haploinsufficiency of TRAIL-R, with driver mutations in EP300, MLL2, and EIF2A, have more recently been described in acquired ibrutinib resistance.⁹

To learn more about potential toxicity associated with ibrutinib, investigators conducted a retrospective analysis that included patients with CLL who were treated commercially or in clinical trials with ibrutinib. Of 616 ibrutinib-treated patients, 546 (88%) were treated commercially. The mean age of patients from clinical trials was 58 years vs 61 years in the commercial population (P = .01). Approximately 41% of patients ended up discontinuing therapy with ibrutinib, with a median time to discontinuation of 7 months.¹⁰

Toxicity was the most common reason for discontinuation of ibrutinib. The most common toxicities in the frontline setting that led to discontinuation were arthralgia (46.0%), atrial fibrillation (25.0%), and rash (16.7%). The most common toxicities that led to discontinuation in patients with relapsed/ refractory disease were atrial fibrillation (12.3%), infection (10.7%), pneumonitis (9.9%), bleeding (9.0%), and diarrhea (6.6%). Outcomes did not differ among patients treated commercially vs in clinical trials. Investigators concluded that strategies are needed to lessen intolerance to ibrutinib, to further improve efficacious outcomes with this drug.¹⁰

In comparison with the second-generation BTK inhibitors acalabrutinib and zanubrutinib, single-agent ibrutinib has been shown to have a greater toxicity profiles (grade >3) in CLL; clinical trial results have shown a greater percentage of patients receiving ibrutinib who experienced hypertension, neutropenia, infections, atrial fibrillation, and anemia.¹¹

Acalabrutinib

Acalabrutinib has a higher biochemical and cellular selectivity than ibrutinib, with a design to limit inhibition of off-target kinases.¹² It is currently approved for patients with MCL who have had 1 previous therapy and in patients with CLL/SLL.¹³

Both single-agent acalabrutinib and acalabrutinib in combination with obinutuzumab have shown durable responses in patients with previously untreated CLL. The phase 3 ELEVATE-TN trial (NCT02475681) tested efficacy and safety of acalabrutinib plus obinutuzumab vs acalabrutinib alone vs obinutuzumab plus chlorambucil in treatment-naïve patients with CLL 65 years or older, or patients younger than 65 years with coexisting conditions. Patients were randomized 1:1:1 with a primary end point of independent review committee– assessed PFS with acalabrutinib/obinutuzumab vs obinutuzumab/chlorambucil.¹⁴ This trial met its primary end point early at interim analysis, showing statistically and clinically meaningful advances in PFS with acalabrutinib/obinutuzumab vs obinutuzumab/chlorambucil. It was the second crucial trial to meet its primary end point early with acalabrutinib in CLL; the first was the ASCEND trial (NCT02970318).¹⁵

The randomized, global, open-label phase 3 ASCEND trial evaluated the efficacy and safety of acalabrutinib as a monotherapy in patients with relapsed/refractory CLL. Acalabrutinib was tested against investigator’s choice of rituximab plus idelalisib or bendamustine. The safety and tolerability of acalabrutinib proved consistent with its already recognized profile. Acalabrutinib showed major improvements in PFS compared with the other regimens. Patients with del(17p), TP53 mutation, and Rai stage also saw improvements in PFS with acalabrutinib vs rituximab plus idelalisib or bendamustine.^16,17Acalabrutinib showed durable responses in patients with relapsed/refractory MCL. In an open-label, phase 2 study, acalabrutinib was given to patients with relapsed/refractory MCL until disease progression (median age, 68 years; median previous therapies, 2). The ORR was 81%, and 40% had a

CR at a median follow-up of 15.2 months. Most frequently, adverse events (AEs) were grade 1 or 2, and 44% of patients discontinued therapy mainly due to disease progression (31%) or AEs (6%).¹⁸

Zanubrutinib

Zanubrutinib is a more selective drug than is ibrutinib, with a higher exposure and complete target inhibition in the tissues.¹⁹ It is approved for patients with MCL with 1 prior therapy,²⁰ and it is being studied in patients with CLL and WM. In nonclinical works, zanubrutinib has been shown to have attractive pharmacodynamic and pharmacokinetic properties.²¹

In MCL, zanubrutinib has been shown to be a commonly tolerable therapy in patients with relapsed/refractory disease. A phase 2 trial tested the efficacy and safety of zanubrutinib in relapsed/refractory MCL in patients aged 18 to 75 years who had 1 to 4 previous therapies: The ORR was 84%, and 59% of patients had a CR. Twenty-eight patients experienced grade 3 or higher AEs; the most common were decreased neutrophil count, lung infection, anemia, and decreased white blood cell count. Overall, this therapy was found to be very active in this patient population.²²

Zanubrutinib is also being studied in relapsed/refractory CLL against ibrutinib in the phase 3 ALPINE trial (NCT03734016). Recruitment, begun in late 2018, continues in 14 countries to reach an estimated enrollment of 600 participants. ALPINE’s primary end point is ORR as assessed by an independent review committee. Secondary end points being explored include PFS, safety, ORR, duration of response, OS, and patient-reported outcomes. Study completion is expected in August 2022.^21,23

Another potential use for zanubrutinib is in treating WM. The randomized, open-label, multicenter, phase 3 ASPEN clinical trial (NCT03053440) evaluated zanubrutinib vs ibrutinib in patients with relapsed/refractory or treatment-naïve WM.²⁴ The primary end points were CR or very good partial response (VGPR). Results from ASPEN demonstrated VGPR rates of 28.4% and 19.2% of patients in the zanubrutinib and ibrutinib arms, respectively. In the zanubrutinib arm, 58.4% of patients experienced grade 3 or higher AEs, compared with 63.3% in the ibrutinib arm. A total of 4.0% of patients in the zanubrutinib arm discontinued treatment due to AEs and 1.0% experienced fatal AEs; in the ibrutinib arm, 9.2% discontinued due to AEs and 4.1% experienced fatal AEs.

LOXO-305

The long-term efficacy of covalent BTK agents, such as ibrutinib and acalabrutinib, are limited by the development of resistance, commonly through BTK cysteine-481 (C481) mutations; therefore, new therapeutic options are needed for patients who have progressed on such covalent BTK inhibitors. A noncovalent, next-generation inhibitor, LOXO-305, holds equal potency against wild-type and C481-mutated BTK.²⁵

The open-label, multicenter, phase 1/2 BRUIN trial (NCT03740529) is currently evaluating oral LOXO-305 in patients with previously untreated CLL/SLL or non-Hodgkin’s lymphoma (NHL). Key end points of the study include the evaluation of safety, tolerability, pharmacokinetics, ORR/du- ration of response based on disease criteria, and the determination of maximum tolerated dose or recommended phase 2 dose. Key eligibility criteria include being 18 years or older, ECOG 0 to 2, having active disease in need of treatment, and having histologically confirmed CLL/SLL, WM, or NHL that has been intolerant to 2 or more previous lines of therapy, including BTK intolerant.^26,27

The phase 1 trial evaluated 28 patients with a median age of 66 years and median of 3 previous therapies; 79% had a prior BTK inhibitor. Thirteen patients with CLL, 6 patients with MCL, and 2 others were eligible for response evaluation. Seventy-seven percent of these CLL patients and 50% of the MCL patients achieved an overall response. Most AEs were grade 1/2, with 2 grade 3 treatment-related AEs. Thus far, LOXO-305 has shown antitumor activity in both CLL and MCL. The trial continues to recruit patients at 18 sites
in 3 countries.²⁷

Stakeholder Insights on the Evolving BTK Spectrum

The selection of BTK inhibitors has become reliant on the ease of prescribing, as well as toxicity profiles. Due to concerns regarding tolerability, stakeholders are largely moving away from ibrutinib and favoring acalabrutinib and zanubrutinib. One stakeholder pointed out that the safety profile marks the primary difference between second-generation and first-generation BTK inhibitors. In particular, the cardiovascular toxicity profile of second-generation agents is compelling enough to favor them over first-generation agents.

Because efficacy and tolerability profiles are similar between acalabrutinib and zanubrutinib, the cost difference between the 2 may be a deciding factor. The price of zanubrutinib is lower than that of acalabrutinib or ibrutinib, and if that translates to a lower copay, then zanubrutinib may be more accepted in the community, according to stakeholders.

In the treatment of WM, stakeholders noted that the PFS curves of the ASPEN trial support that both ibrutinib and zanubrutinib are efficacious, and that the VGPR data associated with zanubrutinib may translate to improved quality of life. Nevertheless, stakeholders agreed that safety profiles will be the focus when deciding which agents are best to treat WM.

Preferences varied between zanubrutinib and acalabrutinib in MCL, given their similar safety and efficacy profiles. One stakeholder pointed out that acalabrutinib was associated with lower rates of discontinuation and may therefore be better tolerated, but that it wasn’t necessarily a clear advantage given the difficulty of comparing results across trials. An advantage of zanubrutinib in the MCL setting is that it can be taken with a proton pump inhibitor. Another fact that may affect treatment selection in MCL is that resistance is not as commonly seen in patients with this lymphoma compared with patients with CLL.

In CLL, therapeutic selection is arguably more complex because of the numerous available combinations. Moreover, ongoing head-to-head studies (such as zanubrutinib vs ibrutinib and acalabrutinib vs ibrutinib) will likely reveal more about the safety profiles of the second-generation agents compared with ibrutinib. Stakeholders noted that they want to see more data on sequencing strategies, including efficacy in later-line settings, and the potential use of cellular treatments after BTK inhibition to clean up residual disease.

Regarding BTK resistance, stakeholders were generally not comfortable using a second-generation BTK inhibitor after resistance to ibrutinib. Data are insufficient, they say, in showing how another BTK inhibitor that would bind to the same exact site as ibrutinib could be efficacious. However, stakeholders noted that the investigational agent LOXO-305 may be particularly promising as a therapeutic option for patients with BTK resistance, especially those with Cys481S resistance. LOXO-305 appears to be a “cleaner” agent, with more on-target inhibition and fewer off-target effects, in addition to being well tolerated. They represent potentially exciting developments in a treatment landscape that is rapidly expanding.

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