Oncology Live®
Vol. 25 No. 7
Volume 25
Issue 7

BTK Inhibitor Combinations Move to Forefront of CLL Investigations, Conversations


Mazyar Shadman, MD, MPH, details the efficacy of BTK inhibitors in the frontline treatment of CLL as well as safety considerations in the relapsed/refractory setting.

Mazyar Shadman, MD, MPH

Mazyar Shadman, MD, MPH

As the frontline setting of chronic lymphocytic leukemia (CLL) further examines the use of combination strategies, the selection of optimal Bruton tyrosine kinase (BTK) inhibitors in the relapsed or refractory setting remains, with sequencing questions arising as well.

In the OncLive Scientific Interchange and Workshop Chronic Lymphocytic Leukemia: Applying the Latest Data to Clinical Practice, Mazyar Shadman, MD, MPH, moderated a program with 11 expert clinicians in the field of hematologic oncology focused on treatment approaches in the frontline and relapsed/refractory settings in CLL; updated data regarding the use of zanubrutinib (Brukinsa), acalabrutinib (Calquence), and other agents were key focuses.

Shadman is the Innovators Network Endowed Chair and an associate professor in the Clinical Research Division at Fred Hutch Cancer Center, and an associate professor in the Medical Oncology Division at the University of Washington School of Medicine, both in Seattle, Washington.

Efficacy in the Frontline: Examining BTK Inhibitors

Zanubrutinib Shows Efficacy as Monotherapy

The phase 3 SEQUOIA trial (NCT03336333) examined zanubrutinib vs bendamustine plus rituximab (Rituxan) in patients with treatment-naive CLL or small lymphocytic lymphoma (SLL). At a median follow-up of 43.7 months (range, 0.0-60.0), the median overall survival (OS) for patients in cohort 1, which enrolled those without a del(17p) mutation, was not evaluable (NE; 95% CI, NE-NE) in the zanubrutinib arm (n = 241) compared with NE (95% CI, NE-NE) in the bendamustine plus rituximab arm (n = 238; HR, 0.87; 95% CI, 0.50-1.48; P = .5995); the 42-month OS rates were 89.4% vs 88.3%, respectively. Additionally, the median progression-free survival (PFS) was NE (95% CI, NE-NE) with zanubrutinib vs 42.2 months (95% CI, 38.4-49.8) with bendamustine plus rituximab (HR, 0.30; 95% CI, 0.21-0.43; P < .0001).1

Additional data revealed that, at a median follow-up of 47.9 months (range, 5.0-56.9), patients with del(17p) mutations, which comprised the cohort 2 population, who received zanubrutinib (n = 110) achieved a 42-month OS rate of 89.5% (95% CI, 81.9%-94.1%) and a 42-month PFS rate of 79.4% (95% CI, 70.4%-85.9%).

“The take-home point is that patients with IGHV-mutated [disease] are also seeing benefit with zanubrutinib and there’s not much of a difference in terms of PFS in del17p or normal p53 [patients],” Shadman explained. “[There were also] no new safety signals—the hypertension rate and atrial fibrillation rates [in the zanubrutinib arm] were not different from the bendamustine plus rituximab [group] in the unplanned analysis that was done.”

Patients with IGHV mutations in cohort 1 treated with zanubrutinib (n = 109) achieved a median PFS of NE (95% CI, NE-NE) vs 49.4 months (95% CI, 44.4-NE) in the bendamustine plus rituximab arm (n = 110; HR, 0.35; 95% CI, 0.19-0.64; P = .00033). In the IGHV-unmutated group, patients treated with zanubrutinib vs bendamustine plus rituximab achieved a median PFS of NE (95% CI, NE-NE) vs 33.7 months (95% CI, 29.5-39.1), respectively (HR, 0.23; 95% CI, 0.14-0.37; P < .0001).

Acalabrutinib Plus Obinutuzumab

When asked about the use of acalabrutinib plus obinutuzumab (Gazyva) in treatment-naive CLL based on findings from the phase 3 ELEVATE-TN trial (NCT02475681) during the workshop, Alan Skarbnik, MD, explained that “more [clinicians] are picking it up based on these data, but most patients that we’re putting on continuous BTK [inhibition] of this day and age are patients who have del17p or TP53 mutations where the addition of obinutuzumab makes no difference. I am of the thought that if we’re going to do obinutuzumab, let’s do obinutuzumab [plus] venetoclax [Venclexta] because a lot of the time you’re giving acalabrutinib because of the ease. [Certain] patients have aid, ‘I don’t want to have all-day infusion.’ It’s still okay, but we [usually] prefer a fixed-duration therapy, except for in high-risk patients. [Additionally], in patients with high-risk disease obinutuzumab made no difference, so I don’t see a reason to add that.”

Skarbnik is the director of the lymphoma and chronic lymphocytic leukemia program and director of experimental therapeutics, malignant hematology, at Novant Health in Charlotte, North Carolina.

Furthermore, updates from ELEVATE-TN presented at the 65th American Society of Hematology Annual Meeting & Exposition (ASH 2023), which took place in December 2023, revealed that acalabrutinib plus obinutuzumab (n = 179) improved investigator-assessed PFS vs acalabrutinib monotherapy (n = 179) in patients with untreated CLL who were 65 years or older or aged 18 to 64 years with comorbidities (HR, 0.58; 95% CI, 0.39-0.86; P = .0229). Acalabrutinib plus obinutuzumab also improved PFS vs chlorambucil plus obinutuzumab (n = 177; HR, 0.14; 95% CI, 0.10-0.20; P < .0001).2

Additional Combination Approaches

“The phase 3 CLL14 study [NCT02242942] is another study that we are getting updates from very routinely. The 6-year follow-up [revealed that] 5 years after stopping the 1-year therapy [with obinutuzumab and venetoclax], the 6-year PFS rate was 53.1%, which is amazing in all comers. We now know that both the p53 abnormality and IGHV mutation predict a shorter PFS [too in this patient population],” Shadman said.

The clinicians went on to discuss additional relevant data in CLL, including findings from a phase 2 trial (NCT03824483) which demonstrated that patients with untreated CLL/SLL given zanubrutinib plus obinutuzumab with ramp-up venetoclax (n = 52) achieved frequent undetectable minimal residual disease (MRD; < 10–4) in the peripheral blood (96%) and in both the peripheral blood and bone marrow (92%); the median MRD-free survival was 29.8 months (range, 3.6-35.1+).3

“If you’re going to do an MRD-[guided] treatment, you need venetoclax [as part of the regimen],” Skarbnik said. Clinicians also discussed the option of enrolling patients in the phase 3 MAJIC trial (NCT05057494), as treatment with acalabrutinib plus venetoclax vs venetoclax plus obinutuzumab is MRD-guided.

Safety Considerations With BTK Inhibitors in Relapsed/Refractory CLL

All eyes are on various combination strategies with the BTK inhibitors acalabrutinib, ibrutinib (Imbruvica), and zanubrutinib, with updated safety findings from the phase 3 ELEVATE-RR (NCT02477696) and ALPINE (NCT03734016) trials presented during ASH 2023 (Figure).4,5



Safety data from ELEVATE-RR revealed that the rate of discontinuation due to adverse effects (AEs) was lower for patients who received acalabrutinib (n = 266) compared with those treated with ibrutinib (n = 263; HR, 0.62; 95% CI, 0.41-0.93). Incidences of cardiac events overall were similar between the 2 arms. The common any-grade AEs of diarrhea, arthralgia, urinary tract infection, back pain, muscle spasms, and dyspepsia were higher with ibrutinib than acalabrutinib with 1.5- to 4.1-fold higher exposure-adjusted incidence rates. However, headache and cough occurred more frequently with acalabrutinib vs ibrutinib, with 1.6- and 1.2-fold higher exposure-adjusted incidence rates, respectively.4

Further, rates of cardiac AEs were lower for patients who received zanubrutinib (n = 324) vs ibrutinib (n = 324), according to updated data from ALPINE. Any-grade (23.5% vs 33.0%), grade 3 or higher (7.1% vs 11.1%), and serious (3.1% vs 9.6%) cardiac AEs were observed in both arms, respectively. Additionally, no patients died from cardiac AEs in the zanubrutinib arm compared with 6 patients in the ibrutinib arm. The discontinuation rates due to cardiac toxicities were 0.6% vs 4.6%, respectively.5

“Ibrutinib and zanubrutinib have similar rates of hypertension, [and] acalabrutinib has [lower rates] than ibrutinib,” Skarbnik said. “There’s more headache with acalabrutinib for some patients—I’ve had patients who had to stop [treatment] because of bad headaches. You have to nitpick here. To some extent in terms of efficacy, they’re somewhat interchangeable [drugs] here. To the point that if I prescribe acalabrutinib and insurance tells me you have to use zanubrutinib, I’m not going to argue and the other way around [too]. [However], I will argue if they tell me I have to use ibrutinib.”

Clinicians in the workshop also added that when determining between acalabrutinib and zanubrutinib, they will consider AEs and adherence to the dosing schedules of both agents.

Up Next: Noncovalent Inhibition With Pirtobrutinib

The accelerated approval of pirtobrutinib (Jaypirca) by the FDA, which occurred in December 2023 and was supported by findings from the phase 1/2 BRUIN trial (NCT03740529), represents a notable advancement in the relapsed/refractory CLL treatment paradigm, and clinicians highlighted that additional sequencing data are needed as a next step.6

Subgroup analysis results from BRUIN presented during ASH 2023 showed that patients who did not receive a prior BCL2 inhibitor and were treated with pirtobrutinib (n = 154) achieved a median PFS of 23.0 months (95% CI, 19.6-28.4); 6-, 12-, 18-, and 24-month PFS rates were 87.1%, 72.8%, 62.5%, and 48.3%, respectively. Patients treated with pirtobrutinib who previously received a BCL2 inhibitor (n = 128) experienced a median PFS of 15.9 months (95% CI, 13.6-17.5); 6-, 12-, 18-, and 24-month PFS rates were 82.2%, 60.7%, 39.6%, and 24.3%, respectively.7

Regarding safety, AEs of special interest occurring at any grade vs grade 3 or higher with pirtobrutinib included infections (71.0% vs 28.1%), bleeding (42.6% vs 2.2%), neutropenia (32.5% vs 26.8%), bruising (30.3% vs 0.0%), hemorrhage (21.1% vs 2.2%), hypertension (14.2% vs 3.5%), and atrial fibrillation/flutter (3.8% vs 1.3%).8 Shadman added that he “believes clinicians will use a lot of pirtobrutinib plus a covalent BTK inhibitor,” and that checking mutation status is key.


  1. Shadman M, Munir T, Robak T, et al. Zanubrutinib vs bendamustine + rituximab in patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma: extended follow-up of the SEQUOIA study. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023; Lugano, Switzerland. Abstract 154.
  2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib ± obinutuzumab vs obinutuzumab + chlorambucil in treatment-naive chronic lymphocytic leukemia: 6-year follow-up of Elevate-TN. Blood. 2023;142(suppl 1):636. doi:10.1182/blood-2023-174750
  3. Soumerai JD, Dogan A, Seshan V, et al. Long-term follow-up of multicenter phase II trial of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in previously untreated patients with CLL/SLL. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023; Lugano, Switzerland.
  4. Seymour JF, Byrd JC, Ghia P, et al. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial. Blood. 2023;142(8):687-699. doi:10.1182/blood.2022018818
  5. Brown JR, Eichhorst BF, Lamanna N, et al. Extended follow-up of ALPINE randomized phase 3 study confirms sustained superior progression-free survival of zanubrutinib versus ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL). Blood. 2023;142(suppl 1):202. doi:10.1182/blood-2023-174289
  6. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. Updated December 7, 2023. Accessed April 18, 2024.
  7. Woyach JA, Brown JR, Ghia P, et al. Pirtobrutinib in post-cBTKi CLL/SLL: ~30 months follow-up and subgroup analysis with/without prior BCL2i from the phase 1/2 BRUIN study. Blood. 2023;142(suppl 1):325. doi:10.1182/blood-2023-185852
  8. Mato AR, Woyach JA, Brown JR, et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med. 2023;389(1):33-44. doi:10.1056/NEJMoa2300696
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