Patients With Progressive CLL After Zanubrutinib or Ibrutinib Therapy Often Do Not Have BTK-Mutated Disease

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Patients with chronic lymphocytic leukemia (CLL) who experienced disease progression following treatment with zanubrutinib (Brukinsa) or ibrutinib (Imbruvica) had a low rate of BTK-mutated disease, according to findings from an analysis of the phase 3 ALPINE trial (NCT03734016) published in Blood Advances.1

At a median follow-up of 25.7 months for the final progression-free survival (PFS) analysis, data demonstrated that BTK mutations occurred in 5 and 3 evaluable patients with relapsed/refractory CLL who experienced disease progression following treatment with zanubrutinib (n = 24) or ibrutinib (n = 28), respectively. A total of 17 acquired BTK mutations occurred; 82.4% of mutations were at C481 (zanubrutinib, n = 11/14; ibrutinib, n = 3/3). No BTK mutations were reported at baseline.

“Our results suggest that the mechanisms of early progression on covalent BTK inhibitors may be largely independent of BTK mutations, and our reported mutation frequencies are therefore not likely to be representative of all patients with CLL with disease progression on these BTK inhibitors,” the study authors wrote. “The low incidence [17%] of patients with BTK/PLCG2 mutations in this study highlights that at this short median follow-up time of 25.7 months, this data set includes more patients who relapsed early in the ALPINE study. Thus, in these patients, other mechanisms within or outside of the B-cell receptor pathway, potentially including mutations in other genes, may be driving disease progression.”

Prior data from ALPINE supported the January 19, 2023, FDA approval of zanubrutinib in patients with CLL or small lymphocytic lymphoma (SLL).2 Patients with relapsed/refractory CLL or SLL who received zanubrutinib (n = 327) achieved an overall response rate of 80% (95% CI, 76%-85%) compared with 73% (95% CI, 68%-78%) among patients who received ibrutinib (n = 325; response rate ratio, 1.10; 95% CI, 1.01-1.20; 2-sided P = .0264).3 The median duration of response (DOR) was not estimable (NE; 95% CI, NE-NE) and NE (95% CI, NE-NE), respectively. The 12-month DOR rates were 92% (95% CI, 87%-95%) and 86% (95% CI, 80%-91%), respectively.

ALPINE was a multicenter, open-label study that enrolled patients with relapsed/refractory CLL or SLL. Eligible patients also had to have measurable disease per CT scan or MRI, an ECOG performance status of 2 or less, and a life expectancy of at least 6 months, as well as adequate bone marrow, renal, and hepatic function.4

Eligible patients were randomly assigned 1:1 to received 160 mg of oral zanubrutinib twice daily or oral ibrutinib at a dose of 420 mg daily until disease progression or unacceptable toxicity. The primary end points were investigator- and independent review committee (IRC)–assessed ORR. Secondary end points included PFS, DOR, overall survival, and safety.

In the analysis published in Blood Advances, disease progression was determined by IRC or the investigator.1 Peripheral blood mononuclear cell samples were collected at baseline and at disease progression or following disease progression and before the receipt of subsequent CLL therapy.

At baseline, 91.2% of total patients who experienced disease progression (n = 52/57) had matched baseline samples for disease progression. The median age was 65 years and the median number of prior lines of treatment was 1 (range, 1-3) among patients who received zanubrutinib and 1 (range, 1-7) among patients who received ibrutinib.

The median duration of treatment in the zanubrutinib and ibrutinib groups was 20.2 months (range, 4.4-39.9) and 16.8 months (range, 3.5-36.2), respectively. Among patients with progressive disease without BTK mutations, the median duration of treatment was 16.8 months (range, 5.0-33.3) and 15.9 months (range, 5.9-29.4), respectively. Among patients with BTK-mutated disease at baseline, the median duration of treatment was 29.7 months (range, 18.4-34.6) and 30.8 months (range, 11.8-34.5), respectively.

Additional findings from the analysis showed that all patients with acquired BTK and/or PLCG2 mutations (n = 9) experienced disease progression during treatment per IRC and investigator assessment, except for 1 patient who received ibrutinib who was deemed to have progressive disease after treatment per investigator assessment. In patients with acquired BTK mutations, the median number of acquired mutations in the zanubrutinib and ibrutinib groups was 3 (range, 1-6) and 1 (range, 1-2), respectively. Most single-nucleotide variants in both the zanubrutinib (n = 11/14) and ibrutinib (n = 3/4) groups were at C481. Non-C481 mutations were reported in 12.4% (n = 3/24) of patients who experienced disease progression following treatment with zanubrutinib.

Notably, no clear associations between baseline driver gene mutations and BTK mutational status were reported. Most patients (n = 48/52) had disease harboring mutations in 1 of the 27 CLL driver genes at baseline. Most patients (61.5%) had disease harboring at least 2 driver gene mutations; the median number of mutations in these patients was 3 (range, 1-5). The median number of driver mutations among patients who developed BTK mutations and those who retained wild-type BTK at disease progression was 2 in both cases.

“These data suggest that salvage therapy with noncovalent BTK inhibitors, including pirtobrutinib [Jaypirca] or BTK-targeted protein degraders that have in vitro activity against several non-C481 mutations, should remain viable treatment options after zanubrutinib or ibrutinib treatment, although clinical studies will be required to demonstrate the efficacy of these agents in this population,” the study authors wrote in their conclusion.

References

1. Brown JR, Li J, Eichhorst BF, et al. Acquired mutations in patients with relapsed/refractory CLL who progressed in the ALPINE study. Blood Adv. 2025;9(8):1918-1926. doi:10.1182/bloodadvances.2024014206
2. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. January 19, 2023. Accessed May 8, 2025.https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma
3. Brukinsa. Prescribing information. BeiGene; 2019. Accessed May 8, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/213217s007lbl.pdf
4. A study of zanubrutinib (BGB-3111) versus ibrutinib in participants with relapsed/​refractory chronic lymphocytic leukemia (ALPINE). ClinicalTrials.gov. Updated March 30, 2025. Accessed May 8, 2025. https://clinicaltrials.gov/study/NCT03734016