Subgroup and Toxicity Analyses Favor Zanubrutinib Vs Ibrutinib in CLL

Lori A. Leslie, MD

Director, Indolent lymphoma and Chronic Lymphocytic Leukemia Research Programs

John Theurer Cancer Center

Assistant Professor,

Hackensack Meridian School of Medicine

Hackensack, NJ

CASE SUMMARY

History and presentation:​

• A 70-year-old White man with asymptomatic lymphocytosis, identified 4 years ago​.
• Initially monitored​
• Two years later, he developed anemia, night sweats, and splenomegaly​.
• PET scan: no evidence of transformation
• Treated with venetoclax (Venclexta) plus obinutuzumab​ (Gazyva)
• Twenty-four months later, he had ECOG performance status of 1​, palpable splenomegaly​, and a CT of chest, abdomen, pelvis showed the largest node at 4.2 x 2.8 cm; all others <3 cm.​

Comorbidities:​

• Coronary artery disease
• High cardiovascular risk due to history of non–ST-elevation myocardial infarction, status post 2 stents​

Medications:​

• Simvastatin​
• Amlodipine​
• Clopidogrel, aspirin ​

Diagnostic workup:​

• White blood cell count: 35.0 x 10³ cells/μL​
• Absolute lymphocyte count: 22.0 x 10³ cells/μL​
• Hemoglobin level: 9.5 g/dL​
• Platelet count: 80 x 10³/μL​
• Lactate dehydrogenase level: 255 U/L​
• Karyotype: complex, 4 abnormalities​
• Fluorescence in situ hybridization (FISH): 11q deletion (del[11q]), without 17p deletion (del[17p]) ​
• IGHV: unmutated​
• Mutations of interest: unmutated TP53​
• Largest node on imaging: 4.2 x 2.8 cm​

Due to progression of disease after a BCL2 inhibitor, the decision was made to initiate therapy with a Bruton tyrosine kinase (BTK) inhibitor.

Targeted Oncology: What did you think of the efficacy for patients with del(17p) or TP53 relapsed/refractory chronic lymphocytic leukemia (CLL) on the ALPINE trial (NCT03734016)?

LORI A. LESLIE, MD: My personal opinion is zanubrutinib [Brukinsa] has done a nice job teasing out that del(17p) population. Looking at those patients that did have del(17p) or TP53 mutation or both, that difference with progression-free survival [PFS] is certainly sustained, if not numerically slightly higher [PFS HR, 0.52; 95% CI, 0.33-0.83; P = .0047).¹ So definitely within that subgroup analysis of the secondary end point, it seems to be favorable in TP53-mutated patients.

What were the toxicities seen for patients on ALPINE?

Looking at adverse events [AEs], the ALPINE and ELEVATE-RR [NCT02477696] studies also occurred at a different time. ALPINE started right as COVID-19 was starting, so the entire study was more or less was done during the COVID-19 era. The majority of the AEs were COVID-related; that hadn't been teased out previously. Atrial fibrillation/atrial flutter with zanubrutinib of any grade was 6.8%, grade 3 or higher at 3.1% compared with 16.4% and 4.9% with ibrutinib [Imbruvica], respectively. [In terms of] atrial flutter events, there was significantly less with zanubrutinib compared with ibrutinib. So, we saw the overall response rate difference, PFS difference, and cardiovascular toxicity, specifically atrial fibrillation/atrial flutter, difference [from ibrutinib].

Hypertension [was also seen in] this study. The rates of hypertension were similar with zanubrutinib [grade 3 or higher, 16.4%] and ibrutinib [grade 3 or higher, 14.5%] here so it's something many people quote from the study as well. Further investigation has been done or is being reported regarding why that may be.

How did ALPINE and ELEVATE-RR differ for patients with CLL?

With ELEVATE-RR and ALPINE in relapsed/refractory disease, looking at head-to-head BTK inhibitors, median follow-up was 40.9 months with ELEVATE,² 29.6 months with ALPINE....³ There was also a sensitivity analysis in Jennifer R. Brown, MD, PhD’s presentation at the 2023 American Society of Hematology Annual Meeting for zanubrutinib vs ibrutinib to try to tease out further and people would say, is the PFS [benefit associated with] this or that?1 Correcting for COVID-19–related deaths, subsequent therapies, and only patients whose disease progressed while they were on treatment—in all of those sensitivity analyses, the PFS difference remained with zanubrutinib over ibrutinib.

_References:

_{1. 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(1):202. doi:10.1182/blood-2023-174289.}

_{2. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210}

_{3. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332. doi:10.1056/NEJMoa2211582}