Zanubrutinib Exhibits Superior Overall Response Rate for Adult Patients With Chronic Lymphocytic Leukemia

According to the latest data,¹ experts estimate more than 60,000 newly cases of leukemia will be diagnosed in the United States in 2022—20,160 of which are attributed to chronic lymphocytic leukemia (CLL).

CLL primarily affects older adults—aged an average of 70 years or older—with the risk for men being slightly higher than for women.¹ The American Cancer Society¹ measures the average persons’ lifetime risk of developing CLL to about 1 in 175 or 0.57%. An estimated 4,410 deaths will be attributed to CLL in 2022.¹

While leukemia may affect red blood cells, white blood cells, and platelets, CLL occurs when bone marrow produces excess lymphocytes and progresses relatively slowly compared to other cancers, despite it being one of the most common leukemia types.²

Patients with CLL commonly present with swollen lymph nodes and fatigue² and undergo several tests and procedures prior to diagnoses. These tests include³ but are not limited to complete blood count with differential and chemistry panel, flow cytometry, TP53 and IgHV mutation analysis, and more.

“In this disorder, lymphocyte counts in the blood are usually greater than or equal to 5,000/mm³ with a characteristic immunophenotype (CD5- and CD23-positive B cells),” per the National Cancer Institute at the National Institutes of Health.³

CLL is often linked with small lymphocytic lymphoma (SLL) as they are considered the same disease with the primary difference being the location of the cancer cells. CLL cells are mostly found in the blood and marrow, whereas SLL cells are found in the lymph nodes.⁴

Current Therapy Landscape

“Treatment of patients with chronic lymphocytic leukemia (CLL) must be individualized on the basis of the clinical behavior of the disease,” states the National Cancer Institute at the National Institutes of Health.³ “Because this disease is generally not curable, occurs in an elderly population, and often progresses slowly, it is most often treated in a conservative fashion.”

Per National Comprehensive Cancer Network Guidelines,⁵ therapy must be determined and reevaluated throughout treatment period due to individual patient biomarkers that could change effectiveness of certain therapies.

First-line treatment is determined by age, overall health and medications, biomarkers, length of remission achieved by treatments, and patient wishes for lifestyle.⁵ Additionally, a key factor for determining the most optimal therapy is whether a patient presents with a 17p deletion or TP53 mutation—especially for patients who have already received treatment for CLL.

Bruton’s tyrosine kinase (BTK) inhibitors are the standard, preferred therapy for patients with CLL as they block B cell receptor (BCR) signals and can be administered via pill form at home for as long as they remain effective.

Ibrutinib was the first BTK inhibitor approved⁶ in 2014 for patients with CLL or who had already received 1 therapy. Its indication was expanded later in 2014 to patients with 17p deletion and then as a first-line therapy in 2016. Since then it has been approved for all CLL indications, as well as SLL.

While generally successful, serious side effects like heart disease have found to be associated with ibrutinib therapy.⁵

Acalabrutinib, a next-generation selective BTK inhibitor was approved⁷ for CLL and SLL in November 2019. In one of its first direct comparisons⁸ to ibrutinib, “After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median [progression free survival] of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00; 95% CI, 0.79 to 1.27)."

Other options could include obinutuzumab, approved as an add-on therapy for acalabrutinib, and venetoclax with obinutuzumab.⁵ Depending on a patient's biomarker status, other regimens could include chemoimmunotherapy, alkylating agents like bendamustine or chlorambucil with CD20 antibodies. The antibody rituximab also has demonstrated success when used as an add-on to other therapies.⁵

Newest Breakthroughs

In February 2022, the FDA accepted⁹ a supplemental new drug application for zanubruti­­­nib, a small molecule BTK inhibitor for CLL. Zanubrutinib is previously approved for mantle cell lymphoma in adult patients who have received at least one prior therapy (November 2019); for the treatment of adult patients with Waldenström’s macroglobulinemia (August 2021); and for the treatment of adult patients with relapsed or refractory marginal zone lymphoma who have received at least one anti-CD20-based regimen (September 2021).

The latest data¹⁰ released from the phase 3 ALPINE clinical trial demonstrates overall response rate superiority for BTK inhibitor zanubruti­­­nib compared with ibrutinib for adult patients with relapsed or refractory CLL/SLL.

“After achieving superiority in the primary endpoint of investigator-assessed overall response rate at the interim analysis, in this final response analysis, [zanubruti­­­nib] met the primary endpoint of superiority over ibrutinib in [overall response rates] as determined by [an independent review committee], with a response rate of 80.4% vs 72.9% (2-sided P = .0264),” stated Beigene in a press release.¹⁰

These results¹⁰ are based on a median 24.2 month observation of 652 patients based in Europe (60%), the United States (17%), China (14%), and New Zealand/Australia (9%). Overall, zanubruti­­­nib has demonstrated to be well-tolerated and safe.

Additional outcome measures¹⁰ included the rate comparison of atrial fibrillation or flutter, for zanubruti­­­nib compared with ibrutinib, which was found to be 4.6% (n=15) and 12.0% (n=39), respectively.

Further, of the 324 patients across both arms, 13% and 17.6% of patients discontinued zanubruti­­­nib and ibrutinib treatment due to adverse events.¹⁰

“The most commonly reported grade 3 or higher adverse events for [zanubruti­­­nib] vs ibrutinib, respectively, were neutropenia (14.2% vs 13.9%), hypertension (12.7% vs 10.2%), pneumonia (4% vs 7.4%), neutrophil count decreased (4.3% vs 4.0%), and COVID-19 pneumonia (4.3% vs 3.1%),” said Beigene in a press release.¹⁰

For the next step in the analysis of the phase 3 ALPINE trial outcomes, researchers will be examining progression-free survival rates.

“We are pleased to announce updated topline data from the phase 3 ALPINE trial for [zanubruti­­­nib], which demonstrated a superior overall response rate vs ibrutinib in CLL patients who have seen their disease return or spread after prior therapy,” said Lai Wang, PhD,  Global Head of Research & Development at BeiGene. “We understand that for people living with CLL and their families, relapse and treatment resistance are especially devastating. That's why we are encouraged by this final response analysis, which adds to the growing body of clinical evidence for [zanubruti­­­nib] as a potential treatment for CLL.”

References:

1. American Cancer Society. Key statistics for chronic lymphocytic leukemia. Updated January 12, 2022. Accessed May 31, 2022. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/key-statistics.html
2. National Cancer Institute at the National Institutes of Health. Chronic lymphocytic leukemia treatment (PDQ)–patient version. Updated March 4, 2022. Accessed May 31, 2022https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq
3. National Cancer Institute at the National Institutes of Health. Chronic lymphocytic leukemia treatment (PDQ)–health professional version. Updated February 25, 2022. Accessed May 31, 2022. https://www.cancer.gov/types/leukemia/hp/cll-treatment-pdq
4. National Cancer Institute. CLL/SLL. Accessed May 31, 2022. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/cll-sll
5. National Comprehensive Cancer Network. NCCN guidelines: chronic lympcytic leukemia/small lymphocytic lympoma. Updated March 2022. Accessed May 31, 2022. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478
6. Koffman B. Ibrutinib’s approval history and its use as frontline therapy for CLL. August 13, 2019. May 31, 2022. https://cllsociety.org/2018/08/ibrutinibs-approval-history-and-its-use-as-frontline-therapy-for-cll/
7. US Food & Drug Administration. Project Orbis: FDA approved acalabrutinib for CLL and SLL. November 11, 2019. Accessed May 31, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/project-orbis-fda-approves-acalabrutinib-cll-and-sll
8. 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
9. Biospace. BeiGene Announces US FDA acceptance of supplemental new drug application for brukinsa (zanubrutinib) in chronic lymphocytic leukemia. February 22, 2022. Accessed May 31, 2022. https://www.biospace.com/article/releases/beigene-announces-u-s-fda-acceptance-of-supplemental-new-drug-application-for-brukinsa-zanubrutinib-in-chronic-lymphocytic-leukemia-/
10. Beigene. IRC determines Brukinsa (zanubruti­­­nib) demonstrates superior overall response rate versus ibrutinib in final response analysis of ALPINE trial in chronic lymphocytic leukemia. April ­­11, 2022. Accessed May 31, 2022. https://hkexir.beigene.com/news/irc-determines-brukinsa-zanubrutinib-demonstrates-superior-overall-response-rate-versus-ibrutinib-in-final-response-analysis/a75d4291-d8cd-40ee-aace-2088ea287ac5/