People who live with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) are faced with the expectation of consecutive relapses. A study presented at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans reports that a "next generation" BTK inhibitor, zanubrutinib (Brukinsa), is significantly better than a currently used BTK inhibitor, ibrutinib (Imbruvica), in treating relapsed/refractory CLL/SLL and is better tolerated by patients.

Relapsed disease is defined as when the disease responds to therapy for a time, then stops responding. Refractory disease is when it does not respond to a treatment right from the start. While CLL/SLL are generally slow growing blood cancers, response to therapy ultimately dictates patient survival.

BTK (Bruton tyrosine kinase) is an enzyme essential to the growth and survival of B-cell leukemias and lymphomas, such as CLL and SLL. The BTK inhibitor ibrutinib is used to block the enzyme and stop cancer cell growth. It has significant side effects, however, which can limit its use.

“Zanubrutinib has now proven superiority to ibrutinib in both ORR (overall response rate) and PFS (progression-free survival),” in patients with relapsed/refractory (R/R) CLL or SLL, according to Jennifer R. Brown, MD, PhD, of Dana Farber Cancer Institute, who presented results of the phase 3 clinical trial known as the ALPINE study.

This was the first head-to-head comparison between zanubrutinib and ibrutinib in the treatment of relapsed/refractory CLL/SLL.

Is This Practice Changing?

When asked if the data are practice changing, Lee Greenberger, PhD, chief scientific officer at the Leukemia & Lymphoma Society, said, “I think so…These head-to-head large studies are the gold standard to see if you should use one treatment over another.”

Unfortunately, progression is expected on BTK inhibitors, according to Dr. Greenberger, as they only induce a partial response. Many people are going to relapse, he added. “The good news is that new therapies are evolving faster than patients are relapsing. So, when they do relapse, there’s a new option.”

About the ALPINE Study

The benefits of zanubrutinib were seen across all major patient subgroups, including high-risk patients. Importantly, zanubrutinib had a lower rate of treatment discontinuation and less cardiac toxicity. The study showed that zanubrutinib is more effective and better tolerated than ibrutinib as treatment for R/R CLL/SLL.

Across 15 countries, 652 patients who had received at least one prior therapy and had measurable disease were randomly divided to receive either zanubrutinib or ibrutinib, until either disease progression or unacceptable toxicity. Patient demographics – including age, sex, geographical region, disease, and mutational status – were balanced between the two groups. The median age was approximately 67 years.

Among those treated with zanubrutinib, the overall response rate was 86.2% compared with 75.7% among those treated with ibrutinib. In addition, progression-free survival (PFS) was longer in patients treated with zanubrutinib compared with ibrutinib. Specifically, the researchers found that after two years of treatment, 79% of patients taking zanubrutinib were living without cancer progression. This compares to 67% for those treated with ibrutinib.

As therapeutic options for CLL have expanded, the use of biological predictors of response to therapy have become increasingly important. In this study, such “therapeutic biomarkers” were used to form subgroups to evaluate the two drugs within higher risk patient groups with the same mutational status. One example is patients with a mutation identified as del(17p)/TP53. Another is IGHV (immunoglobulin heavy-chain variable region) gene mutational status. Progression-free survival with zanubrutinib was consistently longer in these predefined subgroups.

Overall, at the time of the current data analysis, 48 (14.7%) patients treated with zanubrutinib and 60 (18.5%) treated with ibrutinib had died.

If there were any surprises from the study, it is “the magnitude of PFS,” particularly in these high-risk groups, Dr. Brown told reporters, calling it “quite remarkable.”

“The PFS data gives me a bit more confidence when prescribing (zanubrutinib over ibrutinib, which has been) our tried and true standard of care for the past five years,” said Jerome Goldschmidt, MD, oncologist with The US Oncology Network.

Who might benefit most? “We have a lot of patients who receive BR (B-cell receptor inhibitors) or obi plus ven (obinutuzumab and venetoclax) first line for whom this is a logical next line of therapy,” said Dr. Goldschmidt.

Zanubrutinib, while approved by the U.S. Food and Drug Administration (FDA) for other blood cancers, is not yet approved for CLL. Dr. Brown said that with the latest results from the ALPINE study, the benefits are “more definitive . . . and this should filter down” into community-level practice.

The Alpine trial was sponsored by BeiGene, which makes zanubrutinib. Dr. Brown reports serving as a consultant for or receiving research funding from several companies including Beigene.

Dr. Goldschmidt reports serving as a consultant for or on the speakers bureau for several companies, Amgen, G1 Therapeutics, TG Therapeutics, AstraZeneca, and Bristol-Meyers Squibb.

Dr. Greenberger reports no relevant relationships to disclose.

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