BTK Inhibitors Gain New Ground in Follicular Lymphoma

John M. Burke, MD

Articles about cars these days are often about electric vehicles (EVs), such as those from Tesla, which has dominated headlines for years, to the new darling Rivian, with its sleek offerings that cause heartbeats to race. In the EV era, an article about the Chevrolet Malibu isn’t going to garner a lot of attention.

Writing an article about Bruton tyrosine kinase (BTK) inhibitors almost feels like writing an article about the Malibu.

Not that anyone would argue that BTK inhibitors haven’t had a major impact on the treatment of hematologic malignancies in the last decade. It quickly became recognized that the lives of patients who otherwise would have died from CLL were being saved. The impact of ibrutinib (Imbruvica) and the other BTK inhibitors, acalabrutinib (Calquence) and zanubrutinib (Brukinsa), was felt beyond CLL, as these drugs demonstrated benefit in patients with marginal zone lymphoma, mantle cell lymphoma, Waldenström macroglobulinemia, primary central nervous system lymphoma, and diffuse large B-cell lymphoma.

But one disease in which BTK inhibitors seemed unlikely to have a major
impact was follicular lymphoma (FL). Yet, BeiGene announced that the FDA had accepted its supplemental new drug application for zanubrutinib in combination with obinutuzumab (Gazyva) for patients with relapsed or refractory FL. The application was based on the ROSEWOOD trial (NCT03332017) in which patients with FL who had received at least 2 prior therapies were randomly assigned to receive either the combination of zanubrutinib plus obinutuzumab
or obinutuzumab alone. Zanubrutinib clearly had activity against FL, increasing the overall response rate from 46% to 69% and the complete response rate from 19% to 39%.

In addition, combining zanubrutinib with obinutuzumab reduced the risk
of progression or death by 50% compared with obinutuzumab alone. Clearly, zanubrutinib has considerable activity in relapsed FL.

One cannot help but wonder whether the BTK inhibitors, right under our
nose for the past decade, have more activity in FL than we were previously aware of.

Years ago, I remember hearing that oncologists were using ibrutinib off label for patients with FL. At the time, I asked myself what they were thinking. Now I wonder if they were right all along. And Chevy Malibus are still getting a lot of people from one place to the next