ASH 2021: BTK Inhibitors and CLL Clinical Trials

Two Doctors Share Their ASH Conference CLL Research Highlights

Promising results from clinical trials focusing on Bruton’s tyrosine kinase (BTK) inhibitors and new treatment combinations are just some of the advances in chronic lymphocytic leukemia (CLL) presented at the American Society of Hematology (ASH) Annual Meeting & Exposition. Anthony Mato, MD, MSCE, director of the CLL program at the Memorial Sloan Kettering Cancer Center in New York City, and Kerry Rogers, MD, a hematologist-oncologist at The Ohio State University Comprehensive Cancer Center in Columbus, share their conference highlights below.

SEQUOIA Trial Results

Currently, CLL patients may receive the originally approved BTK inhibitor, ibrutinib (Imbruvica), or a second-generation BTK inhibitor, acalabrutinib (Calquence). One clinical trial at ASH, the SEQUOIA study, tested whether CLL patients could benefit from another BTK inhibitor, zanubrutinib (Brukinsa). This drug was previously approved by the U.S. Food and Drug Administration (FDA) for patients with other types of blood cancer, but not for CLL.

BTK inhibitors are targeted therapies that bind and inhibit a protein that can drive the growth of certain blood cancers. Similar to ibrutinib, zanubrutinib irreversibly attaches to the BTK protein. However, zanubrutinib is more selective in its binding of BTK than ibrutinib, and it is less likely to interfere with other proteins.

For the SEQUOIA study, researchers tested zanubrutinib in patients who had not yet received treatment for their CLL. Participants were required to either be 65 or older, or deemed ineligible for an aggressive chemoimmunotherapy regimen consisting of fludarabine (Fludara), cyclophosphamide (Cytoxan or Neosar), and rituximab (Rituxan). This combination is known as FCR, which is sometimes used for patients who are younger or have stronger immune systems.

Patients were randomly assigned to either receive zanubrutinib or a less intensive chemoimmunotherapy regimen consisting of bendamustine (Bendeka and Treanda) and rituximab. Results showed that patients who received zanubrutinib were likely to survive longer without disease progression than those who got the chemoimmunotherapy combination. After two years, around 86% of patients who got zanubrutinib had not had cancer progression, compared with 70% of those who underwent chemoimmunotherapy.

In general, the safety profile was comparable to that seen in other trials of zanubrutinib. Notably, though, researchers saw fewer cardiovascular events among patients taking zanubrutinib than they had in previous trials with ibrutinib. Dr. Rogers said that the reduction in cardiovascular risk with zanubrutinib relative to ibrutinib would be important for patients.

“This is the trial that will potentially lead to the [FDA] approval of zanubrutinib,” said Dr. Mato, adding that having another BTK inhibitor widely available to patients could ultimately be “transformative.”

BRUIN Trial Results

Meanwhile, an early-phase trial showed that a new type of BTK inhibitor, pirtobrutinib (LOXO-305), has promising activity in patients with CLL whose cancer is resistant to the approved BTK inhibitors ibrutinib and acalabrutinib. These previously-approved BTK inhibitors, which are covalent inhibitors, work by irreversibly sticking to the BTK protein and blocking its ability to promote cell growth. But mutations in the BTK gene can prevent these drugs from binding to the BTK protein, making the cancer resistant to the treatment. To get around that type of drug resistance, researchers have developed pirtobrutinib, which is a noncovalent BTK inhibitor that reversibly binds to the protein, even when the covalent inhibitors no longer can.

Now, the early phase 1/2 BRUIN study showed encouraging results for pirtobrutinib in patients with CLL who have already tried multiple other treatments, including covalent BTK inhibitors. The researchers found that 63% of CLL patients in the trial responded to the treatment, and that the response rate remained similarly high when looking at patients who had been previously treated with a BTK inhibitor.

“It was well-tolerated, active, and addresses an unmet need, which is resistance to covalent BTK inhibitors, as well as progression of disease and intolerance to several other lines of therapy,” said Dr. Mato, the primary author of the presentation.

“It’s remarkable that the response rates among the prior treatment groups are very similar – in the 60s – and that it seems to work in all these different subgroups,” said Dr. Rogers, who was not involved with the study. “I expect that pirtobrutinib will continue to be a drug that advances and hopefully becomes available as a standard of care in the future if it continues to look as good as it does now.”

GAIA Trial Results

Venetoclax (Venclexta) is approved to treat CLL in combination with obinutuzumab (Gazyva), and in combination with rituximab. The phase 3 randomized GAIA trial evaluated the efficacy and safety of these combinations, as well as a novel combination of three drugs in fit CLL patients who have not received prior therapy. Participants could also receive chemoimmunotherapy. In practice, BTK inhibitor therapy has been replacing chemoimmunotherapy in fit CLL patients as the standard of care. However, the GAIA trial provided the first set of data on use of the therapies in these patients.

Patients were only able to enroll in the trial if they did not have TP53 mutations, which are present at diagnosis in less than 10% of CLL patients and are associated with a greater risk of aggressive disease.

Compared to patients receiving chemoimmunotherapy, those on a regimen of venetoclax plus obinutuzumab, venetoclax plus rituximab, or venetoclax plus obinutuzumab and ibrutinib were significantly more likely to have undetectable minimal residual disease (MRD) at fifteen months. Patients are said to have undetectable MRD when the number of remaining cancer cells in the body is so small that tests for the disease turn out negative. Response rates in the groups treated with a venetoclax-obinutuzumab combination were fairly similar.

“Although there was a numerically higher response rate in the venetoclax, obinutuzumab, and ibrutinib arm, I think longer follow up is needed to really determine which regimen might be more effective in terms of progression-free survival down the line,” Dr. Rogers said.

Patients treated with venetoclax plus obinutuzumab and ibrutinib reported more side effects than those who received other combinations.

“It looked to me that adding a third drug to obinutuzumab and venetoclax appeared to add significant toxicity without any obvious clinical benefit,” Dr. Mato said. “I walked away thinking obinutuzumab and venetoclax is still the standard of care.”

Neither Dr. Mato nor Dr. Rogers found the results surprising, but “it’s the first time these regimens have been compared directly,” Dr. Mato said.

See Our Sources:

• 63^rd American Society of Hematology Annual Meeting & Exposition (2021). “Zanubrutinib in Combination with Venetoclax for Patients with Treatment-Naïve (TN) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with del(17p): Early Results from Arm D of the SEQUOIA (BGB-3111-304) Trial”

• 63^rd American Society of Hematology Annual Meeting & Exposition (2021). “A Randomized Phase III Study of Venetoclax-Based Time-Limited Combination Treatments (RVe, GVe, GIVe) Vs Standard Chemoimmunotherapy (CIT: FCR/BR) in Frontline Chronic Lymphocytic Leukemia (CLL) of Fit Patients: First Co-Primary Endpoint Analysis of the International Intergroup GAIA (CLL13) Trial”

• 63^rd American Society of Hematology Annual Meeting & Exposition (2021). “Pirtobrutinib, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL/SLL: Updated Results from the Phase 1/2 BRUIN Study”