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An investigational, third-generation Bruton tyrosine kinase (BTK) inhibitor yielded impressive response rates in heavily pretreated patients with B-cell malignancies, even those with prior exposure to the class of drugs, a phase I/II study showed.

In 139 evaluable patients with chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) -- the study's largest cohort -- the overall response rate (ORR) with various pirtobrutinib doses reached 63% (95% CI 55-71), reported Anthony Mato, MD, of Memorial Sloan Kettering Cancer Center in New York City, and colleagues in the .

And ORRs in this subgroup were similar regardless of prior treatment exposure:

• Prior BTK inhibition: 62% (95% CI 53-71)
• Prior BCL2 inhibition: 65% (95% CI 50-78)
• Prior PI3K inhibition: 60% (95% CI 41-77)
• Prior BTK/BCL2: 64% (95% CI 49-78)

"Across the board, no matter how you look at the patient population, even patients who had failed five prior classes of therapy, you see response rates that are quite similar," Mato told 番茄社区app during an expert roundtable discussion following the 2020 American Society of Hematology, where the data were first presented.

"It's early data, but I think what's unique here is this is the first prospective data for a BTK inhibitor following another BTK inhibitor in the setting of progression where we see, across a large patient population, pretty significant activity and durable remissions," said Mato.

ORRs were 52% (95% CI 38-65) in patients with mantle cell lymphoma (MCL) and 68% (95% CI 44-87) in a small subset with Waldenström macroglobulinaemia, with nearly identical levels of activity for those previously treated with a BTK inhibitor. Four of eight patients with follicular lymphoma responded to the drug as well.

"I've also worked with this drug, and even before we had the data it was pretty clear to me that it's a very highly active and very well-tolerated drug," Jennifer Brown, MD, of Dana-Farber Cancer Institute in Boston, said during the roundtable talk.

Currently available BTK inhibitors -- ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa) -- are all covalent and irreversible inhibitors and are highly active, but patients often develop resistance mutations at the drugs' C481 binding site.

In this regard, pirtobrutinib offers particular advantages, said Jean-Marie Michot, MD, and Vincent Ribrag, MD, both of Gustave Roussy in France, in an .

"First, the selectivity of the drug on BTK appears to be increased; however, full pharmacological data would be interesting for the detailed kinase activities," they wrote. "Second, this class does not bind BTK to the C481 residue, and the efficacy of the drug is therefore not affected by mutations in the BTK binding site. These two properties offer additional potential therapeutic activity and avoid off-target toxicities."

ORRs with pirtobrutinib were similar in the CLL/SLL subgroup whether patients had or did not have C481 mutations (71% vs 66%, respectively).

The so-called BRUIN study evaluated various doses of pirtobrutinib (formerly LOXO-305) in 323 patients with B-cell malignancies, including 170 with CLL/SLL, 61 with MCL, 26 with Waldenström macroglobulinemia, and 66 with other hematologic malignancies. In the phase I portion, doses ranged from 25 mg to 300 mg once per day, with no dose-limiting toxicities found. The phase II dose was 200 mg.

Across cancer types, patients had a median of three prior lines of treatment: 76% had previous exposure to an earlier-generation BTK inhibitor, 87% had received chemotherapy, 94% an anti-CD20 antibody, and 25% had received a BCL2 inhibitor such as venetoclax (Venclexta). Some patients had also received PI3K inhibitors, lenalidomide (Revlimid), and transplant or cellular therapies.

Common adverse events (AEs) of any grade included fatigue (20%), diarrhea (17%), and contusion (13%). Grade 3/4 AEs included neutropenia in 10%, anemia in 4%, fatigue and headache in 1% each, as well as abdominal pain, dyspnea, constipation, and pyrexia each in less than 1% of patients.

There were no grade 3/4 cases of atrial fibrillation (1% overall) or flutter observed, a concern with previous-generation BTK drugs, and only 1% of patients stopped treatment due to toxicity.

Michot and Ribrag noted that there were few infections reported in the study, and no severe infections.

"As a powerful inhibition of BTK could theoretically affect the anti-infectious defences in humans, the results of a prolonged follow-up will be interesting to scrutinise, specifically in terms of the effects on the immune system and infection," the editorialists wrote.

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