Next-Generation BTK Inhibitor Taking on Ibrutinib in CLL

Anita T. Shaffer @Shaffer1
Published: Tuesday, Dec 08, 2015

John C. Byrd, MD

John C. Byrd, MD

Less than 2 years after the groundbreaking Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica) gained approval for patients with chronic lymphocytic leukemia (CLL), a second-generation agent has demonstrated a 95% response rate and durable remissions with a favorable safety profile in a phase I/II study, setting the stage for a head-to-head battle between the 2 drugs.

Acalabrutinib (ACP-196) generated responses in a heavily pretreated population with relapsed/refractory CLL, including patients with high-risk prognostic factors, according to research presented at the 2015 ASH Annual Meeting1 and reported simultaneously in The New England Journal of Medicine.2

After a median 14.3-month follow-up, 57 of the 60 evaluable patients had achieved a partial response (PR), including 6 patients with a PR with lymphocytosis, for a total overall response rate of 95%, said John C. Byrd, MD, chair of Leukemia Research and director of the Division of Hematology at The Ohio State University Comprehensive Cancer Center, while describing the study results at the meeting.

He said remissions were durable, with only 1 case of progression, irrespective of whether patients had high-risk CLL with a 17p deletion. In fact, the response rate among the 18 patients with the deletion was 100%.

“The data are very exciting,” Byrd said in a statement. “What is particularly remarkable is how well patients are tolerating this therapy. BTK inhibitors are transforming CLL from an incurable to a chronic disease, especially considering that standard CLL therapies typically produce a 35%-40% response rate in this disease setting.”

Byrd presented the findings about the emerging BTK inhibitor a day before he was honored for his contributions to CLL research, which include leading the development of the first-in-class ibrutinib. He was honored during the conference with the 2015 William Dameshek Prize.

During his presentation on acalabrutinib, Byrd stressed the importance of inhibiting BTK, part of the BCR signaling network. “BCR signaling is incredibly important in the pathogenesis of CLL,” he said. “Targeting BTK with the first-generation irreversible inhibitor ibrutinib represents a major advance in the treatment of this disease.”

Although ibrutinib has delivered “substantial single-agent activity” in patients with relapsed and treatment-naïve CLL, it also has been associated with adverse events (AEs) including rash, diarrhea, atrial fibrillation, and major hemorrhage, Byrd and colleagues wrote in the journal article.2  This may be because ibrutinib binds to other kinases, such as EGFR, TEC, ITK, and TXK, in addition to BTK, the researchers theorize.

In acalabrutinib, investigators believe they have developed a second-generation BTK inhibitor structurally and biochemically different from ibrutinib that does not target other kinases. Acerta Pharma, the company developing the drug, recently launched a phase III trial comparing acalabrutinib monotherapy with single-agent ibrutinib that seeks to enroll an estimated 500 previously treated patients with high-risk CLL.3

“Having an alternative BTK inhibitor with more selective pharmacodynamics features for clinical use may be attractive and offers the potential opportunity to improve on the efficacy and safety observed with ibrutinib,” Byrd and colleagues wrote in their article.2

The phase I/II acalabrutinib study was a dose-escalation trial restricted to patients with relapsed/refractory CLL who had not taken prior BTK inhibitors. The patients were a median age of 62 years and had undergone a median of 3 prior therapies (range, 1-13), with 52% of the participants having received ≥3 previous treatments.

Overall, 67% of participants (n = 41) had stage III/IV disease, 46% (n = 28) had bulky lymph nodes ≥5 cm, and 72% (n = 44) had cytopenia at baseline. High-risk prognostic factors included 17p deletion (31%), 11q deletion (29%), and unmutated immunoglobulin heavy-chain variable genes (75%).

During the first phase of the trial, patients were treated with doses of 100 mg to 400 mg of acalabrutinib once daily. That changed to 100 mg twice daily in the expansion phase, which Byrd said helps maintain BTK inhibition without harmful plasma exposure.

Currently, only 8 of the 61 patients originally enrolled in the trial have discontinued treatment, with several reasons cited that included AEs, patient or investigator decision, and CLL progression in 1 case. One patient died due to pneumonia.

Additionally, all patients experienced “rapid reductions in lymphadenopathy,” Byrd and colleagues said in the conference abstract. “Treatment-related lymphocytosis (defined as ≥ 50% increase from baseline and above absolute lymphocyte count [ALC] of 5 K/µL) occurred in 61% (37/61) of patients and resolved in 81% (31/37) of these patients,” they wrote.




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