Next-Generation Drug Challenging Imbruvica in Chronic Lymphocytic Leukemia

Less than two years after the groundbreaking Bruton tyrosine kinase (BTK) inhibitor Imbruvica (ibrutinib) gained approval for patients with chronic lymphocytic leukemia (CLL), a second-generation agent has demonstrated a 95 percent response rate and durable remissions with a favorable safety profile in a phase 1/2 study, setting the stage for a head-to-head battle between the two drugs.

Acalabrutinib (ACP-196) generated responses in a heavily pretreated population with relapsed/refractory CLL, including patients with high-risk prognostic factors. This research was presented at the 2015 meeting of the American Society of Hematology, a gathering of more than 25,000 hematologists and other hematology/oncology professionals,¹ and was 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 six patients with a PR with lymphocytosis, for a total overall response rate of 95 percent, said John C. Byrd, 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 one 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 percent.

“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 to 40 percent 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 Imbruvica. 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 B cell receptor (BCR) signaling network. “BCR signaling is incredibly important in the pathogenesis of CLL,” he said. “Targeting BTK with the first-generation irreversible inhibitor Imbruvica represents a major advance in the treatment of this disease.”

Although Imbruvica 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 Imbruvica 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 Imbruvica that does not target other kinases. Acerta Pharma, the company developing the drug, recently launched a phase 3 trial comparing acalabrutinib monotherapy with single-agent Imbruvica 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 [Imbruvica],” Byrd and colleagues wrote in their article.²

The phase 1/2 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 three prior therapies (ranging from one to 13), with 52 percent of the participants having received at least three previous treatments.

Overall, 67 percent of participants (41 patients) had stage 3/4 disease, 46 percent (28 patients) had bulky lymph nodes of at least 5 cm and 72 percent (44 patients) had cytopenia at baseline. High-risk prognostic factors included 17p deletion (31 percent), 11q deletion (29 percent) and unmutated immunoglobulin heavy-chain variable genes (75 percent).

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 one 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 an increase of at least 50 percent from baseline and above absolute lymphocyte count [ALC] of 5 K/µL) occurred in 61 percent (37 of 61) of patients and resolved in 81% (31 of 37) of these patients,” they wrote.

Most of the AEs that patients experienced during the trial were grade 1/2 severity and resolved over time. The most common treatment-related AEs (reported in at least 5 percent of patients) were headache (20 percent), an increased tendency to bruise (12 percent) and petechiae (12 percent). The most common treatment-emergent AEs (reported in at least 20 percent of patients) were headache (43 percent), diarrhea (38 percent) and increased weight (25 percent).

In the category of serious treatment-emergent AEs, there were six cases of grade 3-5 pneumonia, including the fatal case, and two cases each of grade 3 autoimmune hemolytic anemia and grade 2/3 pyrexia. There were no atrial fibrillation or major bleeding events.

“Early onset treatment-related lymphocytosis was not as significant or persistent as reported with other BCR antagonists,” Byrd said.

Notably, Byrd said, none of the patients had disease that evolved into an aggressive large cell lymphoma, which occurs in about 5 percent of patients with CLL. “Most interesting to me is that despite a median follow-up of greater than one year, we have not observed a single case of Richter’s transformation on this agent,” Byrd said.

References

1. Byrd JC, Wierda W, Jones J, et al. The Bruton tyrosine kinase (Btk) inhibitor ACP-196: marked activity in relapsed/refractory CLL with a favorable safety profile. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract 831.
2. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia [published online December 7, 2015]. N Engl J Med. doi:10.1056/NEJMoa1509981.
3. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02477696.