ORLANDO, FL—The second-generation BTK inhibitor acalabrutinib (ACP-196) can elicit durable partial responses in patients with chronic lymphocytic leukemia (CLL) while producing minimal side effects, according to researchers.
They said data suggest that, compared to the first-generation BTK inhibitor ibrutinib, acalabrutinib more selectively blocks the BTK pathway.
And it does so without disrupting other molecular pathways that are important for preserving platelet and immune function, thereby avoiding or minimizing certain side effects.
John C. Byrd, MD, of The Ohio State University Comprehensive Cancer Center in Columbus, and his colleagues reported data from an ongoing phase 1/2 trial of acalabrutinib in NEJM and at the 2015 ASH Annual Meeting (abstract 831). The study was sponsored by Acerta Pharma.
The researchers reported on 61 patients with relapsed CLL. They had a median age of 62 (range, 44-84) and a median of 3 prior therapies (range, 1-13).
Most patients had an ECOG performance status of 1 (59%) or 0 (36%). Most had high-risk (67%) or intermediate-risk disease (31%) according to Rai classification. Forty-six percent of patients had lymph nodes ≥ 5 cm in diameter, and 5% had lymph nodes ≥ 10 cm.
Seventy-five percent of patients had unmutated immunoglobulin variable-region heavy-chain gene, 31% had 17p deletion, 29% had 17q deletion, and 81% had β2-microglobulin > 3.5 mg/liter.
Patients enrolled in the phase 1 portion of the study received escalating doses of acalabrutinib, with a maximum dose of 400 mg once daily. Patients involved in the phase 2 portion of the study were treated with a 100 mg dose twice daily.
Adverse events and discontinuation
At a median follow-up of 14.3 months (range, 0.5 to 20), 53 patients are still receiving treatment.
The primary reasons for treatment discontinuation were investigator or patient decision (n=2), active autoimmune hemolytic anemia that required additional therapy (n=1), fatal pneumonia (n=1), CLL progression, and adverse events of diarrhea (n=1), gastritis (n=1), and dyspnea (n=1).
The most common adverse events of all grades (occurring in at least 20% of patients) were headache (43%), diarrhea (39%), increased weight (26%), pyrexia (23%), upper respiratory tract infection (23%), fatigue (21%), peripheral edema (21%), hypertension (20%), and nausea (20%).
Grade 3/4 adverse events included diarrhea (2%), increased weight (2%), pyrexia (3%), fatigue (3%), hypertension (7%), and arthralgia (2%).
Response
The overall response rate among the 60 evaluable patients was 95%. This included partial responses in 85% of patients and partial responses with lymphocytosis in 10%. The rate of stable disease was 5%.
The researchers noted that responses occurred in all dosing cohorts, and the response rate increased over time.
All 18 patients with 17p deletion experienced a partial response (89%) or partial response with lymphocytosis (11%). But 1 of these patients later progressed.
All 4 patients who previously received idelalisib responded to acalabrutinib, with partial responses in 75% and partial responses with lymphocytosis in 25%.
There were no cases of Richter’s transformation.
In all, 1 patient experienced progression at 16 months, and 1 patient died of pneumonia at 13 months.
“This data is very exciting because it illustrates that acalabrutinib is a highly potent and selective oral BTK inhibitor that can be given safely in patients with relapsed CLL,” Dr Byrd said. “What is particularly remarkable is how well patients are tolerating this therapy.”
Clinical trials of acalabrutinib in CLL are ongoing, including a phase 3 head-to-head comparison of ibrutinib and acalabrutinib.
