Acalabrutinib Shows High Response, Prolonged Survival in Ibrutinib-Intolerant R/R CLL

Bruton tyrosine kinase (BTK) inhibitor acalabrutinib (Calquence) demonstrated a high rate of response, prolonged survival, and high tolerability in patients with chronic lymphocytic leukemia (CLL) who demonstrated intolerance to ibrutinib (Imbruvica). Findings were presented at the 15th International Conference on Malignant Lymphoma.¹

Following acalabrutinib treatment, the investigator-assessed overall response rate (ORR; partial response [PR] or better) was 72% in ibrutinib-intolerant patients with relapsed or refractory (R/R) CLL; the ORR plus late partial response with lymphocytosis (PRL) was 77% (TABLE). The complete response (CR) rate was achieved by 5% of patients, 67% had a PR, 5% had PRL, and 8% had stable disease (SD). Progressive disease occurred in 2% of patients, another 2% had unknown response, and 12% were not evaluated.

Patients with dell(17p) demonstrated an ORR (≥ PR) of 71% (91% Cl, 44%-90%).

“The primary reason patients discontinued the trial was intolerance in 50% to 63% of patients,” said lead study author Kerry A. Rogers, MD, assistant professor of internal medicine in the Division of Hematology at The Ohio State University College of Medicine in Columbus.

Both ibrutinib and acalabrutinib target BTK, which plays a key role in B-cell receptor signaling and has become a well-validated therapeutic target in CLL.

“Acalabrutinib is a highly selective, potent, covalent BTK inhibitor with minimal off-target activity; given the in vitro selectivity of acalabrutinib, we hypothesized that it would be tolerable in patients with CLL who were intolerant to ibrutinib,” Rogers said.

On the heels of the conference, the FDA granted a breakthrough therapy designation to single-agent acalabrutinib for the treatment of adult patients with CLL.²The designation was given based on the results of interim analyses from 2 phase III trials: ELEVATE-TN and ASCEND.

Rogers reported findings from this phase II trial evaluating acalabrutinib in ibrutinib-intolerant patients with R/R CLL who had received ≥1 prior therapy. The study population had a median age of 70 years (range, 43-88), 63% were men, 97% had an ECOG performance score ≤1, 32% had bulky disease ≥5 cm, and 52% were Rai stage III/IV. Patients had also been treated with chemotherapy, rituximab (Rituxan), lenalidomide (Revlimid), and other agents. Regarding genetic mutations, 28% of patients had del(17p), 23% had del(11q), 79% had unmutatedIGHV, and 95% had available baseline samples that were wild-type forBTKandPLCG2(FIGURE).

Eligibility criteria required patients to have progressive disease after discontinuing ibrutinib, and treatment discontinuation was due to grade 3/4 adverse events (AEs) or persistent/recurrent grade 2 AEs. The median duration of prior ibrutinib therapy was 6 months (range, <1-55). The most commonly reported AEs leading to ibrutinib discontinuation were atrial fibrillation/flutter (25%), diarrhea (12%), arthralgia (10%), and rash (12%). The median time from the last ibrutinib dose to acalabrutinib initiation was 9.2 months (range, 0.8-31.1). Sixty patients received oral acalabrutinib at 100 mg twice daily in 28-day cycles until progressive disease or unacceptable toxicity. The primary endpoint was ORR, and key secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), time to next treatment, and safety. At a median follow-up of 19 months (range, 1-31), PFS was not reached; the 18-month rate was 73.5% (95% CI, 59.2%-83.4%). Among patients who responded to acalabrutinib, the median DOR was not reached and the 21-month rate was 77.1% (95% CI, 59.1%- 87.9%). The median OS was not reached; the 18-month rate was 89.7% (95% CI, not estimable), according to investigators.

At a median follow-up of 23 months (range, 1-36), 62% of patients remained on acalabrutinib and 80% remained on the study. Acalabrutinib discontinuations occurred in 38% of patients and were due to progressive disease (16%); AEs (12%); and patient withdrawal, investigator decision, or other (7% each). AEs leading to acalabrutinib discontinuation included pneumonia (n = 2) and diarrhea, subdural hematoma, endometrial cancer, headache, and arthralgia (n = 1).

The most common grade &ge;3 AEs occurring in &ge;5% patients with acalabrutinib were pneumonia (10%), neutropenia (8%), decreased lymphocyte count (7%), lymphocytosis (7%), and decreased platelet count and anemia (3% each).

Bleeding events occurred in 37 (62%) patients, and 2 (3%) patients had major hemorrhage. Hypertension was seen in 7 (12%) patients; 1 (2%) patient experienced it as a grade 3 event.

Eight (13%) deaths occurred on study, and of the 4 grade 5 AEs, none were considered treatment related.

&ldquo;Acalabrutinib is tolerable and effective in ibrutinib-intolerant patients; these data suggest that acalabrutinib may provide a potential strategy for retreatment with BTK inhibitor therapy after intolerance to ibrutinib,&rdquo; said Rogers.

References

1. Rogers KA, Thompson PA, Allan JN, et al. Phase 2 study of acalabrutinib in ibrutinib (IBR)-in- tolerant patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).Hematol Oncol. 2019;37(suppl 2; abstr 029). doi: 10.1002/hon.29_2629.
2. Calquence granted US breakthrough therapy designation for chronic lymphocytic leukaemia [news release]. Kenilworth, NJ: AstraZeneca; August 14, 2019. bit.ly/2MfbCja. Accessed August 14, 2019.