Acalabrutinib for relapsed or refractory CLL/SLL: Updated results of a phase II trial

On 28 January 2016, John C. Byrd (Comprehensive Cancer Center, Ohio, US) and colleagues, published in Blood a multicenter phase 1/2 study (NCT02029443)¹ demonstrating the efficacy and safety profile of acalabrutinib in patients with relapsed chronic lymphocytic leukemia (CLL). Acalabrutinib is a second-generation highly selective Bruton tyrosine kinase (BTK) inhibitor designed to improve on the safety and efficacy of ibrutinib which was the first inhibitor of BTK approved for the treatment of CLL. Although ibrutinib has demonstrated considerable efficacy in the treatment of CLL, it is also associated with toxicities which can limit its continuous use.^2,3

 Study design¹

• Phase Ib/II multicenter study in 135 patients with relapsed or refractory (R/R) CLL (n = 132) or small lymphocytic lymphoma (SLL; n = 3)
• Phase II dosing: acalabrutinib 100 mg twice daily or 200 mg once daily
• Evaluations (medical history, physical examination, and laboratory studies) were performed at screening, weekly for the first month, biweekly for the second month, monthly for the next 4 months and every 3 months thereafter
• Follow-up protocol amendment: patients who had completed at least 6 months of treatment were followed twice yearly; those who completed at least 3 years of treatment were followed once yearly
• Endpoints: overall response rate (ORR), duration of response (DOR) progression-free survival (PFS) and safety

 Patient characteristics, disposition, and exposure

• Patient baseline demographic and clinical characteristics can be seen in Table 1
• Of the 135 patients enrolled
  • 134 received ≥ 1 dose of acalabrutinib
  • 130 patients had ≥ 1 post-baseline assessment

Table 1. Baseline demographic and clinical characteristics

ANC, absolute neutrophil count; ECOG, Eastern Cooperative Oncology Group *derived at screening
Characteristic	N = 134
Median age (range), years	66 (42–85)
Age, n (%) ≥ 65 years ≥ 75 years	77 (57) 27 (20)
Male sex, n (%)	99 (74)
Diagnosis of CLL, n (%)	132 (99)
ECOG performance status, n (%) 0 1 2	48 (36) 82 (61) 4 (3)
Bulky lymph nodes, n = 133, n (%), cm in diameter ≥ 5 ≥ 10	52 (39) 10 (8)
Rai risk classification, n (%)* Low Intermediate High Missing	0 38 (28) 65 (49) 31 (23)
Median prior therapies, (range)	2 (1–13)
Cytopenia at baseline, n (%) ANC, ≤ 1500 µL Hemoglobin, ≤ 11.0 g/dL Platelet count, ≤ 100 000/ µL	92 (69) 28 (21) 43 (32) 65 (49)
Prognostic factor, n/N (%) Unmutated IGHV Chromosome 17p13.1 deletion Chromosome 11q22.3 deletion Complex karyotype, ≤ 3 abnormalities B2-microglobulin, > 3.5 mg/L	81/111 (73) 27/116 (23) 21/116 (18) 20/57 (35) 76/101 (75)

 

• In the dose-escalation portion of the study, patients received acalabrutinib at 100 (n = 9), 175 (n = 8), 250 (n = 7), and 400 mg once daily (n= 6) and 200 mg twice daily (n= 6)
• In the phase II portion of the study, patients received acalabrutinib 100 mg twice daily (n = 65) and 200 mg once daily (n = 33)
• Patients received acalabrutinib for a median of 41 months (range, 0.2–58)
• There were 26% of patients who received acalabrutinib for > 4 years and 56% that remained on treatment at data cutoff
• In total 44% of patients (n = 59) discontinued treatment, with the main reasons for discontinuation being progressive disease (PD; 21%) and adverse events (AEs;11%)
• There were 17 patients (13%) who died:
  • 10 patients due to AEs. Five patients due to pneumonia and n = 1 each for candida sepsis, congestive cardiac failure, metastatic lung adenocarcinoma, metastatic prostate cancer, and respiratory failure
  • 7 due to PD, including 2 patients with Richter’s transformation

Safety

• All patients experienced ≥ 1 AE and generally, these were mild to moderate, with the most common being
  • Diarrhea (52%)
  • Headache (51%)
  • Upper respiratory tract infection (37%)
  • Fatigue (34%)

• Grade ≥ 3 AEs (n = 89) included
  • Neutropenia (14%)
  • Pneumonia (11%)
  • Hypertension (7%)
  • Anemia (7%)
  • Diarrhea (5%)

• AEs of special interest
  • Major bleeding events (5%)
  • Atrial fibrillation (7%)
• Treatment discontinuation due to AEs occurred in 13% of patients

Efficacy

• The ORR was 94% (95% CI, 89–97%)
• Investigator-assessed best responses to acalabrutinib are presented in Table 2

 Table 2. Best response to acalabrutinib

CR, complete response; PD, progressive disease; PR, partial response; PRL, partial response with lymphocytosis † Patients did not have on-treatment assessments
	N = 134
	n/n	% (95% CI) or n (%)
ORR: CR + PR + PRL		94 (89–97)
ORR: CR + PR		88 (81–93)
Best response CR PR PRL Stable disease PD Unknown†		6 (4) 112 (84) 8 (6) 2 (1) 2 (1) 4 (3)
ORR by high-risk subgroup: CR + PR + PRL Chromosome 17p13.1 deletion Chromosome 11q22.3 deletion Unmutated IGHV Complex karyotype, ≥ 3 abnormalities	25/27 20/21 77/81 18/20	93 (76– 99) 95 (76 – 100) 95 (88 – 99) 90 (68–99)

 

• Median DOR was not reached; estimated 45-month DOR for partial response with lymphocytosis (PRL) or better was 63% (95% CI, 52–72%)
• Median time to initial PRL or better was 1.9 months (range, 1.4–43.7)
• Median time to initial PR or better was 4.7 months (range, 1.6–43.7)
• Improvement versus baseline in cytopenias: the majority of patients who were anemic, neutropenic and thrombocytopenic achieved normal values during therapy
• Median PFS was not reached; estimated 45-month PFS was 62% (95% CI, 51–71%)
• Median event-free survival (EFS) was not reached in the overall population; estimated 45-month EFS was 58% (95% CI, 48–67%)

 Conclusions

The updated results of the expanded cohort confirmed the efficacy, durability of response and long-term safety of acalabrutinib in patients with R/R CLL or SLL. Treatment with acalabrutinib resulted in a high ORR, regardless of genomic characteristics. AEs were generally mild-to-moderate. The authors’ noted that the favorable AE profile of acalabrutinib supports the combination with other therapeutics for the treatment of CLL.

Currently, there is a randomized phase III trial ongoing to compare acalabrutinib to ibrutinib in high-risk relapsed CLL (NCT02477696).