First results of a head-to-head trial of acalabrutinib versus ibrutinib in patients with high-risk CLL

Ibrutinib is a novel irreversible Bruton’s tyrosine kinase inhibitor (BTKi) approved for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma. However, treatment with ibrutinib is associated with adverse events (AEs), including cardiovascular toxicities and treatment discontinuation. Acalabrutinib is a next-generation irreversible BTKi with an improved tolerability profile. The Lymphoma Hub previously reported the approval of acalabrutinib in patients with CLL. Acalabrutinib was also recently recommended for the same indication by the National Institute for Health and Care Excellence (NICE) in England.

The ELEVATE-RR trial (NCT02477696) was the first to compare two types of BTKi (acalabrutinib vs ibrutinib) in patients with CLL, and in January 2021 it was reported that acalabrutinib had met its primary endpoint. The results from this head-to-head trial were recently reported by Professor John C. Byrd at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting¹ and the Lymphoma Hub is pleased to present a summary of the key findings here.

Study design

ELEVATE-RR is a phase III randomized non-inferiority open-label trial of acalabrutinib vs ibrutinib in previously heavily treated patients with high-risk CLL with the presence of a 17p or 11q deletion and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. Patients (N = 533) were randomized to either acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily. Randomization was stratified by del17p status, ECOG performance status, and the number of prior therapies (1–3 vs ≥4).

• The primary endpoint was Independent Review Committee (IRC)-assessed progression-free survival (PFS). The secondary endpoints included incidence of all grade atrial fibrillation/flutter, Grade ≥3 infection, Richter’s transformation, and overall survival.
• When non-inferiority for the primary endpoint was met (2-sided 95% confidence interval [CI] for hazard ratio [HR]<1.429), superiority on secondary endpoints was tested at 0.05 significance level.

Baseline characteristics

The median age was 66 years and the median number of prior therapies was two. The baseline characteristics across both arms were comparable as shown in Table 1.

Table 1. Baseline characteristics*

ECOG PS, Eastern Cooperative Oncology Group performance status; IGHV, immunoglobulin heavy chain variable region; TP53, tumor protein 53. *Adapted from Byrd et al.1 †Patients with ≥3 chromosomal abnormalities.
Characteristic	Acalabrutinib (n = 268)	Ibrutinib (n = 265)
Age, median (range), years	66 (41–89)	65 (28–88)
≥75 years, %	16	16
Sex, male, %	69	73
ECOG PS score, %
0–1	92	92
2	8	8
Bulky disease ≥5 cm, %	48	51
Rai stage 3 or 4, %	49	51
Cytogenic abnormalities, %
del (17p)	45	45
del (11p)	62	66
Complex karyotype†	46	47
TP53 mutated	37	42
IGHV unmutated	82	89
Prior therapies, median (range)	2 (1–9)	2 (1–2)
1–3, %	88	89
≥4, %	12	11

Results

Efficacy

• At a median follow-up of 41 months (range, 0–59 months), acalabrutinib demonstrated non-inferiority to ibrutinib with a median PFS of 38 months in both arms (HR, 1.00; 95% CI, 0.79–1.27). IRC-assessed PFS across the prespecified subgroups in both arms was comparable, as shown in Table 2.
• Median overall survival was not attained in either arm (HR, 0.82; 95% CI, 0.59–1.15); 63 patients died in the acalabrutinib arm (24%), compared with 73 (28%) in the ibrutinib arm.
• At data cutoff (September 2020), 46% vs 41% of patients continued receiving treatment in the acalabrutinib and ibrutinib arms, respectively.
• Disease progression, including Richter’s transformation, occurred in 30% vs 26% in the acalabrutinib and ibrutinib arms, respectively.

Table 2. IRC-assessed PFS*

CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; IGHV, immunoglobulin heavy chain variable region; IRC, Independent Review Committee; PFS, progression-free survival; TP53, tumor protein 53. *Adapted from Byrd et al.1 †Randomization stratification factors. ††Patients with ≥3 chromosomal abnormalities and ≥1 structural abnormalities.
Subgroup	Number of events/patients		Hazard ratio (95% CI)
	Acalabrutinib	Ibrutinib
Age, years
<65	77/124	66/122	1.00 (0.79–1.52)
≥65	66/144	70/143	0.91 (0.65–1.27)
Sex, Male	105/185	101/194	1.06 (0.81–1.40)
ECOG at randomization†
0–1	128/248	119/244	1.03 (0.80–1.33)
2	15/20	17/21	0.64 (0.32–1.29)
No. of prior therapies
1–3	122/239	117/238	0.99 (0.77–1.27)
≥4	21/29	19/27	1.07 (0.57–2.02)
Presence of del(17p)†
Yes	76/124	72/121	1.00 (0.73–1.38)
No	67/144	64/144	1.00 (0.71–1.41)
Presence of del(11q)
Yes	85/167	79/175	1.08 (0.80–1.47)
No	58/100	57/90	0.86 (0.59–1.24)
TP53 mutation
Yes	64/100	73/112	0.95 (0.68–1.33)
No	79/167	63/153	1.11 (0.80–1.55)
IGHV
Mutated	13/44	13/28	0.60 (0.28–1.31)
Unmutated	130/220	123/237	1.09 (0.85–1.40)
Complex karyotype††
Yes	74/124	66/125	1.04 (0.74–1.44)
No	52/116	56/116	0.92 (0.63–1.35)

Safety

• Acalabrutinib was statistically superior to ibrutinib (9% vs 16%; p = 0.023) in relation to the incidence of any grade atrial fibrillation (see Table 3). The difference in the incidence rate of any grade atrial fibrillation or flutter was −6.6% (95% CI, −12.2 to −0.9; p = 0.02).
• Treatment discontinuation due to atrial fibrillation or flutter was seen in seven patients in the ibrutinib arm and none in the acalabrutinib arm.
• The cumulative incidence of any grade atrial fibrillation or flutter (HR 0.52; 95% CI, 0.32–0.86) and hypertension (HR, 0.34; 95% CI, 0.21–0.54) was lower in the acalabrutinib arm compared with the ibrutinib arm.
• Acalabrutinib also showed lower incidence of any grade hypertension (9% vs 23%), arthralgia (16% vs 23%), and diarrhea (35% vs 46%) compared with ibrutinib. However, there was a higher incidence of headache (35% vs 20%) and cough (29% vs 21%) in the acalabrutinib arm compared with the ibrutinib arm, respectively.
• The cumulative incidence of any grade bleeding (HR, 0.63; 95% CI, 0.49–0.82), diarrhea (HR, 0.61; 95% CI, 0.46–0.80), and arthralgia (HR, 0.61; 95% CI, 0.41–0.90) was lower for acalabrutinib compared with ibrutinib.
• Incidence of Grade ≥3 infections (31% vs 30%) and Richter’s transformation (4% vs 5%) was comparable for acalabrutinib and ibrutinib, respectively.
• The most common AEs included diarrhea, headache, cough, upper respiratory tract infection, arthralgia, and hypertension. Treatment discontinuation due to AEs occurred in 15% vs 21% of patients, and deaths due to AEs occurred in 6% vs 10% in the acalabrutinib and ibrutinib arms, respectively.

Table 3. Events of clinical interest*

ILD, interstitial lung disease; NMSC, nonmelanoma skin cancer; SPMs, second primary malignancies. *Adapted from Byrd et al.1 †Bold font indicates a statistically significant higher incidence. ‡Defined as any hemorrhagic event that was serious, Grade ≥3 in severity, or a central nervous system hemorrhage (any severity grade). §Included events with the preferred terms of hypertension, blood pressure increased, and blood pressure systolic increased. ‖Most common Grade ≥3 infections were pneumonia, sepsis, and urinary tract infection.
Events, %	Any grade†		Grade ≥3†
	Acalabrutinib (n = 266)	Ibrutinib (n = 263)	Acalabrutinib (n = 266)	Ibrutinib (n = 263)
Cardiac events	24	30	9	10
Atrial fibrillation/flutter	9	16	5	4
Bleeding events	38	51	4	5
Major bleeding events‡	5	5	4	5
Hypertension§	9	23	4	9
Infections‖	78	81	31	30
ILD/pneumonitis	3	7	0	1
SPMs excluding NMSC	9	8	6	5

Conclusion

The findings from this first head-to-head trial of two types of BTKi demonstrated that acalabrutinib was well tolerated in patients with previously treated CLL, including lower incidences of cardiotoxicity and discontinuation due to AEs compared with ibrutinib. The trial also demonstrated that acalabrutinib had a similar efficacy to ibrutinib.