General

General Safety

Safety Summary
Most Common AEs
Cumulative Incidence Curves
Events of Clinical Interest
Grade ≥3 infections and Richter transformation
Summary of Deaths

Safety Summary

Safety Summary¹

Safety summary after median treatment exposure of at least 36 months¹

Event	Acalabrutinib (n=266)	Ibrutinib (n=263)
Duration of treatment exposure, median (range), months	38.3 (0.3-55.9)	35.5 (0.2-57.7)
Any grade AEs	260 (97.7)	256 (97.3)
Grade ≥3 AEs	183 (68.8)	197 (74.9)
AEs leading to treatment discontinuation	39 (14.7)	56 (21.3)
Serious AEs	143 (53.8)	154 (58.6)
Deaths due to AEs^a	17 (6.4)	25 (9.5)

Note: Values are reported as n (%) unless stated otherwise.

^aIncludes deaths occurring within 30 days of last dose; deaths occurring after the start of subsequent anticancer therapy were not included in the assessment of deaths within 30 days of last dose, regardless of time after last dose.

Most Common AEs

Acalabrutinib was associated with a lower incidence of any grade diarrhea, arthralgia, hypertension, contusion, and atrial fibrillation but a higher incidence of any grade headache and cough¹

Most Common Adverse Events in ELEVATE-RR¹

	Any grade		Grade ≥3
Events, n (%)	Acalabrutinib (n=266)	Ibrutinib (n=263)	Acalabrutinib (n=266)	Ibrutinib (n=263)
Diarrhea^a^,^b	92 (34.6)	121 (46.0)	3 (1.1)	13 (4.9)
Headache^a^,^b	92 (34.6)	53 (20.2)	4 (1.5)	0
Cough^a	77 (28.9)	56 (21.3)	2 (0.8)	1 (0.4)
URTI	71 (26.7)	65 (24.7)	5 (1.9)	1 (0.4)
Neutropenia	56 (21.1)	65 (24.7)	52 (19.5)	60 (22.8)
Pyrexia	62 (23.3)	50 (19.0)	8 (3.0)	2 (0.8)
Arthralgia^a	42 (15.8)	60 (22.8)	0	2 (0.8)
Hypertension^a^,^b	23 (8.6)	60 (22.8)	11 (4.1)	23 (8.7)
Anemia	58 (21.8)	49 (18.6)	31 (11.7)	34 (12.9)
Fatigue^b	54 (20.3)	44 (16.7)	9 (3.4)	0
Nausea	47 (17.7)	49 (18.6)	0	1 (0.4)
Contusion^a	31 (11.7)	48 (18.3)	0	1 (0.4)
Pneumonia	47 (17.7)	43 (16.3)	28 (10.5)	23 (8.7)
Atrial fibrillation^a	24 (9.0)	41 (15.6)	12 (4.5)	9 (3.4)
Thrombocytopenia	40 (15.0)	35 (13.3)	26 (9.8)	18 (6.8)

Notes: Higher incidence in bold for terms with statistical differences. Includes AEs reported at ≥15% incidence (any grade) in either arm.

Among most common AEs above, grade 5 were reported in 5 (1.9%) acalabrutinib patients (pyrexia, n=1; pneumonia, n=4) and 4 (1.5%) ibrutinib patients (URTI, n=1; pneumonia, n=3).

^aBased on Barnard's exact test, two-sided P-value <0.05 without multiplicity adjustment for any grade events; ^bBased on Barnard's exact test, two-sided P-value <0.05 without multiplicity adjustment for grade ≥3 events.

Cumulative Incidence Curves

Cumulative Incidence KM Curves for Select AEs¹

Events of Clinical Interest

Events of Clinical Interest²

Events of clinical interest²

	Acalabrutinib (n=266)		Ibrutinib (n=263)
Events, n (%)	Any grade	Grade ≥3	Any grade	Grade ≥3
Cardiac events	64 (24.1)	23 (8.6)	79 (30)	25 (9.5)
Atrial fibrillation^a	25 (9.4)^b	13 (4.9)	42 (16)	10 (3.8)
Hypertension^c	25 (9.4)	11 (4.1)	61 (23.2)	24 (9.1)
Bleeding events^d	101 (38)	10 (3.8)	135 (51.3)	12 (4.6)
Major bleeding events^e	12 (4.5)	10 (3.8)	14 (5.3)	12 (4.6)
Cytopenia	108 (40.6)	78 (29.3)	113 (43)	94 (35.7)
Anemia	58 (21.8)	31 (11.7)	49 (18.6)	34 (12.9)
Neutropenia	62 (23.3)	58 (21.8)	68 (25.9)	63 (24)
Thrombocytopenia	42 (15.8)	27 (10.2)	36 (13.7)	18 (6.8)
Hepatoxicity	15 (5.6)	5 (1.9)	22 (8.4)	4 (1.5)
Infections	208 (78.2)	82 (30.8)	214 (81.4)	79 (30)
ILD/pneumonitis^d	7 (2.6)	1 (0.4)	17 (6.5)	2 (0.8)
SPMs	50 (18.8)	23 (8.6)	36 (13.7)	15 (5.7)
SPMs excluding NMSC	24 (9)	16 (6)	20 (7.6)	14 (5.3)

^aIncludes events with the preferred terms of atrial ﬁbrillation and atrial ﬂutter (a patient was only counted once if he or she experienced both types of events); atrial ﬂutter was reported in one patient in the acalabrutinib arm and two patients in the ibrutinib arm (one of the two ibrutinib patients also had an atrial ﬁbrillation event and was counted only once for the combined atrial ﬁbrillation or ﬂutter term; ^bPart of multiple testing procedure, difference in any grade incidence was -6.6% (95% CI: -12.2, -0.9), P=0.02; ^cIncludes events with the preferred terms of hypertension, blood pressure increased, and blood pressure systolic increased; two-sided p value on the basis of Barnard’s exact test without multiplicity adjustment, p=0.001 (any grade) and p=0.0214 (grade 3 or higher); ^dTwo sided p-value for any grade event comparisons <0.05 without multiplicity adjustment; ^eDefined as any hemorrhagic event that was serious, grade ≥3 in severity, or that was a central nervous system hemorrhage (any severity grade).

Grade ≥3 infections and Richter transformation

Grade ≥3 infections and Richter transformation were similar for both arms¹

Incidence of Grade ≥3 infections and Richter transformation in ELEVATE-RR¹

Difference in the Incidence of grade 3 or higher infection: p=0.8777

Summary of Deaths

Summary of Deaths²

Events, no. (%)	Acalabrutinib (n=266)	Ibrutinib (n=263)
Death	62 (23.3)^a	73 (27.8)
Primary cause of death
CLL disease progression	21 (7.9)	22 (8.4)
Richter transformation	3 (1.1)	7 (2.7)
Other^b	5 (1.9)	3 (1.1)
Unknown	5 (1.9)	8 (3.0)
Adverse event	28 (10.5)	33 (12.5)
Within 30 days of last dose	17 (6.4)	25 (9.5)
Beyond 30 days after last dose^c	11 (4.1)	8 (3.0)

^aOne patient randomized to the acalabrutinib arm died before receiving treatment and was not included in the safety population; ^bCauses of death reported as “other” included death preferred terms of respiratory failure related to bacterial pneumonia (N=1), atrial fibrillation (N=1), septic shock (bacterial) (N=1), cerebral hemorrhage (N=1), and acute respiratory failure (N=1) in the acalabrutinib arm and codeine and dihydrocodeine toxicity (N=1), heart failure (N=1), and infection complications (N=1) in the ibrutinib arm. All occurred over 30 days after the last treatment dose in both arms; ^cDeaths occurring after the start of subsequent anticancer therapy were included in the “beyond 30 days after last dose” category regardless of time after last dose.

Abbreviations

AE = adverse event

;

AEs = adverse events

;

CI = confidence interval

;

CLL = chronic lymphocytic leukemia

;

HR = hazard ratio

;

HR = heart rate

;

ILD = interstitial lung disease

;

NE = not estimable

;

NMSC = non-melanoma skin cancer

;

No. = number

;

OS = overall survival

;

RT = Richter transformation

;

SPM = second primary malignancies

;

URTI = upper respiratory tract infection

References

1. Byrd JC, Hillmen P, Ghia P, et al. First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic lymphoma [oral presentation]. Presented at: American Society of Clinical Oncology (ASCO) Virtual Annual Meeting; June 4-8, 2021. Chicago, IL. Abstract 7500.
2. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: Results of the first randomized Phase III trial. J. Clin. Oncol. 2021. https://doi.org/10.1200/JCO.21.01210.

Document ID: b5f1a3c0-28eb-4186-8709-e3ddba7b6695
Last updated: 17-April-2023