Entospletinib monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia previously treated with B-cell receptor inhibitors: results of a phase 2 study

Figures & data

Table 1. Patient demographics and baseline disease characteristics.

n (%), unless otherwise indicated	Non-RT/prior BTKi (n = 33)	Non-RT/prior PI3Kδi (n = 8)	RT/prior BTKi (n = 5)	RT/prior PI3Kδi (n = 3)	Total (N = 49)
Age, median (range)	73 (53–83)	59 (44–76)	71 (59–80)	68 (63–87)	70 (44–87)
≥65 years of age	26 (78.8)	3 (37.5)	4 (80.0)	2 (66.7)	35 (71.4)
Race
White	27 (81.8)	8 (100.0)	5 (100.0)	3 (100.0)	43 (87.8)
Black	3 (9.1)	0	0	0	3 (6.1)
Race not reported	3 (9.1)	0	0	0	3 (6.1)
Ethnicity
Hispanic/Latino	1 (3.0)	1 (12.5)	0	0	2 (4.1)
Karnofsky Performance  Status ≥80	27 (81.8)	8 (100)	4 (80.0)	2 (66.7)	41 (83.7)
IGHV unmutated	27 (81.8)	5 (62.5)	4 (80.0)	2 (66.7)	38 (77.6)
TP53/Del 17p mutations	13 (39.4)	2 (25.0)	2 (40.0)	2 (66.7)	19 (38.8)
Years since initial CLL diagnosis, median (range)	7.6 (0.1–21.3)	8.0 (2.1–13.6)	7.5 (0.1–13.4)	9.6 (7.8–22.7)	7.8 (0.1–22.7)
Number of prior therapies, median (range)	3 (1–7)	3 (1–5)	3 (2–7)	6 (5–8)	3 (1–8)
Months since last prior therapy, median (range)	1.8 (0.1–12.2)	2.4 (1.3–8.7)	0.2 (0.1–7.8)	0.6 (0.2–0.9)	1.6 (0.1–12.2)
Prior BCR therapy
Ibrutinib	32 (97.0)	0	5 (100)	0	37 (75.5)
Spebrutinib	1 (3.0)	0	0	0	1 (2.0)
Idelalisib	0	7 (87.5)	0	3 (100)	10 (20.4)
Umbralisib	0	1 (12.5)	0	0	1 (2.0)

BCR: B-cell receptor; BTKi: Bruton's tyrosine kinase inhibitor; CLL: chronic lymphocytic leukemia; IGHV: immunoglobulin heavy chain variable; PI3Kδi: phosphoinositide 3-kinase inhibitor; RT: Richter's transformation.

Figure 1. Kaplan–Meier curves of progression-free survival by cohort. (A) Non-Richter’s with prior BTKi exposure. (B) Non-Richter’s with prior PI3Kδi exposure.

Table 2. ORR and PFS by reason for discontinuing prior BCR – IRC assessment.

	Non-RT/prior BTKi (n = 33)		Non-RT/prior PI3Kδi (n = 8)		RT/prior BTKi (n = 5)		RT/prior PI3Kδi (n = 3)
	Intolerant (n = 13)	PD (n = 20)	Intolerant (n = 4)	PD (n = 4)	Intolerant (n = 1)	PD (n = 4)	Intolerant (n = 0)	PD (n = 3)
ORR, n (%)	4 (30.8)	4 (20.0)	3 (75.0)	3 (75.0)	1 (100.0)	1 (25.0)	n/a	0
90% CI	11.3–57.3	7.1–40.1	24.9–98.7	24.9–98.7	5.0–100.0	1.3–75.1		0.0–63.2
PFS rate at week 16, %	90	46	100	100	100	0	n/a	50
(95% CI)	(47.3, 98.5)	(21.5, 67.6)	(NR, NR)	(NR, NR)	(NR, NR)	(NR, NR)		(0.6, 91)
PFS, months	8.2	3.7	NR	11.1	5.6	2.4	n/a	4.6
(95% CI)	(3.7, NR)	(1.9, 5.6)	(5.2, NR)	(5.6, NR)	(NR, NR)	(2.4, 3.5)		(1.0, 8.3)

n/a: not applicable; BCR: B-cell receptor; BTKi: Bruton's tyrosine kinase inhibitor; CI: confidence interval; IRC: independent review committee; NR: not reached; ORR: objective response rate; PD: progressive disease; PI3Kδi: phosphoinositide 3-kinase inhibitor; PFS: progression-free survival; RT: Richter's transformation.

Figure 2. Best percent change from baseline in tumor size (sum of the product of the diameters [SPD] of nodal or tumor mass).

Table 3. Treatment-emergent adverse events.

n (%)	Non-RT/prior BTKi (n = 33)	Non-RT/prior PI3Kδi (n = 8)	RT/prior BTKi (n = 5)	RT/prior PI3Kδi (n = 3)	Total (N = 49)
AEs, any grade	33 (100)	8 (100)	5 (100)	3 (100)	49 (100)
Most common AEs (≥15% in overall population)
Fatigue	21 (63.6)	4 (50.0)	2 (40.0)	0	27 (55.1)
Diarrhea	15 (45.5)	7 (87.5)	2 (40.0)	0	24 (49.0)
Anemia	15 (45.5)	1 (12.5)	2 (40.0)	0	18 (36.7)
Nausea	10 (30.3)	3 (37.5)	1 (20.0)	1 (33.3)	15 (30.6)
Constipation	8 (24.2)	1 (12.5)	1 (20.0)	0	10 (20.4)
Cough	10 (30.3)	0	0	0	10 (20.4)
Upper respiratory tract infection	7 (21.2)	2 (25.0)	0	1 (33.3)	10 (20.4)
Dizziness	6 (18.2)	3 (37.5)	0	0	9 (18.4)
Decreased appetite	5 (15.2)	2 (25.0)	1 (20.0)	0	8 (16.3)
Pyrexia	6 (18.2)	1 (12.5)	1 (20.0)	0	8 (16.3)
AEs related to entospletinib	25 (75.8)	6 (75.0)	2 (40.0)	1 (33.3)	34 (69.4)
AEs ≥ grade 3	24 (72.7)	5 (62.5)	3 (60.0)	2 (66.7)	34 (69.4)
Most common AEs ≥ grade 3 (≥5% in overall population)
Anemia	9 (27.3)	0	2 (40.0)	0	11 (22.4)
Neutropenia	5 (15.2)	2 (25.0)	0	0	7 (14.3)
Fatigue	5 (15.2)	0	0	0	5 (10.2)
Dehydration	2 (6.1)	1 (12.5)	0	0	3 (6.1)
Sepsis	2 (6.1)	0	1 (20.0)	0	3 (6.1)
Stomatitis	2 (6.1)	1 (12.5)	0	0	3 (6.1)
Thrombocytopenia	3 (9.1)	0	0	0	3 (6.1)

AEs: adverse events; BTKi: Bruton's tyrosine kinase inhibitor; PI3Kδi: phosphoinositide 3-kinase inhibitor; RT: Richter's transformation.