Study design

ASPEN was a phase 3, open-label, randomised multicentre trial comparing BRUKINSA^®▼ with ibrutinib in patients with Waldenström’s macroglobulinemia (WM; Figure 1).^1,2

Figure 1. ASPEN: Study design.¹^,2

Patients

The ASPEN study enrolled patients with WM, who had relapsed/refractory (R/R) disease and had received at least one prior line of therapy, but were BTKi-naïve, or patients who were treatment-naïve and unsuitable for standard chemotherapy.¹ Patients with disease transformation, active central nervous system lymphoma, clinically significant cardiovascular disease, and patients requiring warfarin or other vitamin K antagonists were not included.¹

Stratification

For patients in Cohort 1, randomisation was stratified by warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM; CXCR4^WHIM) syndrome-like mutation status and number of prior lines of therapy.¹

Patients in Cohort 2 had wild-type MYD88 (MYD88^WT) disease or undetermined MYD88 mutation status and received BRUKINSA in a third non-randomised arm.^1,2

Key baseline characteristics

Cohort 1
Cohort 2

The key baseline characteristics for Cohort 1 are summarised below in Table 1.

Table 1. ASPEN: Baseline demographic and disease characteristics for patients in Cohort 1.¹

	R/R		TN		Overall
Characteristic	Ibrutinib (n=81)	BRUKINSA® (n=83)	Ibrutinib (n=18)	BRUKINSA® (n=19)	Ibrutinib (n=99)	BRUKINSA® (n=102)
Age, median (min, max), years Age >75 years, n (%)	69 (52, 90)  16 (20)	69 (45, 87)  27 (33)	72 (38, 89)  6 (33)	74 (50, 81)  7 (37)	70 (38, 90)  22 (22)	70 (45, 87)  34 (33)
Males, n (%)	53 (65)	58 (70)	12 (67)	11 (58)	65 (66)	69 (68)
ECOG-PS, n (%)  0/1  2	76 (94)  5 (6)	78 (94)  5 (6)	16 (89)  2 (11)	18 (95)  1 (5)	92 (93)  7 (7)	96 (94)  6 (6)
Prognostic category at study entry, n (%)*  Low  Intermediate  High	12 (15)  34 (42)  35 (43)	16 (19)  30 (36)  37 (45)	1 (6)  8 (44)  9 (50)	1 (5)  8 (42)  10 (53)	13 (13)  42 (42)  44 (44)	17 (17)  38 (37)  47 (46)
Time from initial diagnosis, median (min, max), y	5.9 (0.1, 25)	5.3 (0.1, 23)	1.7 (0.1, 17)	0.5 (0.1, 9)	4.9 (0.1, 25)	4.4 (0.1, 23)
Prior lines of therapy, median (min, max), n  0, n (%)  1–3, n (%)  >3, n (%)	1 (1, 6)  0  74 (91)  7 (9)	1 (1, 8)  0  76 (92)  7 (8)	0 (0, 0)  18 (100)  0  0	0 (0, 0)  19 (100)  0  0	1 (0, 6)  18 (18)  74 (75)  7 (7)	1 (0, 8)  19 (19)  76 (75)  7 (7)
Prior stem cell transplant, n (%)	1 (1)	3 (4)	0	0	1 (1.0)	3 (2.9)
IgM, median (min, max), g/L^†  ≥40 g/L, n (%)  <40 g/L, n (%)  Missing data, n (%)	33.4 (2.4, 108)  30 (37)  50 (62)  1 (1)	30.4 (5.8, 73)  288 (34)  55 (66)  0	36.8 (9.9, 100)  8 (44)  10 (56)  0	35.7 (8.1, 87)  8 (42)  11 (58)  0	34.2 (2.4, 108)  38 (38)  60 (61)  1 (1.0)	31.8 (5.8, 87)  36 (35)  66 (65)  0
β2-microglobulin, median, (min, max), mg/L  >3 mg/L, n (%)	4.2 (1.7, 13.6)  60 (74)	4.1 (1.6, 21.7)  62 (75)	4.1 (1.8, 10.3)  14 (78)	4.7 (2.1, 12.1)  13 (68)	4.2 (1.7, 13.6)  74 (75)	4.3 (1.6, 21.7)  75 (74)
MYD88^‡/CXCR4 genotype, n (%)  MYD88^L265P/CXCR4^WT  MYD88^L265P/CXCR4^WHIM  MYD88^L265P/CXCR4^UNK§	73 (90)  8 (10)  0	73 (88)  10 (12)  0	17 (94)  0 (0)  1 (6)	18 (95)  1 (5)  0	90 (91)  8 (8)  1 (1.0)	91 (89)  11 (11)  0
Bone marrow involvement, n (%)  Tumor cells, median (min, max), %	72 (89)  60 (0, 90)	77 (93)  60 (0, 90)	17 (94)  70 (8, 90)	19 (100)  70 (10, 90)	89 (90)  60 (0, 90)	96 (94)  60 (0, 90)
Extramedullary disease, n (%)^\|\|  Lymphadenopathy  Splenomegaly  Other^¶	58 (72)  53 (65)  10 (12)  3 (4)	64 (77)  63 (76)  14 (17)  0	15 (83)  14 (78)  3 (17)  0	17 (90)  16 (84)  3 (16)  1 (5)	73 (74)  67 (68)  13 (13)  1 (1)	81 (79)  79 (78)  17 (17)  4 (2)
Peripheral blood cytopenias  Hemoglobin ≤110 g/L, n (%)  Platelet count ≤100 x 10⁹/L, n (%)  Absolute neutrophil count ≤1.5 x 10⁹/L, n (%)	43 (53)  12 (15)  7 (9)	51 (61)  10 (12)  8 (10)	10 (56)  0  0	16 (84)  2 (11)  3 (16)	53 (54)  12 (12)  7 (7)	67 (66)  12 (12)  11 (11)

ECOS-PS, Eastern Cooperative Oncology Group performance status; maximum; min, minimum; R/R, relapse/refractory; TN, treatment naïve; WHIM, warts, hypogammaglobulinemia, infections, myelokathexis; WT, wild-type. Percentages may not add to 100% because of rounding. *Patients were assigned 1 point for each of the following baseline characteristics: age >65 years; haemoglobin ≤11.5 g/dL; platelet count ≤ 100 x 10⁹/L; β2-microglobulin level >3 mg/L; and M paraprotein levels >7.0 g/dL. Patients with a score of 0 or 1 (excepting age) were assigned to the low-risk category, those >65 years old or with a score of 2 were assigned to the intermediate-risk category. and those with a score ≥3 were assigned to the high-risk category. M-paraprotein levels were quantitated by serum protein electrophoresis. ^†Central laboratory nephelometric assessments. ^‡Three patients (all BRUKINSA treated and all TN) had second missense mutations detected within the Toll/interleukin-1 receptor (TIR) binding domain of MYD88: M232T, V217F, and P182L. Additional mutations were identified in non-TIR binding domains in 4 patients: D165del (R/R BRUKINSA patient); W91ter, G93ter (R/R ibrutinib patient); L72M (R/R BRUKINSA patient); and T107S, fs24ter (TN BRUKINSA patient). ^§Mutation testing using a next-generation sequencing method performed in a local laboratory revealed the presence of MYD88^L265P in baseline bone marrow aspirate. ^||Based on imaging studies, as assessed by independent review. Lymphadenopathy was defined as the presence of ≥1 lymph node with a long axis >1.5 cm or other extranodal lesions with a short axis >1.0 cm. Splenomegaly was defined as a spleen length (cranial to caudal) >13 cm. ^¶Three patients had discrete extranodal splenic lesions; 1 patient had 2 breast lesions. Adapted from Tam CS, et al. Blood 2020.¹

The key baseline characteristics for Cohort 2 are summarised below in Table 2.

Table 2. ASPEN: Baseline demographic and disease characteristics for patients in Cohort 2.²

Characteristic	TN (n=5)	R/R (n=23)	Overall (N=28)
Age, median (min, max), years Age >75 years, n (%)	81 (71, 87) 4 (80)	71 (39, 87) 8 (35)	72 (39, 87) 12 (43)
Male, n (%)	3 (60)	11 (48)	14 (50)
ECOG-PS, n (%) 0/1 2	4 (80) 1 (20)	20 (87) 3 (13)	24 (86) 4 (14)
Prognostic category at study entry, n (%)* Low Intermediate High	0 3 (60) 2 (40)	5 (22) 8 (35) 10 (44)	5 (18) 11 (39) 12 (43)
Time from initial diagnosis, median (min, max), years	1.5 (0.1, 12.4)	4.0 (0.5, 20.3)	3.7 (0.1, 20.3)
Prior lines of therapy, median (min, max), n 0, n (%) 1–3, n (%) 3, n (%)	0 (0, 0) 5 (100) 0 0	1 (1, 5) 0 20 (87) 3 (13)	1 (0, 5) 5 (18) 20 (71) 3 (11)
Prior stem cell transplant, n (%)	0	1 (4)	1 (4)
IgM, median (min, max), g/L^† ≥40 g/L, n (%) <40 g/L, n (%) Missing data, n (%)	36.1 (13.8, 73.4) 2 (40) 2 (40) 1 (20)	28.5 (5.6, 69.9) 6 (26) 17 (74) 0	28.5 (5.6, 73.4) 8 (29) 19 (68) 1 (4)
β2-microglobulin, median, (min, max), mg/L >3 mg/L, n (%)	3.7 (2.2, 8.1) 3 (60)	3.8 (1.7, 13.7) 17 (74)	3.8 (1.7, 13.7) 20 (71)
MYD88/CXCR4 genotype, n (%) MYD88^WT/ CXCR4^WT MYD88^WT/ CXCR4^WHIM MYD88^WT/ CXCR4^UNK MYD88^UNK/ CXCR4^UNK	5 (100) 0 0 0	18 (78) 1 (4) 2 (9) 2 (9)	23 (82) 1 (4) 2 (7) 2 (7)
Bone marrow involvement, n (%) Tumour cells, median (min, max), %	4 (80) 13 (0, 70)	22 (96) 25 (0, 90)	26 (93) 23 (0, 90)
Extramedullary disease, n (%)^‡ Lymphadenopathy Splenomegaly Other	4 (80) 4 (80) 1 (20) 0	17 (74) 16 (70) 5 (22) 0	21 (75) 20 (71) 6 (21) 0
Peripheral blood cytopenias Haemoglobin ≤110 g/L, n (%) Platelet count ≤100 x 10⁹/L, n (%) Absolute neutrophil count ≤1.5 x 10⁹/L, n (%)	3 (60) 0 1 (20)	12 (52) 3 (13) 0	15 (54) 3 (11) 1 (4)

ECOS-PS, Eastern Cooperative Oncology Group performance status; IgM, immunoglobin M; max, maximum; min, minimum; R/R, relapse/refractory; TN, treatment-naïve; WHIM, warts, hypogammaglobulinemia, infections, myelokathexis; WT, wild-type. Percentages may not total 100 due to rounding. *Patients were assigned 1 point for each of the following baseline characteristics: age, >65 years; haemoglobin ≤11.5 g/dL; platelet count ≤100 x 10⁹/L; β2-microglobulin level >3 mg/L; and M paraprotein levels >7.0 g/dL. Patients with a score of 0 or 1 (excepting age) were assigned to the low-risk category, those >65 years or with a score of 2 were assigned to the intermediate-risk category, and those with a score ≥3 were assigned to the high-risk category. M-paraprotein levels were quantitated by serum protein electrophoresis. ^†Central laboratory nephelometric assessments; n=4 for the treatment-naïve subset. ^‡Based on imaging studies, as assessment by independent review. Lymphadenopathy was defined as the presence of lymph nodes with a long axis or more than 1.5cm. Splenomegaly was defined as a spleen depth (cranial to caudal) or more than 13 cm. Adapted from Dimopoulos M, et al. Blood Adv. 2020.²

Primary endpoint

In the ASPEN study, the primary end point was the proportion of patients in Cohort 1 (MYD88^L265P) who achieved a very good partial response (VGPR) or complete response (CR), as assessed by an independent review committee (IRC).¹ The testing for the superiority of the primary endpoint required testing in the R/R analysis set prior to testing in the intention-to-treat (ITT) Analysis Set.¹

At a median follow-up of 19.4 months, 29% (24/83) of patients with R/R disease in the BRUKINSA arm, and 20% (16/81) in the ibrutinib treatment arm achieved VGPR (2-sided p=0.12; Figure 2), therefore the primary endpoint was not significant in the R/R analysis set.¹ In the ITT analysis set, a higher proportion of patients in the BRUKINSA treatment arm achieved VGPR compared with the ibrutinib arm (28% [29/102] versus 19% [19/99] respectively; 2-sided p=0.09; Figure 2).¹ This trend was also observed amongst treatment-naïve patients (26% [5/19] versus 17% [3/18] in the BRUKINSA and ibrutinib treatment arms respectively; 2-sided p=0.54). No patients in either arm of Cohort 1 achieved a CR (N=201).¹ Extended follow-up results at median 44.4 months showed that VGPR rates increased over time and were numerically higher with BRUKINSA than ibrutinib at all time points.³ VGPR rates were 36.3% with BRUKINSA and 25.3% with ibrutinib.³

Figure 2. ASPEN: Patients with IRC-assessed VGPR in BRUKINSA versus ibrutinib treatment arms in Cohort 1.¹

CI, confidence interval; CR, complete response; IRC, independent review committee; IWWM, 6th International Workshop on Waldenström Macroglobulinemia consensus; VGPR, very good partial response. *Response assessment criteria adapted from criteria established at the 6th International Workshop on Waldenström’s Macroglobulinemia. Adapted from Tam CS, et al. *Blood*. 2020.¹

Patients assigned to Cohort 2 (MYD88^WT) received BRUKINSA; after a median follow-up of 17.9 months, 27% (7/26) of patients had achieved a VGPR.² After a median follow-up of 30 months the VGPR + CR rate was 30.8% with one CR.³

Key secondary endpoints

Major response rate (MRR)

MRRs were similar between treatment groups. MRRs overall were 77% (95% CI 68, 85) and 78% (95% CI 68, 86) in the BRUKINSA and ibrutinib treatment arms respectively.¹ MRRs for treatment-naïve patients were 74% (95% CI 49, 91) and 67% (95% CI 41, 87), and for patients with R/R disease were 78% (95% CI 68, 87) and 80% (95% CI 70, 88) in the BRUKINSA and ibrutinib treatment arms respectively.¹ MRR was 50% (95% CI 30, 70) for patients in Cohort 2.²

After extended follow-up (median 44.4 months for Cohort 1 and 42.9 months for Cohort 2), MRRs were 79.8% (95% CI 70.5, 87.2) and 81.4% (95% CI 72.4, 88.4) with BRUKINSA and ibrutinib respectively in Cohort 1, and 65.4% (95% CI 44.3, 82.8) for Cohort 2.³

Progression-free survival (PFS)

After a median follow-up of 18 and 18.5 months, 15% of patients treated with BRUKINSA and 16% of patients treated with ibrutinib in Cohort 1 progressed or died, and median PFS was not reached for either arm.¹ After a median follow-up of 17.9 months, median PFS was not reached in Cohort 2.²

Based on an updated data cut-off at 30 months, the progression free-survival event-free rate by investigator assessment was 84.9% versus 77.6% for BRUKINSA versus ibrutinib respectively, with an estimated overall hazard ratio of 0.734 (95% CI: 0.380, 1.415).⁴ After extended follow-up (median 44.4 months for Cohort 1 and 42.9 months for Cohort 2) median PFS was not reached for either treatment arm in Cohort 1 and median PFS was 45.8 in Cohort 2.³

Safety

Cohort 1
Cohort 2

In Cohort 1, the most common (reported in >20% of patients) AEs among patients in the BRUKINSA treatment arm were neutropenia, upper respiratory infection, and diarrhoea (Table 3).¹The most common AEs among patients in the ibrutinib treatment arm were diarrhoea, upper respiratory infection, contusion, and muscle spasms.¹

Atrial fibrillation, diarrhoea, contusion, muscle spasms, peripheral oedema, and pneumonia were reported at ≥10% higher incidence for patients treated with ibrutinib compared with those receiving BRUKINSA.¹ Neutropenia was reported at ≥10% higher incidence for patients treated with BRUKINSA compared with those receiving ibrutinib.¹

A similar proportion of patients in each treatment arm experienced ≥1 serious AE (41 % of patients in the ibrutinib treatment arm versus 40% of patients BRUKINSA treatment arm).¹

Table 3. ASPEN: Treatment-emergent AEs for patients in Cohort 1.¹

	BRUKINSA (n=101)	#colspan#	Ibrutinib (n=98)	#colspan#
AE, n (%)	All Grades	Grade ≥3	All Grades	Grade ≥3
Non-haematological AEs
Diarrhoea*	21 (21)	3 (3)	31 (32)	1 (1)
Upper respiratory tract infection	24 (24)	0	28 (29)	1 (1)
Bruising*	13 (13)	0	23 (24)	0
Muscle spasms*	10 (10)	0	23 (24)	1 (1)
Epistaxis	13 (13)	0	19 (19)	0
Peripheral oedema*	9 (9)	0	19 (19)	0
Cough	13 (13)	0	17 (17)	0
Rash	13 (13)	0	16 (16)	0
Hypertension	11 (11)	6 (6)	16 (16)	11 (11)
Arthralgia	13 (13)	3 (3)	16 (16)	0
Fatigue	19 (19)	1 (1)	15 (15)	1 (1)
Atrial fibrillation/flutter*	2 (2)	0	15 (15)	4 (4)
Nausea	15 (15)	0	13 (13)	1 (1)
Vomiting	9 (9)	0	13 (13)	1 (1)
Fever	13 (13)	2 (2)	12 (12)	2 (2)
Pneumonia*	2 (2)	1 (1)	12 (12)	7 (7)
Headache	15 (15)	1 (1)	11 (11)	1 (1)
Urinary tract infection	10 (10)	0	10 (10)	2 (2)
Haematuria	7 (7)	0	10 (10)	2 (2)
Dizziness	13 (13)	0	9 (9)	0
Constipation	16 (16)	0	7 (7)	0
Nasopharyngitis	11 (11)	0	7 (7)	0
Extremity pain	11 (11)	1 (1)	7 (7)	0
Back pain	14 (14)	4 (4)	6 (6)	0
Dyspnea	14 (14)	0	6 (6)	0
Haematological AEs
Neutropenia*	29 (29)	19 (20)^†	13 (13)	8 (8)^†
Febrile neutropenia	4 (4)	4 (4)	0	0
Thrombocytopenia	10 (10)	6 (6)	10 (10)	3 (3)
Anaemia	12 (12)	5 (5)	10 (10)	5 (5)

AE, adverse events. Significant differences are shown in bold. *The difference in all-grade incidence between arms is ≥10%. ^†Includes the MedDRA preferred term “neutrophil count decreased” in 1 and 4 patients in the ibrutinib and BRUKINSA arms, respectively. Adapted from Tam CS, et al. Blood. 2020.¹

Figure 3. ASPEN: Dose reductions and discontinuation rates due to AEs in Cohort 1.¹

AE, adverse events.

Ibrutinib patients discontinued due to AEs: myocardial infarction, bacterial sepsis, sepsis, death, cause unspecified, drug-induced liver injury, hepatitis, interstitial lung disease, pneumonia, and pneumonitis. BRUKINSA patients discontinued due to AEs: subdural haemorrhage, cardiac arrest, neutropenia, and IgA multiple myeloma. Adapted from Tam CS, et al. *Blood*. 2020.¹

Overall, 85.7% (24/28) of patients in Cohort 2 and treated with BRUKINSA had at least one treatment-emergent AE (Table 4).²

Table 4. ASPEN: Treatment-emergent AEs for patients in Cohort 2.²

	BRUKINSA (n=28)	#colspan#
	All Grades	Grade ≥3
Event term, n (%)*
Diarrhoea	8 (29)	2 (7)
Upper respiratory tract infection	6 (21)	0
Contusion	6 (21)	0
Pyrexia	6 (21)	0
Cough	5 (18)	0
Respiratory tract infection	5 (18)	2 (7)
Pruritus	4 (14)	0
Decreased appetite	4 (14)	0
Muscle spasms	4 (14)	0
Peripheral oedema	4 (14)	0
Fatigue	4 (14)	0
Pneumonia	4 (14)	2 (7)
Urinary tract infection	4 (14)	0
Constipation	4 (14)	0
Back pain	4 (14)	0
Rash	3 (11)	1 (4)
Arthralgia	3 (11)	0
Headache	3 (11)	0
Basal cell carcinoma	3 (11)	0
Herpes zoster	3 (11)	0
Skin laceration	3 (11)	0
Hyponatremia	2 (7)	2 (7)
AEs of interest, n (%)
All infections	21 (75)	8 (29)
All haemorrhages	11 (39)	2 (7)
Major haemorrhages	2 (7)	2 (7)
Hypertension	3 (11)	3 (11)
Anaemia	6 (21)	3 (11)
Neutropenia	5 (18)^†	3 (11)^†
Thrombocytopenia	3 (11)	2 (7)
Second primary malignancies	4 (14)	0
Skin cancers	4 (14)	0

AE, adverse event. *Data are for all-grade treatment-emergent adverse events reported in ≥10% of patients or ≥5% of patients for events Grade ≥3. Events are listed in descending order of frequency by all-grade incidence. ^†Includes the MedDRA preferred term “neutrophil count decreased”. Adapted from Dimopoulos M, et al. Blood Adv. 2020.²

In Cohort 2, of 28 patients, two patients discontinued treatment due to adverse events and two patients required dose reductions.²

Patient-reported outcomes (PROs)

QoL outcomes were assessed for BRUKINSA in the ASPEN study using the patient-reported EORTC QLQ-C30 and the EQ-5D.¹ In Cohort 1, patients treated with BRUKINSA trended towards a greater improvement in most quality of life assessments, compared with ibrutinib, especially for patients who achieved VGPR, as determined by the EORTC QLQ-C30 and EQ-5D (Figure 4).^1,5

Patients treated with BRUKINSA had reduced dyspnoea and fatigue, and improved appetite, physical functioning, and role functioning in comparison with patients treated with ibrutinib.¹ The symptom subscale for diarrhoea trended better for patients treated with BRUKINSA than for patients treated with ibrutinib, which was consistent with the frequency of diarrhoea reported in the respective treatment arms.¹

Figure 4. QoL measures over time for patients treated with BRUKINSA versus ibrutinib: EQ-5D (A), and EORTC QLQ-C30 (B) values.⁵

Adapted from Tam CS, et al. *Blood.* 2020. Supplementary appendix.⁵

ED-5D, EuroQoL 5 dimensions; EORTC QLQ-C30, European Organization for the Research and Treatment of Cancer Core Quality of Life questionnaire; QoL, quality of life; VGPR, very good partial response.