Table 2 Vital clinical trial data for the application of BTK inhibitors in hematological malignancies

CLL

Ibrutinib

2

132

TN: 60 (92%)

R/R: 60 (44%)

TN: 60 (92%)

R/R: 60 (60%)

TN: 29%

R/R: 10%

89%

60

PCYC-1102/1103

–

NCT01105247, NCT01109069 [139]

R/R CLL

Ibrutinib

2

144

24 (63%)

24 (75%)

10%

83%

27.6

RESONATE-17

–

NCT01744691 [126]

TN CLL

Ibrutinib

3

363

47.8 months

–

–

–

31

CLL12

–

NCT02863718 [140]

R/R CLL

a. Ibrutinib

b. Rituximab

3

160

8.3 (74% vs. 11.9%)

NR vs. 26.1 months

3.8% vs. 0%

53.8% vs. 7.4%

17.8

–

82.7% vs. 59.6%

NCT01973387 [136]

TN CLL

a. Ibrutinib

b. Chlorambucil

3

267

18 (90% vs. 52%)

24 (98% vs. 85%)

4% vs. 2%

86% vs. 35%

18.4

RESONATE-2

–

NCT01722487 [133]

R/R CLL

a. Ibrutinib

b. Ofatumumab

3

391

44.1 vs. 8.1 months

67.7 vs. 65.1 months

11% (a)

91% (a)

65.3

RESONATE

57% vs. 47%

NCT01578707 [129, 130]

CLL

a. IR

b. FCR

3

529

36 (89.4% vs. 72.9%)

36 (98.8% vs. 91.5%)

17.2% vs. 30.3%

95.8% vs. 81.1%

70

E1912

73.0% vs. 83.5%

NCT02048813 [137, 141]

TN CLL

a. BR

b. Ibrutinib

c. IR

3

547

24 (74% vs. 87% vs. 87%)

24 (95% vs. 90% vs. 94%)

26% vs. 7% vs. 12%

81% vs. 93% vs. 94%

38

–

Hematologic: 61% vs. 41% vs. 39%

Non-hematologic: 63% vs. 74% vs. 74%

NCT01886872 [138]

TN CLL

IV

2

164

30 (≥ 95%)

–

46%

97%

31.3

CAPTIVATE

–

NCT02910583 [142]

TN CLL

IV

2

80

36 (93%)

36 (96%)

75% of uMRD

–

38.5

60%

NCT02756897 [143, 144]

R/R CLL

IV

2

230

–

–

53%

83%

–

VISION

57%

NCT03226301 [145]

R/R CLL

IV

2

53

21.1 (98%)

21.1 (100%)

51%

89%

21.1

CLARITY

–

EudraCT 2015–003,422-14

ISCRTN13751862[146]

CLL

IV + obinutuzumab

2

50

NR

NR

28%

TN: 84%

R/R: 88%

TN: 24.2

R/R: 21.5

–

66%

NCT02427451 [147]

R/R CLL

a. Ibrutinib + ublituximab

b. ibrutinib

3

224

NR vs. 35.9 months

–

19% vs. 5%

83% vs. 65%

41.6

GENUINE

76% vs. 83%

NCT02301156 [148]

TN CLL

Ibrutinib + fludarabine

2

29

24 (91.3%)

24 (95.8%)

44.4%

93.1%

29

–

–

NCT02514083 [149]

TN CLL

(a) Ibrutinib/(b). chlorambucil + obinutuzumab

3

229

30 (79% vs. 31%)

86% vs. 85%

19% vs. 8%

88% vs. 73%

31.3

iLLUMINATE

58% vs. 35%

NCT02264574 [150]

TN CLL

Ibrutinib + obinutuzumab

2

135

36 (95.7%)

36 (98%)

73.3%

–

36.7

ICLL07 FILO

58%

NCT02666898 [151, 152]

R/R CLL

a. Ibrutinib + BR

b. BR

3

578

65.1 vs 14.3

60 (75.7% vs. 61.2%)

40.8% (a)

87.2% vs 66.1%

63.7

HELIOS

77% vs. 74%

NCT01611090 [153, 154]

CLL

Ibrutinib + bendamustine + ofatumumab

2

66

15 (94%)

15 (97%)

6%

92%

–

CLL2-BIO

72%

NCT02689141 [155]

TN CLL

Acalabrutinib

2

99

48 (96)

NR

7

97

53

ACE-CL-001

38%

NCT02029443 [156]

R/R CLL

Acalabrutinib

2

134

45 (62%)

–

4%

94%

41

ACE-CL-001

66%

NCT02029443 [157, 158]

R/R CLL

a. Acalabrutinib

b. Ibrutinib

3

533

38.4 vs. 38.4 months

NR

–

77% vs. 81%

40.9

ELEVATE-RR

68.8% vs. 74.9%

NCT02477696 [96]

TN CLL

a. AO

b. Acalabrutinib

c. Obinutuzumab + chlorambucil

3

535

48 (87% vs. 77.9% vs. 25.1%)

48 (92.9% vs. 87.6% vs. 88.0%)

30.7% vs. 11.2% vs. 13.0%

96.1% vs. 89.9% vs. 82.5%

46.9

ELEVATE-TN

70.2% vs. 49.7% vs. 69.8%

NCT02475681 [159, 160]

R/R CLL

a. acalabrutinib; b. idelalisib plus rituximab or BR

3

310

12 (88% vs. 68%)

12 (94% vs. 91%)

–

81% vs. 75%

16.1

ASCEND

29% vs. 56% (IR) vs. 26% (BR)

NCT02970318 [161]

TN CLL

AO + venetoclax

2

37

NR

NR

38%

100%

27·6

–

–

NCT03580928 [162]

CLL

AO

1b/2

45

TN: 39 (94.4%); R/R: 42 (72.7%)

TN: 39 (100%);

R/R: 42 (82%)

TN: 32%

R/R: 8%

TN: 95%

R/R: 92%

TN: 39% R/R: 42%

–

Naïve: 63%

R/R: 77%

NCT02296918 [117]

R/R CLL

Zanubrutinib

2

91

–

12 (95.6)

3.3

84.6

15.1

–

75.8

NCT03206918 [163]

TN CLL

Zanubrutinib

3

109

18 (88.6%)

18 (95.1%)

3.7%

94.5%

18.2

SEQUOIA

48.6%

NCT03336333[164]

TN CLL

Zanubrutinib + obinutuzumab + venetoclax

2

39

–

–

57%

100%

25.8

–

–

NCT03824483[165]

R/R CLL

Pirtobrutinib

1/2

323

–

–

–

62%

6

BRUIN

13%

NCT03740529 [83]

R/R CLL

a. Tirabrutinib

b. TI

c. TE

1b

53

–

–

7% vs. 7% vs. 10%

83% vs. 93%. vs. 100%

15.5 vs 34 vs. 30.4

–

24.5%

NCT02457598 [166]

R/R MCL

Ibrutinib

2

111

24 (31%)

24 (47%)

23%

67%

26.7

PCYC-1104-CA

–

NCT01236391 [167, 168]

R/R MCL

IR

2

50

36 (87%

36 (94%)

71%

96%

45

–

–

NCT01880567 NCT02427620[169, 170]

Indolent MCL

IR

2

50

36 (93%)

36 (92%)

80%

84%

36

IMCL-2015

–

NCT02682641 [171]

TN MCL

IR + R-HCVAD

2

131

36 (79%)

36 (95%)

87%

98%

42

WINDOW-1

–

NCT02427620 [172]

TN MCL

a. Ibrutinib + BR

b. BR

3

523

80.6 vs 52.9

84 (55.0% vs. 56.8%)

65.5% vs. 57.6%

89.7% vs. 88.5%

84.7

SHINE

81.5% vs. 77.3%

NCT01776840 [173]

R/R MCL

IV

2

24

18 (57%)

18 (57%)

62%

71%

15.9

AIM

58%

NCT02471391 [174]

R/R MCL

IR + lenalidomide

2

50

16

22

56%

76%

17·8

PHILEMON

–

NCT02460276 [175]

R/R MCL

a. Ibrutinib

b. Temsirolimus

3

280

14∙6 vs. 6.2

30.3 vs. 23.5

23% vs 3%

77% vs. 47%

38.7

RAY

68% vs. 72%

NCT01646021 [176]

R/R MCL

Acalabrutinib

2

124

24 (49%)

24 (72.4%)

43%

81%

26

ACE-LY-004

39%

NCT02213926[177, 178]

R/R MCL

Zanubrutinib

2

86

36 (47.6%)

36 (74.8%)

77.9%

83.7%

35.3

BGB-3111–206

57%

NCT03206970[179, 180]

R/R WM

Ibrutinib

2

63

60 (54%)

60 (87%)

79.4%

90.5%

59

–

30.2%

NCT01614821 [181, 182]

R/R WM

Ibrutinib

3

31

18 (86%)

18 (97%)

71%

90%

18·1

–

65%

NCT02165397 [183]

TN WM

Ibrutinib

2

30

48 (76%)

100%

87%

100%

50

–

–

NCT02604511 [184, 185]

WM

a. IR

b. Rituximab

3

150

54 (68% vs. 25%)

54 (86% vs. 84%)

76% v 31%

92% vs. 44%

50

PCYC-1127

60%

NCT02165397 [186, 187]

WM

a. Ibrutinib

b. Zanubrutinib

3

201

18 (85% vs. 84%)

18 (93% vs. 97%)

78% vs. 77%

–

19.4

ASPEN

63% vs. 58%

NCT03053440 [97]

WM

Acalabrutinib

2

122

24 (TN: 90%; R/R: 82%)

24 (TN: 92%; R/R: 89%)

MYD88^L265P: 78%; MYD88^WT: 57%

93%

27·4

–

53%

NCT02180724 [188]

DLBCL

Ibrutinib

1/2

80

1.64 months

6.41 months

ABC: 16%

ABC: 37%; GCB: 5%

ABC: 10.12; GCB: 17.05

–

–

NCT00849654 NCT01325701 [189]

R/R MZL

Ibrutinib

2

63

15.7 months

33 (72%)

10%

58%

33.1

PCYC-1121

44%

NCT01980628 [190, 191]

R/R MZL

Zanubrutinib

2

68

15 (82.5%)

15 (92.9%)

25.8%

74.2%

15.7

MAGNOLIA

39.7%

NCT03846427 [192]

R/R PCNSL

Tirabrutinib

1/2

44

2.9 months

NR

–

63.6%

9.1

–

–

JapicCTI-173646 [193]

R/R PCNSL

Ibrutinib

2

52

4.8 months

19.2 months

19%

70%

25.7

–

–

NCT02542514 [194]

TN FL

IR

2

80

30 (65%–67%)

30 (97%–100%

40%–50%

75%–85%

29–34

PCYC-1125-CA

64%

NCT01980654 [195]