Table 2.

Summary of FDA-approved BTK first- and second-generation inhibitors.

Compound	FDA Approved	Date of FDA	Study	Outcome	Adverse Events	CT Identifier
Ibrutinib (Imbruvica); Janssen Biotech, Inc	With Obinutuzumab for TN CLL	28 Jan,2019	Phase-3, TN 229 CLL	30-month PFS 79% (95% CI 70–85).	Grade 3–4, neutropenia, thrombocytopenia	NCT02264574 (PCYC-1130)
	With Rituximab for WM	27 Aug,2018	Phase-3, 150 WM	30-month PFS 82% (HR,0.20; P < 0.001)	diarrhea, arthralgia; AF: (12% with ibrutinib vs. 1% with Rituximab)	NCT02165397 (PCYC-1127)
	GVDH	2 Aug,2017	Phase-2, 42 GVHD	13.9-month ORR 67%	fatigue, diarrhea, muscle spasms, nausea, bruising	NCT02195869 (PCYC-1129-CA)
Acalabrutinib (ACP-196, (Calquence); AstraZeneca	With Obinutuzumab or monotherapy	21 Nov,2019	Phase-3, 535 TN CLL	HR, 95% CI, 0.006–0.17; P < 0.0001)	neutropenia, 31% vs. 11%, in acalabrutinib plus obinutuzumab vs. acalabrutinib	ELEVATE-TN (ACE-CL-007)
			Phase-3, 306 R/R CLL	HR, 0.31; 95% CI, 0.20–0.49; P < 0.0001	Calquence vs. other group AF: 5% vs. 3%; bleeding: 26% vs. 8%.	ASCEND (ACE-CL-309)
	R/R MCL, one prior therapy	31 Oct,2017	Phase-2, 124 MCL	15·2-months ORR 80%	Grade 1–2 myalgia (21%), diarrhea (31%); Grade 3–4 neutropenia (10%)	NCT02213926 (ACE-LY-004)
Zanubrutinib (Brukinsa); BeiGene Ltd.	MCL, one prior therapy	14 Nov,2019	Phase-2, 86 R/R MCL	18.4-month ORR 84%	Any grade, neutropenia (31.4%), URTI (29.1%), rash (29.1%).	NCT03206970 (BGB-3111-206)
			Phase-1/2, TN 32 MCL	18.8-month ORR 84%	Grade ≥ 3 (≥5%) were neutropenia, pneumonia, thrombocytopenia, and leukopenia	NCT02343120 (BGB-3111-AU-003)

Abbreviations: CLL, chronic lymphocytic leukemia; WM, Waldenstrom macroglobulinemia; MCL mantle cell lymphoma; GVDH, graft-versus-host disease; R/R, relapsed/refractory; ORR, overall response rate; PFS, progression-free survival; TN, treatment-naïve; HR, hazard ratio; AF, atrial fibrillation; URTI, upper respiratory tract infection.