Novel Therapies for Aggressive B-Cell Lymphoma

Table 5

Targeted therapies in clinical development for the treatment of aggressive NHL. [ABC: activated B-cell-like DLBCL; CR: complete response; CRu: unconfirmed CR; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; GCB: germinal-center B-cell-like DLBCL; HDACI: histone deacetylase inhibitor; HL: Hodgkin lymphoma; Hsp: heat shock protein; mAB: monoclonal antibody; MCL: mantle cell lymphoma; mDR: median duration of response; MOA: mechanism of action; mOS: median overall survival; mPFS: median progression-free survival; mTOR: mammalian target of rapamycin; MZL: marginal zone B-cell lymphoma; NHL: non-Hodgkin lymphoma; ORR: overall response rate; OS: overall survival; PI3K: phosphatidylinositol 3-kinase; PFS: progression-free survival; PR: partial response; R: rituximab; R-CHOP: cyclophosphamide, doxorubicin, vincristine, prednisolone plus rituximab; R-ICE: rituximab, ifosfamide, carboplatin, and etoposide; RiPAD+C: bortezomib plus rituximab, doxorubicin, dexamethasone, chlorambucil; R/R: relapsed or refractory; TLR: Toll-like receptor; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor.]

Drug	MOA (target)	Eligibility	Phase	Randomized	Results
Bortezomib [127]	Proteasome inhibitor	Previously untreated DLBCL (with R-CHOP)	I/II	Dose-finding	CR/CRu: 92%
Bortezomib [128]	Proteasome inhibitor	R/R DLBCL (with chemotherapy)	II	No	ABC versus GCB: ORR: 83% versus 13%; mOS: 10.8 versus 3.4 months
Bortezomib [130]	Proteasome inhibitor	R/R indolent nonfollicular + MCL (+R)	II	No	ORR: 53%; CR: 26.5%; PR: 26.5% 2-year OS: 80%; 2-year PFS: 25%
Bortezomib [126]	Proteasome inhibitor	R/R indolent + MCL with R/bendamustine	II	No	ORR: 84%; CR/CRu: 52%
Bortezomib [131]	Proteasome inhibitor	Previously untreated MCL (RiPAD + C)	II	No	ORR: 80%; CR: 51% after 4 cycles
NPI-0052 [141]	Proteasome inhibitor	Multiple tumor types	I/II	Dose-finding	Clinical benefit observed in multiple tumor types including MCL, HL, cutaneous MZL, and FL
Everolimus [150]	mTOR inhibitor	R/R MCL	II	No	ORR: 12%
Everolimus [151]	mTOR inhibitor	R/R NHL	II	No	ORR: 30%; mDR: 5.7 months
Everolimus [152]	mTOR inhibitor	R/R NHL	I	2 dose cohorts	2 responses in DLBCL and 2 responses in FL, in 13 patients
Everolimus [149]	mTOR inhibitor	R/R MCL	II	No	ORR: 20%; mDR: 5.45 months
Temsirolimus [153]	mTOR inhibitor	R/R MCL (2 doses, compared with investigators’ choice therapy)	III	Yes	ORR: 22% (temsirolimus 175/75 mg) versus 2% (investigators’ choice); mPFS: 4.8 months (temsirolimus 175/75 mg) versus 3.4 months (temsirolimus 175/25 mg) versus 1.9 months (investigators’ choice); OS: 12.8 months (temsirolimus 175/75 mg) versus 9.7 months (investigator's choice)
Temsirolimus [154]	mTOR inhibitor	R/R MCL (with rituximab)	II	No	ORR: 59%; CR: 19%; PR: 40%
Vorinostat [167]	Deacetylase inhibitor	R/R lymphoma (with R-ICE)	I	No	19/27 responses
Vorinostat [168]	Deacetylase inhibitor	R/R lymphoma (with DOXIL)	I	Dose-finding	4/14 disease control
Oblimersen sodium [183]	Bcl-2 antisense oligonucleotide	R/R B-cell NHL (with R)	II	No	ORR: 42%; ORR in FL: 60%
PF-3512676 [209]	TLR9-antagonist	R/R NHL (with R)	I	Dose-finding	ORR: 24%; ORR in extended treatment cohort: 50%
17-AAG [216]	HSP90 inhibitor	R/R MCL or HL	II	No	ORR: 11% (all PR)
Bevacizumab [221]	Anti-VEGF mAb	Previously untreated DLBCL (with R-CHOP)	II	No	1-year PFS rate: 77%; 2-year PFS rate: 69%; 1-year OS rate: 86%; 2-year OS rate: 79%
Aflibercept [220]	VEGF fusion protein	Previously untreated B-cell lymphoma (with R-CHOP)	I	Dose-finding	ORR: 100%; CR: 80%
CAL-101 [157]	PI3K inhibitor	R/R NHL	I	No	RR: relapsed MCL: 73%;RR: refractory MCL: 40%
Valproic acid [171]	HDACI	R/R NHL	II	No	ORR: 29% (all PR)