The Evolving Role of Brentuximab Vedotin in Classical Hodgkin Lymphoma

Figures & data

Table 1 Studies That Led to FDA Approval of Brentuximab Vedotin

Study	Regimen	Patient Type (N)	F/U	ORR	CR	PFS	OS
Younes,^Citation14 Chen^Citation15 (5 year update)	BV	Relapsed/Refractory after ASCT (102)	5 years	75%	CR = 34% OS*= 64% PFS* = 52%, medians not reached	22%,* median 9.3 months	41%* median 40.5 months
Moskowitz^Citation16 (AETHERA), Moskowitz^Citation17 (5 year update)	BV	Consolidation s/p ASCT in high risk pts (329)	5 years	_	_	59%	_
	Placebo					41%
Connors^Citation32 (ECHELON-1)	BV + AVD (AAVD)	Treatment naïve Stage III-IV disease (1334)	2 years	86%	73%	82.1% (Median)	96.6%
	ABVD			83%	70%	77.2% (Median)	94.2%

Notes: *estimated, ⁺modified.

Abbreviations: N, number of cHL patients on agent of interest; F/u, follow-up time; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; CR, complete response rate; BV, brentuximab vedotin; AVD, doxorubicin+vinblastine+dacarbazine; AAVD, BV+doxorubicin+vincristine+dacarbazine; ASCT autologous stem cell transplant, pts patients.

Table 2 Recent Clinical Trials with Brentuximab Vedotin Therapy

Study	Regimen	Disease Setting (N)	F/U	CR	ORR	PFS	OS
Kumar^Citation33	BV + AVD ± RT	High risk stage II disease (30)	Median 18.8 months	90% after 2 cycles, 93% after 4 cycles, 100% of those who received RT	_	93.3% at 1 year	_
Eichenauer^Citation36	BrECADD	Advanced stage, treatment naïve (104)	17 mos.	88%	_	89%	_
	BrECAPP			94%		95%
Evens^Citation34	BV + AVD	Treatment naïve (> 60 years) (48)	2 years	36% after BV only, 90% after AVD	82% after BV only, 95% after AVD	84%	93%
Herrera^Citation48	BV + nivolumab (BN)	Relapsed/Refractory (61)	Median 7.8 mos.	61%	82%	89%*, median not reached at 6 months	_
Harker-Murray^Citation52	BN, BV + bendaumustine intensification if suboptimal response	Relapsed/Refractory (< 30 years) prior to ASCT (32)	_	64% after BN, 100% after intensification	80% after BN	_	100%
Diefenbach^Citation49	BN	Relapsed/Refractory (30)	2 years	61%	88%	68% (1-yr), median not reached	median not reached
	BV + nivolumab + ipilimumab (BNI)			73%	82%	72% (1-yr), median not reached	median not reached

Note: *estimated.

Abbreviations: N, number of cHL patients on agent of interest; F/u, follow-up; ORR, overall response rate; OS, overall survival; PFS, progression free survival; CR, complete response; SSE, significant side effects; m, modified; BV, brentuximab vedotin; AVD, doxorubicin+vinblastine+dacarbazine; BN, BV+nivolumab; BrECADD, BV+etoposide+cyclophosphamide+doxorubicin+dacarbazine+dexamethasone; BrECAPP, BV+etoposide+cyclophosphamide+doxorubicin+procarbazine+prednisone; RT, radiation therapy; pts, patients.

Table 3 Current Clinical Trials with Brentuximab Vedotin Therapy

NCT #	Regimen	Phase	Disease Setting	Estimated Enrollment	Primary Endpoint
NCT02298283 (BRAPP2)	BV consolidation after eBEACOPP and ISRT escalation	II	- supradiaphragmatic stage I-II with Deauville score >3 after 2 cycles of ABVD	40 (actual)	Two-year PFS
NCT03138499 (CheckMate 812)	BV vs BN	III	- R/R patients after ASCT or ineligible for ASCT	340	PFS up to four years
NCT03057795	BN consolidation post-ASCT	II	- high risk relapsed or refractory patients - BV naive or no progression with prior BV therapy	65	18-month PFS
NCT02758717	BN in those unsuitable for standard therapy	II	- treatment naive - age ≥ 60 or EF < 50% or DLCO < 80%, or CrCl 30–60 mL/min	75	ORR
NCT01716806	BV monotherapy vs BV + dacarbazine vs BV +bendamustine vs BV + nivolumab	II	- treatment naive - > 75 YO or > 60 YO with reduced EF or CrCl	160	ORR up to 16 months
NCT03712202	PET/CT-2 negative: BN vs ABVD+nivolumab PET/CT-2 positive: AAVD±nivolumab	II	- Treatment naïve early stage patients having received 2 lead-in cycles of ABVD followed by interval PET/CT-2	264	18-month PFS
NCT03233347	AAVD x 3 cycles → Interim PET + → BN Interim PET - → nivolumab only	II	- treatment naive non-bulky early stage patients	82	3-year PFS
NCT01703949	BV vs BN	II	- R/R patients after at least 2 cycles of BV	40	ORR
NCT03013933	BV, cyclosporine, and verapamil	I	- R/R after at least one line of therapy	39	MTD

Abbreviations: PFS, progression free survival; MTD, max tolerated dose; AE, adverse event; ORR, objective response rate; CR, complete response rate; pts, patients; r/r, relapsed/refractory; ASCT, autologous stem cell transplant; BV, brentuximab vedotin; eBEACOPP, escalated bleomycin+etoposide+ doxorubicin+cyclophosphamide +vincristine+procarbazine+prednisone; ISRT, involved site radiation therapy; ABVD, doxorubicin+bleomycin+ vincristine+dacarbazine; AAVD, BV+doxorubicin+vincristine+dacarbazine; AAV, BV+doxorubicin+vincristine; BN, brentuximab+nivolumab; PML, progressive multifocal leukoencephalopathy; PD-(L)1, programmed cell death protein 1 or programmed death-ligand 1; EF, ejection fraction; DLCO, diffusing capacity of the lung for carbon monoxide; CrCl, creatinine clearance.

Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183–2189. doi:10.1200/JCO.2011.38.041022454421

 PubMed Web of Science ®Google Scholar

Chen R, Gopal AK, Smith SE, et al. Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2016;128(12):1562–1566. doi:10.1182/blood-2016-02-69985027432875

 PubMed Web of Science ®Google Scholar

Moskowitz CH, Nademanee A, Masszi T, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853–1862. doi:10.1016/S0140-6736(15)60165-925796459

 PubMed Web of Science ®Google Scholar

Moskowitz CH, Walewski J, Nademanee A, et al. Five-year PFS from the AETHERA trial of brentuximab vedotin for Hodgkin lymphoma at high risk of progression or relapse. Blood. 2018;132(25):2639–2642. doi:10.1182/blood-2018-07-86164130266774

 PubMed Web of Science ®Google Scholar

Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. 2018;378(4):331–344. doi:10.1056/NEJMoa170898429224502

 PubMed Web of Science ®Google Scholar

Kumar A, Casulo C, Yahalom J, et al. Brentuximab vedotin and AVD followed by involved-site radiotherapy in early stage, unfavorable risk Hodgkin lymphoma. Blood. 2016;128(11):1458–1464. doi:10.1182/blood-2016-03-70347027458003

 PubMed Web of Science ®Google Scholar

Eichenauer DA, Plutschow A, Kreissl S, et al. Incorporation of brentuximab vedotin into first-line treatment of advanced classical Hodgkin’s lymphoma: final analysis of a phase 2 randomised trial by the German Hodgkin Study Group. Lancet Oncol. 2017;18(12):1680–1687. doi:10.1016/S1470-2045(17)30696-429133014

 PubMed Web of Science ®Google Scholar

Evens AM, Advani RH, Helenowski IB, et al. Multicenter phase II study of sequential brentuximab vedotin and doxorubicin, vinblastine, and dacarbazine chemotherapy for older patients with untreated classical Hodgkin lymphoma. J Clin Oncol. 2018;36(30):3015–3022. doi:10.1200/JCO.2018.79.013930179569

 PubMed Web of Science ®Google Scholar

Herrera AF, Moskowitz AJ, Bartlett NL, et al. Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2018;131(11):1183–1194. doi:10.1182/blood-2017-10-81122429229594

 PubMed Web of Science ®Google Scholar

Pro B, Advani R, Brice P, et al. Bretuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190–2196. doi:10.1200/JCO.2011.38.040222614995

 PubMed Web of Science ®Google Scholar

Diefenbach CS, Hong F, Ambinder R, et al. Extended follow-up of a phase I trial of ipilimumab, nivolumab, and brentuximab vedotin in relapased Hodgkin lymphoma: a trial of the ECOG-ACRIN Research Group (E4412). Hematol Oncol. 2019;37:(S2):123–4. doi:10.1002/hon.83_2629

 Google Scholar