Trial watch: bispecific antibodies for the treatment of relapsed or refractory large B-cell lymphoma

Figures & data

Figure 1. Mechanism of action of antiCD20 and antiCD3 bispecific antibodies. Mosunetuzumab, IgG1 ab with a rituximab-like antiCD20 domain; epcoritamab, IgG1 ab with an ofatumumab-like antiCD20 domain; glofitamab, IgG1 ab with a ratio 2:1 CD20:CD3 and an obinutuzumab-like antiCD20 domain; odronextamab, IgG4 ab with an ofatumumab-like antiCD20 domain.Illustration created with biorender-individual version.

Table 1. BsAb single-agent studies in r/r aNHL patients with published results.

Clinical Trial	Phase	Drug(s)	Histology	Modifiers	N	ORR	CR	mPFS (months)	mDOR (months)	Grade 3–4 CRS	Grade 3–4 ICANS	Grade 3–4 NP	mFU (months)
NCT02500407	I/II	MOSUNETUZUMAB	DLBCL	Dose expansion cohort	88	40%	24%	3.2	7	2.3%	None	21.6%	10.1
NCT03625037	I/II	EPCORITAMAB	DLBCL	Dose expansion cohort	157	63%	39%	4.4	12	2.5%	0.6%	14.6%	10.7
NCT03075696	II	GLOFITAMAB	DLBCL	Dose expansion cohort	155	52%	39%	4.4	18.4	4%	3%	27%	12.6
NCT04657302	I	GLOFITAMAB	DLBCL	Dose expansion cohort	27	67%	52%	8.6	14.4	3.3%	3.3%	30%	15
NCT03888105	II	ODRONEXTAMAB	DLBCL	Dose expansion cohort	127	52%	31%	N/A	10.2	0.7%	None	N/A	26.2
NCT02924402	I	PLAMOTAMAB	DLBCL	Dose escalation cohort	19	47%	26%	N/A	N/A	None	None	16.7%	N/A
NCT04082936	I	IgM-2323	B-NHL	Dose escalation cohort	23	35%	22%	N/A	N/A	3.4%	N/A	N/A	N/A
NCT04594642	I	AZD0486	DLBCL	Dose escalation cohort	5	40%	20%	N/A	N/A	None	7%	15%	3.8
NCT04923048	I/II	GB261	B-NHL	Dose escalation cohort	22	73%	45%	N/A	NR	None	None	14.9%	4.1

Reported abstract data refer to the time of their publication. DLBCL includes DLBCL, not otherwise specified, high-grade B-cell lymphoma, and transformed indolent NHL. Abbreviations: CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; NP, neutropenia; ORR, overall response rate; CR, complete response; mFU, median follow-up; mPFS, median progression-free survival; mDOR, median duration of response; NR, not reached; N/A, not assessed.

Table 2. BsAb combination studies in r/r aNHL patients with published results.

Clinical Trial	Phase	Drug(s)	Modifiers	Histology	N	ORR	CR	mPFS (months)	mDOR (months)	G. 3–4 CRS	G. 3–4 ICANS	G. 3–4 NP	mFU (months)
Planned ASCS Consolidation
NCT04663347	I/II	EPCORITAMAB + R-DHAX/C	Planned ASCS after cycle 3	DLBCL	15	100%	80%	N/A	NR	None	None	N/A	9.2
No ASCS consolidation
NCT04663347	I/II	EPCORITAMAB + R-DHAX/C	3 cycles of combined therapy. Epcoritamab monotherapy continued until PD or toxicity	DLBCL	11	64%	45%	N/A	NR	None	None	N/A	9.2
NCT04663347	I/II	EPCORITAMAB + GemOx	4 cycles of combined therapy. Epcoritamab monotherapy continued until PD or toxicity	DLBCL	34	91%	59%	N/A	N/A	3%	None	N/A	20.3
NCT05283720	I/II	EPCORITAMAB + LENALIDOMIDE	12 cycles of combined therapy	DLBCL	24	75%	58%	N/A	N/A	8%	3.8%	58%	N/A
NCT03671018	II	MOSUNETUZUMAB + POLATUZUMAB	6 cycles of combined therapy. If CR after C8, mosunetuzumab discontinued. If SD or PR after C8, mosunetuzumab continued up to C17	DLBCL	98	59%	46%	11.4	20.8	3.1%	2%	20.4%	23.9
NCT03533283	I/II	GLOFITAMAB + POLATUZUMAB	6 cycles of combined therapy. Glofitamab continued up to C12	DLBCL	125	80%	59%	10.4	N/A	0.8%	None	N/A	21.6
NCT05335018	II	GLOFITAMAB + LENALIDOMIDE + POSELTINIB	12 cycles of combined therapy	DLBCL	6	100%	50%	N/A	N/A	None	None	33%	N/A

Reported abstract data refer to the time of their publication. DLBCL includes DLBCL, not otherwise specified, high-grade B-cell lymphoma, and transformed indolent NHL. Abbreviations: G., grade; CRS, cytokine release syndrome; ICANS, immune effector cell- associated neurotoxicity syndrome; NP, neutropenia; ASCS, autologous stem cell support; R-DHAX/C, rituximab, dexamethasone, cytarabine, oxaliplatin/carboplatin; GemOx, gemcitabine, oxaliplatin; SUD, step-up dosing; Q3W, every 3 weeks; ORR, overall response rate; CR, complete response; SD, stable disease; PR, partial response; PD, progressive disease; mFU, median follow-up; mPFS, median progression-free survival; mDOR, median duration of response; NR, not reached; N/A, not assessed.

Table 3. BsAb studies in R/R aNHL patients without published results.

Clinical Trial	Phase	Drug(s)	Histology	Comments	Primary Endpoints	Key Secondary endpoints	Estimated Enrollment
Planned ASCS Consolidation
NCT05464329	I	MOSUNETUZUMAB + DHAX/ICE	B-NHL	Planned ASCS after cycle 3	Frequencies and grades of TEAEs	CR rates; PFS and OS	40
NCT05852717	II	EPCORITAMAB + GDP	DLBCL	Planned ASCS after cycle 3	CR rates	ORR; PFS, DOR and OS; feasibility of ASCS or CAR-T cell consolidation	32
NCT05364424	I	GLOFITAMAB + R-ICE	DLBCL	Planned ASCS after cycle 3	ORR	CR rates; PFS, DOR and OS; TEAEs	40
Planned CAR-T Consolidation
NCT05260957	II	MOSUNETUZUMAB + POLATUZUMAB	B-NHL	Mosunetuzumab + Anti-CD79b ADC; Planned CAR-T therapy after cycle 8	CR rates	ORR; PFS, DOR and OS; CRS and ICANS rates following CAR-T	40
NCT05852717	II	EPCORITAMAB + GDP	DLBCL	Planned CAR-T therapy after cycle 3	CR rates	ORR; PFS, DOR and OS; feasibility of ASCS or CAR-T cell consolidation	32
No Consolidation Planned: Single Agent
NCT05412290	I	MOSUNETUZUMAB	B-NHL	Administered following ASCS	Frequencies and grades of TEAEs	PFS and OS following ASCS	15
NCT04889716	II	MOSUNETUZUMAB	B-NHL	Administered following CAR-T	CR rates; DLT	PFS, DOR and OS	42
NCT03677154	I/II	MOSUNETUZUMAB	DLBCL	Administered either SC or IV following 1st line therapy	CR rates; ORR; frequencies and grades of TEAEs	PFS, DOR and OS; quality of life	188
NCT05451810	II	EPCORITAMAB	B-NHL	Administered as Outpatient	Frequencies and grades of TEAEs	CR rates; best ORR; PFS, DOR and OS	184
NCT04628494	III	EPCORITAMAB vs chemotherapy	DLBCL	Investigator’s choice as control arm, either BR or R-GemOx	OS	CR rates; ORR; PFS, DOR and TTNT; rate and duration of MRD negative status; TEAEs; quality of life	552
NCT04703686	II	GLOFITAMAB	B-NHL	For patients with relapse after CAR-T	OS	CR rates; ORR; PFS, DOR; quality of life	78
NCT05619367		ODRONEXTAMAB	B-NHL	Compassionate use program	N/A	N/A	N/A
NCT05991388	II	ODRONEXTAMAB	B-NHL	For pediatric and young adult patients	CR rates; ORR	PFS, DOR and OS; frequencies and grades of TEAEs	210
No Consolidation Planned: Combinations with Chemotherapeutic Agents
NCT04313608	I	MOSUNETUZUMAB/GLOFITAMAB + GemOx	DLBCL	8 cycles of combined therapy. Glofitamab monotherapy continued until C12	Frequencies and grades of TEAEs	CR rates; ORR; pharmacokinetics	23
NCT05533775	I/II	GLOFITAMAB + R-ICE	B-NHL	Pediatric and young adult patients	CR rates; frequencies and grades of TEAEs	ORR; PFS, DOR and OS	65
NCT04408638	III	GLOFITAMAB + GemOx vs R-GemOx	DLBCL	8 cycles of combined therapy. Glofitamab monotherapy continued until C12	OS	ORR; PF and DOR; frequencies and grades of TEAEs; quality of life	270
No Consolidation Planned: Combinations with Non-Chemotherapeutic Agents
NCT04970901	I	MOSUNETUZUMAB/GLOFITAMAB + LONCASTUXIMAB	B-NHL	Mosunetuzumab/Glofitamab + anti-CD19 ADC	Frequencies and grades of TEAEs	CR rates; ORR; PFS, DOR; pharmacokinetics	200
NCT05672251	II	MOSUNETUZUMAB + LONCASTUXIMAB	DLBCL	Mosunetuzumab + anti-CD19 ADC	ORR; Frequencies and grades of TEAEs	CR rates; ORR; PFS, DOR; TEAEs	36
NCT05171647	III	MOSUNETUZUMAB + POLATUZUMAB vs R-GemOx	B-NHL	Mosunetuzumab + anti-CD79b ADC	PFS	CR rates; ORR; DOR and OS; TEAEs; quality of life	222
NCT05315713	I/II	MOSUNETUZUMAB + TIRAGOLUMAB ± ATEZOLIZUMAB	B-NHL	Mosunetuzumab + anti-TIGIT Ab ± anti-PDL1 Ab	Frequencies and grades of TEAEs; ORR	CR rate; PFS, DOR and OS	118
NCT05615636	II	MOSUNETUZUMAB + POLATUZUMAB + TAFASITAMAB + LENALIDOMIDE	DLBCL	Mosunetuzumab + anti-CD79b ADC + anti-CD19 Ab + immune modulator	Best ORR	N/A	36
NCT05169515	I	MOSUNETUZUMAB + CC-220 MOSUNETUZUMAB + CC-99282 GLOFITAMAB + CC-99282	B-NHL	Mosunetuzumab/Glofitamab + cereblon E3 ligase modulator (CELMoD)	Best ORR; DLT; frequencies and grades of TEAEs	Best CR rate; PFS, DOR and OS up to 2 y; serum concentration of CC-220 and CC-99282	121
NCT05283720^a	I/II	EPCORITAMAB + immuno-modulating agents	B-NHL	Multi-arm study.	DLT	Best ORR; CR rates; PFS, DOR, OS and TTNT up to 5 y; rate and duration of MRD negative status	394
NCT04077723	I/II	GLOFITITAMAB + RO7227166	B-NHL	Glofitamab + CD19×CD137 BsAb	DLT; TEAEs; CR rates; ORR; PFS, DOR and OS	Pharmacokinetics; quality of life	46
NCT05219513	I	GLOFITAMAB + RO7443904	B-NHL	Glofitamab + CD19×CD28 BsAb	Frequencies and grades of TEAEs	Pharmacokinetics	200
NCT05896163	I/II	GLOFITAMAB + MAPLIRPACEPT	DLBCL	Glofitamab + anti-CD47 Ab	DLT; ORR	CR rates; PFS and DOR; TEAEs	70
NCT02651662	I	ODRONEXTAMAB + CEMIPLIMAB	B-NHL	Odronextamab + anti-PD1 Ab	Frequencies and grades of TEAEs	CR rates; ORR; DOR	62
NCT05685173	I	ODRONEXTAMAB + REGN5837	B-NHL	Odronextamab + CD22×CD28 BsAb	Frequencies and grades of TEAEs	CR rates; ORR; PFS, DOR and OS	91
NCT05328102	II	PLAMOTAMAB + TAFASITAMAB + LENALIDOMIDE vs TAFASITAMAB + LENALIDOMIDE	DLBCL	Study terminated early by the sponsor	frequencies and grades of TEAEs; PFS	N/A	3
Novel Constructs
NCT05210868	I/II	CM355	B-NHL	CD3×CD20 BsAb	frequencies and grades of TEAEs; ORR	CR rates; ORR; PFS, DOR and OS; pharmacokinetics endpoints	184
NCT05618327	I	JS203	B-NHL	CD3×CD20 BsAb	DLT	CR rates; ORR; PFS, DOR and OS; TEAEs; pharmacokinetics	219
NCT04056975	I	A-319	B-NHL	CD3×CD19 BsAb	Frequencies and grades of TEAEs	Pharmacokinetics endpoints	54
NCT04540796	I	JNJ-75348780	B-NHL	CD3×CD22 BsAb	Frequencies and grades of TEAEs	CR rates; ORR; DOR; pharmacokinetics	148
NCT05424822	I	JNJ-80948543	B-NHL	CD3×CD20×CD79b TsAb	Frequencies and grades of TEAEs	CR rates; ORR; DOR	180
NCT05348889	I	CMG1A46	B-NHL	CD3×CD19×CD20 TsAb	Frequencies and grades of TEAEs	CR rates; ORR; PFS and OS; pharmacokinetics	165
NCT05397496	I	PIT565	B-NHL	CD3×CD2×CD19 TsAb	Frequencies and grades of TEAEs	CR rates; ORR; PFS, DOR; pharmacokinetics	140
NCT05623982	I/II	EMFIZATAMAB	B-NHL	CD3×CD137×PD-L1×CD19 TesAb	Frequencies and grades of TEAEs	CR rates; ORR; PFS, DOR and OS; pharmacokinetics	40
NCT06088654	I/II	IPH6501	B-NHL	NKp46×CD16a×CD122×CD20 TesAb	Frequencies and grades of TEAEs	ORR; DOR and PFS; pharmacokinetics	184

Reported abstract data refer to the time of their publication. DLBCL includes DLBCL, not otherwise specified, high-grade B-cell lymphoma, and transformed indolent NHL.

^aEpcoritamab investigated in combination with multiple agents across different histologies (DLBCL, FL, MZL). For r/r DLBCL patients, combination therapies encompass lenalidomide, ibrutinib, and CC-99282.

Abbreviations: TEAEs, treatment-emergent adverse events; ADAs, anti-drug antibodies; DLT, dose-limiting toxicity; SC, subcutaneous; IV, intravenous; PFS, progression-free survival; DOR, duration of response; TTNT, time to next treatment; OS, overall survival; ASCS, autologous stem cell support; CAR-T, chimeric antigen receptor T-cell; Cmax, maximum serum concentration; AUC, area under the curve; EORTC, European Organisation for Research and Treatment of Cancer; FACT-Lym, functional assessment of cancer therapy-lymphoma; DHAX, dexamethasone, cytarabine, oxaliplatin; R-ICE, rituximab, ifosfamide, carboplatin, etoposide; GDP, gemcitabine, dexamethasone, cisplatin; R-GemOx, rituximab, gemcitabine, oxaliplatin; BR, bendamustine, rituximab; Ab, antibody; ADC, antibody–drug conjugate; MRD, minimal residual disease; ORR, overall response rate; CR, complete remission; SD, stable disease; PR, partial response; N/A, not assessed; TsAb, trispecific antibody; TesAb, tetraspecific antibody.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article.