Antibody–drug conjugates for previously treated aggressive lymphomas: focus on polatuzumab vedotin

Figures & data

Figure 1. Structure of polatuzumab vedotin [36,43,46]

MMAE: monomethyl auristatin E; vc: maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl

Figure 2. Factors affecting the potency, efficacy and safety of ADCs [2,5,7,9,10,21–23]

ADC: antibody–drug conjugate; mAb: monoclonal antibody

Table 1. Structural and mechanistic differences between ADCs approved for the treatment of hematologic malignancies

ADC	Target antigen	mAb	Linker	Payload	Mechanism(s) of action
Gemtuzumab ozogamicin	CD33	Humanized IgG4	Cleavable, hydrolysable (acid labile)	Calicheamicin	Double-strand DNA breaks, cell-cycle arrest and apoptosis
Brentuximab vedotin	CD30	Chimeric IgG1	Protease-cleavable (vc)	MMAE	Microtubule disruption, cell-cycle arrest and apoptosis, plus ADCP
Inotuzumab ozogamicin	CD22	Humanized IgG4	Cleavable, hydrolysable (acid labile)	Calicheamicin	Double-strand DNA breaks, cell-cycle arrest and apoptosis
Moxetumomab pasudotox	CD22	Recombinant murine mAb (Fv fragment)	Recombinant fusion protein with furin cleavage site	Pseudomonas aeruginosa exotoxin (PE38)	Adenosine diphosphate-ribosylation of elongation factor 2, inhibition of protein synthesis, and apoptotic cell death
Polatuzumab vedotin	CD79b	Humanized IgG1	Protease-cleavable (vc)	MMAE	Microtubule disruption, cell-cycle arrest and apoptosis, plus antibody-mediated opsonization and ADCC

ADC: antibody-drug conjugate; ADCC: antibody-dependent cellular cytotoxicity; ADCP: antibody-dependent cellular phagocytosis; Fv: fragment variable; Ig: immunoglobulin; mAb: monoclonal antibody; MMAE: monomethyl auristatin E; vc: maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl

Figure 3. Mechanism of action of polatuzumab vedotin. Adapted with permission from [6]

MMAE: monomethyl auristatin ECopyright © 2020, American Society of Clinical Oncology

Table 2. Summary of polatuzumab vedotin clinical trials in NHL indications

Trial name (NCT number)	Phase	Patient population(s)	Polatuzumab vedotin (pola) regimen(s)	Status	Primary results publication
GO01294 (NCT01290549)	I	R/R NHL, CLL	Pola, Pola-R	Complete	[19]
GO29044 (NCT01992653)	I/II	1L NHL	Pola plus R-CHP or G-CHP	Complete	[63]
ROMULUS (NCT01691898)	I/II	R/R DLBCL	Pola-R or Pola-G	Complete	[59]
GO29365 (NCT02257567)	I/II	R/R DLBCL, FL	Pola-BR or Pola-BG	Active, not recruiting	[60,61]
POLARIX (NCT03274492)	III	R/R DLBCL	Pola plus R-CHP (versus R-CHOP)	Recruiting	-
POLARGO (NCT04182204)	III	R/R DLBCL	Pola plus R-GemOx (versus R-GemOx)	Recruiting	-
GO29833 (NCT02611323)	I	R/R FL or DLBCL	Pola-R or Pola-G plus venetoclax	Recruiting	-
GO29834 (NCT02600897)	I	R/R FL or DLBCL	Pola-R or Pola-G plus lenalidomide	Recruiting	-
GO40516 (NCT03671018)	I	R/R FL or DLBCL	Pola plus mosunetuzumab	Recruiting	-
GO40515 (NCT03677141)	I/II	R/R B-cell NHL 1L DLBCL	Pola-CHP plus mosunetuzumab	Recruiting	-
BO29561 (NCT02729896)	I/II	R/R FL, R/R DLBCL	Pola-G or Pola-R plus atezolizumab	Complete	-
NP39488 (NCT03533283)	I	R/R B-cell NHL	Pola plus RO7082859	Recruiting	-

1L: first line; CHP: cyclophosphamide, doxorubicin, prednisone; CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone; CLL: chronic lymphocytic leukemia; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; G: obinutuzumab; GemOx: gemcitabine and oxaliplatin; NHL: non-Hodgkin lymphoma, R: rituximab; R/R: relapsed/refractory

Table 3. Efficacy outcomes of polatuzumab vedotin

	Pola-BR (n = 40)	BR (n = 40)
EOT, n (%)
IRC ORR	18 (45.0)	7 (17.5)
CR	16 (40.0)	7 (17.5)
INV ORR	19 (47.5)	6 (15.0)
CR	23 (57.5)	8 (20.0)
IRC median DOR, months (95% CI)	12.6 (7.2–NE)	7.7 (4.0–18.9)
INV median DOR, months (95% CI)	10.3 (5.6–NE)	4.1 (2.6–12.7)
Median OS, months (95% CI)	12.4 (9.0–NE)	4.7 (3.7–8.3)
IRC median PFS, months (95% CI)	9.5 (6.2–13.9)	3.7 (2.1–4.5)
INV median PFS, months (95% CI)	7.6 (6.0–17.0)	2.0 (1.5–3.7)

CI: confidence interval; CR: complete response; DOR: duration of response; EOT: end of treatment, IRC: independent review committee; INV: investigator; NE: not estimable; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; Pola-BR: polatuzumab vedotin plus bendamustine-rituximab

Figure 4. Duration of response by INV of polatuzumab vedotin [61]

BR, bendamustine-rituximab; CR: complete response; INV: investigator; PD: progressive disease; Ph: phase; Pola: polatuzumab vedotin; PR: partial response; SD: stable disease

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