Combination of <sup>177</sup>Lu‐lilotomab with rituximab significantly improves the therapeutic outcome in preclinical models of non‐Hodgkin's lymphoma

Repetto-Llamazares, Ada H. V.; Malenge, Marion Masitsa; O’Shea, Adam; Eiriksdottir, Bergthora; Stokke, Trond; Larsen, Roy H.; Dahle, Jostein

doi:10.1111/ejh.13139

Cited by 19 publications

(16 citation statements)

References 49 publications

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“…The B cell selectivity makes it a potentially valuable therapeutic target [10,12,13], and several CD37 reactive compounds have shown promise for treatment of NHL [12,[15][16][17]. Interestingly, preclinical studies have shown that the combined targeting of CD37 and CD20 with 177 Lu-lilotomab satetraxetan and rituximab can improve the therapeutic outcome of NHL [18].…”

Section: Introductionmentioning

confidence: 99%

FDG PET/CT parameters and correlations with tumor-absorbed doses in a phase 1 trial of 177Lu-lilotomab satetraxetan for treatment of relapsed non-Hodgkin lymphoma

Løndalen

Blakkisrud

Revheim

et al. 2020

Eur J Nucl Med Mol Imaging

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Purpose 177Lu-lilotomab satetraxetan targets the CD37 antigen and has been investigated in a first-in-human phase 1/2a study for relapsed non-Hodgkin lymphoma (NHL). Tumor dosimetry and response evaluation can be challenging after radioimmunotherapy (RIT). Changes in FDG PET/CT parameters after RIT and correlations with tumor-absorbed doses has not been examined previously in patients with lymphoma. Treatment-induced changes were measured at FDG PET/CT and ceCT to evaluate response at the lesion level after treatment, and correlations with tumor-absorbed doses were investigated. Methods Forty-five tumors in 16 patients, with different pre-treatment and pre-dosing regimens, were included. Dosimetry was performed based on multiple SPECT/CT images. FDG PET/CT was performed at baseline and at 3 and 6 months. SUVmax, MTV, TLG, and changes in these parameters were calculated for each tumor. Lesion response was evaluated at 3 and 6 months (PET3months and PET6months) based on Deauville criteria. Anatomical changes based on ceCT at baseline and at 6 and 12 months were investigated by the sum of perpendiculars (SPD). Results Tumor-absorbed doses ranged from 35 to 859 cGy. Intra- and interpatient variations were observed. Mean decreases in PET parameters from baseline to 3 months were ΔSUVmax-3months 61%, ΔMTV3months 80%, and ΔTLG3months 77%. There was no overall correlation between tumor-absorbed dose and change in FDG PET or ceCT parameters at the lesion level or significant difference in tumor-absorbed doses between metabolic responders and non-responders after treatment. Conclusion Our analysis does not show any correlation between tumor-absorbed doses and changes in FDG PET or ceCT parameters for the included lesions. The combination regimen, including cold antibodies, may be one of the factors precluding such a correlation. Increased intra-patient response with increased tumor-absorbed doses was observed for most patients, implying individual variations in radiation sensitivity or biology. Trial registration ClinicalTrials.gov Identifier (NCT01796171). Registered December 2012

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Section: Introductionmentioning

confidence: 99%

FDG PET/CT parameters and correlations with tumor-absorbed doses in a phase 1 trial of 177Lu-lilotomab satetraxetan for treatment of relapsed non-Hodgkin lymphoma

Løndalen

Blakkisrud

Revheim

et al. 2020

Eur J Nucl Med Mol Imaging

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“…Dadurch erwies sich die Therapie mit 177 Lu-Lilotomab insgesamt effizienter als die Therapie mit 177 Lu-Rituximab [28]. Durch eine Kombination von 177 Lu-Lilotomab mit nicht radioaktiv markiertem Rituximab konnte die therapeutische Effizienz weiter gesteigert werden [29]. Im Gegensatz zu CD20-Antikörpern wird 177 Lu-Lilotomab nach Bindung an CD37 rasch internalisiert [24], was die Speicherung im Lymphomgewebe verlängern könnte.…”

Section: Cd37/lilotomabunclassified

Neue Entwicklungen auf dem Gebiet der Theranostik

Weber

2019

Nuklearmediziner

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ZusammenfassungDiese Übersichtsarbeit stellt neue Radiopharmaka für die Tumordiagnostik und -therapie vor, die erfolgversprechende präklinische Ergebnisse gezeigt haben und aktuell in klinischen Studien untersucht werden. Dazu gehören mehrere radioaktiv markierte Antikörper wie 131I-Omburtamab, ein gegen das B7-H3-Protein gerichteter Antikörper, der zur Therapie von Neuroblastomen eingesetzt wird; HuMab-5B1, ein 89Zr/177Lu markierter Antikörper zur Therapie von CA19-9 exprimierenden Tumoren und 177Lu-Lilotomab, ein Antikörper gegen das Oberflächenantigen CD37 für die Therapie von B-Zell-Lymphomen. Weitere Beispiele sind der Neurotensin Rezeptor Ligand 111In/177Lu-3B-227 für die Diagnostik und Therapie von verschiedenen Tumorerkrankungen, insbesondere Adenokarzinomen des Pankreas und der Phospholipidether 131I/124I-CLR1404, der wahrscheinlich aufgrund einer veränderten Membranstruktur in verschiedenen Tumorzelltypen angereichert wird. Neben diesen, von Tumorzellen exprimierten Zielstrukturen wird auch das Fibroblasten Aktivierungs Protein (FAP), das im Tumorstroma gebildet wird, als Zielstruktur für die Bildgebung und Therapie eingesetzt (68Ga/90Y-FAPI-04). Diese neuen Radiopharmaka haben das Potenzial für die Therapie einer ganzen Reihe von Tumorerkrankungen und ihre Effektivität sollte in systematischen Studien untersucht werden.

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“…177 Lu-lilotomab satetraxetan (Betalutin) consists of the anti-CD37 murine monoclonal antibody lilotomab conjugated to the chelator satetraxetan (p-SCN-benzyl-DOTA) that conjugates the b-emitting isotope 177 Lu. 177 Lu-lilotomab satetraxetan has been extensively investigated in preclinical models, [15][16][17] and the radionuclide 177 Lu has shown efficacy in clinical trials with various tumor types. [18][19][20][21][22] This phase 1/2a dose-escalation and expansion study (LYMRIT-37-01; NCT01796171) investigated the safety, biodistribution, and pharmacokinetics (PK) of single-dose RIT with 177 Lu-lilotomab satetraxetan in patients with relapsed indolent NHL.…”

Section: Introductionmentioning

confidence: 99%

Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma

et al. 2020

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For patients with indolent non-Hodgkin lymphoma who fail initial anti-CD20–based immunochemotherapy or develop relapsed or refractory disease, there remains a significant unmet clinical need for new therapeutic approaches to improve outcomes and quality of life. 177Lu-lilotomab satetraxetan is a next-generation single-dose CD37-directed radioimmunotherapy (RIT) which was investigated in a phase 1/2a study in 74 patients with relapsed/refractory indolent non-Hodgkin B-cell lymphoma, including 57 patients with follicular lymphoma (FL). To improve targeting of 177Lu-lilotomab satetraxetan to tumor tissue and decrease hematologic toxicity, its administration was preceded by the anti-CD20 monoclonal antibody rituximab and the “cold” anti-CD37 antibody lilotomab. The most common adverse events (AEs) were reversible grade 3/4 neutropenia (31.6%) and thrombocytopenia (26.3%) with neutrophil and platelet count nadirs 5 to 7 weeks after RIT. The most frequent nonhematologic AE was grade 1/2 nausea (15.8%). With a single administration, the overall response rate was 61% (65% in patients with FL), including 30% complete responses. For FL with ≥2 prior therapies (n = 37), the overall response rate was 70%, including 32% complete responses. For patients with rituximab-refractory FL ≥2 prior therapies (n = 21), the overall response rate was 67%, and the complete response rate was 24%. The overall median duration of response was 13.6 months (32.0 months for patients with a complete response). 177Lu-lilotomab satetraxetan may provide a valuable alternative treatment approach in relapsed/refractory non-Hodgkin lymphoma, particularly in patients with comorbidities unsuitable for more intensive approaches. This trial was registered at www.clinicaltrials.gov as #NCT01796171.

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Combination of ¹⁷⁷Lu‐lilotomab with rituximab significantly improves the therapeutic outcome in preclinical models of non‐Hodgkin's lymphoma

Cited by 19 publications

References 49 publications

FDG PET/CT parameters and correlations with tumor-absorbed doses in a phase 1 trial of 177Lu-lilotomab satetraxetan for treatment of relapsed non-Hodgkin lymphoma

FDG PET/CT parameters and correlations with tumor-absorbed doses in a phase 1 trial of 177Lu-lilotomab satetraxetan for treatment of relapsed non-Hodgkin lymphoma

Neue Entwicklungen auf dem Gebiet der Theranostik

Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma

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Combination of 177Lu‐lilotomab with rituximab significantly improves the therapeutic outcome in preclinical models of non‐Hodgkin's lymphoma

Cited by 19 publications

References 49 publications

FDG PET/CT parameters and correlations with tumor-absorbed doses in a phase 1 trial of 177Lu-lilotomab satetraxetan for treatment of relapsed non-Hodgkin lymphoma

FDG PET/CT parameters and correlations with tumor-absorbed doses in a phase 1 trial of 177Lu-lilotomab satetraxetan for treatment of relapsed non-Hodgkin lymphoma

Neue Entwicklungen auf dem Gebiet der Theranostik

Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma

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Combination of ¹⁷⁷Lu‐lilotomab with rituximab significantly improves the therapeutic outcome in preclinical models of non‐Hodgkin's lymphoma