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.

Beatson West of Scotland Cancer Centre Glasgow United Kingdom

Bristol Cancer Institute Bristol United Kingdom

Department of Diagnostic Physics and

Department of Hemato Oncology Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc Czech Republic; and

Department of Hematooncology University Hospital Ostrava and Faculty of Medicine Ostrava University Ostrava Czech Republic

Department of Medical Biochemistry Oslo University Hospital Radiumhospitalet Oslo Norway

Department of Nuclear Medicine Oslo University Hospital Radiumhospitalet Oslo Norway

Department of Oncology Oslo University Hospital Radiumhospitalet Oslo Norway

Department of Pathology Oslo University Hospital Radiumhospitalet Oslo Norway

Department of Radiology and Nuclear Medicine

Dorset Cancer Centre Poole United Kingdom

Maria Sklodowska Curie National Institute of Oncology Kraków Poland

Nordic Nanovector ASA Oslo Norway

St Olav's Hospital and Department of Cancer Research and Molecular Medicine Norwegian University of Science and Technology Trondheim Norway

University of Manchester National Institutes of Health Research Manchester Biomedical Research Centre Christie Hospital Manchester United Kingdom

Zobrazit více v PubMed

Matasar MJ, Luminari S, Barr PM, et al. Follicular lymphoma: recent and emerging therapies, treatment strategies, and remaining unmet needs. Oncologist. 2019;24(11):e1236-e1250. PubMed PMC

McLaughlin P, Grillo-López AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16(8):2825-2833. PubMed

Mohammed R, Milne A, Kayani K, Ojha U. How the discovery of rituximab impacted the treatment of B-cell non-Hodgkin’s lymphomas. J Blood Med. 2019;10:71-84. PubMed PMC

Casulo C, Byrtek M, Dawson KL, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National Lymphocare Study. J Clin Oncol. 2015;33(23):2516-2522. PubMed PMC

Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016;17(8):1081-1093. PubMed

Food and Drug Administration. Gazyva prescribing information revised 3/2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125486s025lbl.pdf. Accessed April 2020.

Fowler NH, Nastoupil LJ, Chin C, et al. A phase I/II study of lenalidomide plus obinutuzumab in relapsed indolent lymphoma [abstract].

Rodgers TD, Reagan PM. Targeting the B-cell receptor pathway: a review of current and future therapies for non-Hodgkin’s lymphoma. Expert Opin Emerg Drugs. 2018;23(2):111-122. PubMed

Valla K, Flowers CR, Koff JL. Targeting the B cell receptor pathway in non-Hodgkin lymphoma. Expert Opin Investig Drugs. 2018;27(6):513-522. PubMed PMC

Kaminski MS, Zelenetz AD, Press OW, et al. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin’s lymphomas. J Clin Oncol. 2001;19(19):3918-3928. PubMed

Witzig TE, Gordon LI, Cabanillas F, et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol. 2002;20(10):2453-2463. PubMed

Witzig TE, Flinn IW, Gordon LI, et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol. 2002;20(15):3262-3269. PubMed

Link MP, Bindl J, Meeker TC, et al. A unique antigen on mature B cells defined by a monoclonal antibody. J Immunol. 1986;137(9):3013-3018. PubMed

Schwartz-Albiez R, Dörken B, Hofmann W, Moldenhauer G. The B cell-associated CD37 antigen (gp40-52). Structure and subcellular expression of an extensively glycosylated glycoprotein. J Immunol. 1988;140(3):905-914. PubMed

Dahle J, Repetto-Llamazares AHV, Mollatt CS, et al. Evaluating antigen targeting and anti-tumor activity of a new anti-CD37 radioimmunoconjugate against non-Hodgkin’s lymphoma. Anticancer Res. 2013;33(1):85-95. PubMed

Repetto-Llamazares AH, Larsen RH, Patzke S, et al. Targeted cancer therapy with a novel anti-CD37 beta-particle emitting radioimmunoconjugate for treatment of non-Hodgkin lymphoma. PLoS One. 2015;10(6):e0128816. PubMed PMC

Repetto-Llamazares AHV, Malenge MM, O’Shea A, et al. Combination of PubMed

Forrer F, Chen J, Fani M, et al. In vitro characterization of (177)Lu-radiolabelled chimeric anti-CD20 monoclonal antibody and a preliminary dosimetry study. Eur J Nucl Med Mol Imaging. 2009;36(9):1443-1452. PubMed

Sierra ML, Agazzi A, Bodei L, et al. Lymphocytic toxicity in patients after peptide-receptor radionuclide therapy (PRRT) with PubMed

Claringbold PG, Brayshaw PA, Price RA, Turner JH. Phase II study of radiopeptide PubMed

Kunikowska J, Królicki L, Hubalewska-Dydejczyk A, Mikołajczak R, Sowa-Staszczak A, Pawlak D. Clinical results of radionuclide therapy of neuroendocrine tumours with 90Y-DOTATATE and tandem 90Y/177Lu-DOTATATE: which is a better therapy option? Eur J Nucl Med Mol Imaging. 2011;38(10):1788-1797. PubMed PMC

Forrer F, Oechslin-Oberholzer C, Campana B, et al. Radioimmunotherapy with PubMed

Blakkisrud J, Løndalen A, Martinsen AC, et al. Tumor-absorbed dose for non-Hodgkin lymphoma patients treated with the anti-CD37 antibody radionuclide conjugate PubMed

Blakkisrud J, Løndalen A, Dahle J, et al. Red marrow-absorbed dose for non-Hodgkin lymphoma patients treated with PubMed

Blakkisrud J, Holtedahl JE, Løndalen A, et al. Biodistribution and dosimetry results from a phase 1 trial of therapy with the antibody-radionuclide conjugate PubMed

Stokke C, Blakkisrud J, Løndalen A, et al. Pre-dosing with lilotomab prior to therapy with PubMed PMC

Cheson BD, Pfistner B, Juweid ME, et al. ; International Harmonization Project on Lymphoma . Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-586. PubMed

Cheson BD, Horning SJ, Coiffier B, et al. ; NCI Sponsored International Working Group . Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol. 1999;17(4):1244. PubMed

Sachpekidis C, Jackson DB, Soldatos TG. Radioimmunotherapy in non-Hodgkin’s lymphoma: Retrospective adverse event profiling of Zevalin and Bexxar. Pharmaceuticals (Basel). 2019;12(4):E141. PubMed PMC

Witzig TE, Molina A, Gordon LI, et al. Long-term responses in patients with recurring or refractory B-cell non-Hodgkin lymphoma treated with yttrium 90 ibritumomab tiuxetan. Cancer. 2007;109(9):1804-1810. PubMed

Nordic Nanovector. 2018. Regulatory designations. https://www.nordicnanovector.com/node/324. Accessed March 2020.

Nordic Nanovector. 2020. Press releases. https://www.nordicnanovector.com/investors-and-media/press-releases?page=/en/pressreleases/nordic-nanovector%2527s-betalutin%2528r%2529-receives-fast-track-designation-from-us-fda-for-marginal-zone-lymphoma-1822545. Accessed July 2020.

Batlevi CL, Younes A. Revival of PI3K inhibitors in non-Hodgkin’s lymphoma. Ann Oncol. 2017;28(9):2047-2049. PubMed

Krause G, Hassenrück F, Hallek M. Copanlisib for treatment of B-cell malignancies: the development of a PI3K inhibitor with considerable differences to idelalisib. Drug Des Devel Ther. 2018;12:2577-2590. PubMed PMC

Morschhauser F, Tilly H, Chaidos A, et al. Interim update from a phase 2 multicenter study of tazemetostat, an EZH2 inhibitor, in patients with relapsed or refractory (R/R) follicular lymphoma (FL) [oral presentation at EHA23 2018]. Abstract S100. https://library.ehaweb.org/eha/2018/stockholm/214434/gilles.salles.interim.update.from.a.phase.2.multicenter.study.of.tazemetostat.html?f=topic=1574*media=3%27. Accessed April 2020.

Gopal AK, Schuster SJ, Fowler NH, et al. Ibrutinib as treatment for patients with relapsed/refractory follicular lymphoma: Results from the open-label, multicenter, phase II DAWN study. J Clin Oncol. 2018;36(23):2405-2412. PubMed

Rødland GE, Melhus K, Generalov R, et al. The dual cell cycle kinase inhibitor JNJ-7706621 reverses resistance to CD37-targeted radioimmunotherapy in activated B cell like diffuse large B cell lymphoma cell lines. Front Oncol. 2019;9:1301. PubMed PMC

Pichard A, Marcatili S, Karam J, et al. The therapeutic effectiveness of PubMed PMC

Zobrazit více v PubMed

ClinicalTrials.gov
NCT01796171