LYMRIT 37-01: A Phase I/II Study of 177lu-Lilotomab Satetraxetan (Betalutin®) Antibody-Radionuclide-Conjugate (ARC) for the Treatment of Relapsed Non-Hodgkin's Lymphoma (NHL) — Analysis with 6-Month Follow-up
Authors: Kolstad Arne , Madsbu Ulf , Beasley Matthew , Bayne Michael , Illidge Tim M. , O'Rourke Noelle , Lagerlöf Ingemar , Hajek Roman , Jurczak Wojciech , Willenbacher Ella , Fagerli Unn Merete , Obr Aleš , Blakkisrud Johan , Muftuler Løndalen Ayca , Rojkjaer Lisa , Østengen Åse , Bolstad Nils , Spetalen Signe , Erlanson Martin , Galleberg Renate , Nygaard Rudå Stine , Holte Harald 
Published: October 2019

Abstract
Introduction: Most indolent NHL patients (pts) have advanced stage disease at diagnosis, and no curative therapy exists. The mainstay of both first- and second-line (2L) therapy is anti-CD20 chemo-immunotherapy, and although initially effective, most pts relapse, with median PFS decreasing markedly after 2L and 3rd-line therapies. In addition, many pts eventually develop resistance to rituximab (RTX)/RTX-containing regimens, thus therapeutic targets other than CD20 are important. Those who develop resistance to RTX, especially the elderly, need new treatment approaches. With a median age at diagnosis of 67 (seer.gov), NHL is a disease of the elderly, who are at risk of developing cumulative myelosuppression, cardiac toxicity, and severe infections with currently available therapies. CD37 is highly expressed (>90%) in B-cell NHL, providing an alternative target to CD20. Lutetium (177Lu) lilotomab satetraxetan (Betalutin®) is a beta-emitting anti-CD37 ARC in a ready-to-use formulation. LYMRIT 37-01 is a phase I/II open-label, multicenter, dose-escalation study to determine the safety, pharmacokinetics (PK), and preliminary efficacy of a single dose of Betalutin in pts with relapsed iNHL, and to establish a recommended phase II dose (RP2D). We present updated efficacy and safety data for the phase I/IIa part of the study (Part A) as of 22 June 2018; all pts have ≥ 6 months (m) of follow-up, except for 3 (will be completed in August).
Methods: Pts with histologically confirmed iNHL relapsing after ≥1 prior therapy with <25% bone marrow involvement, platelets (plt) >150 x 109/L, no prior SCT/RIT, and a life expectancy of ≥3 months were enrolled into 1 of 4 dose-escalation arms (Part A) to determine the optimal lilotomab pre-dose and Betalutin dose for further evaluation in an expanded phase II cohort. A fifth arm collected additional PK data. All pts received pre-treatment with RTX. Responses were assessed using Cheson IWG response criteria (including CT and FDG PET/CT scans) beginning at week 12.
Results: 74 pts [57 follicular (FL), 7 mantle cell (MCL), 9 marginal zone (MZL), 1 small lymphocytic (SLL)] were enrolled at 13 sites from Dec 2012 to Feb 2018. Median age was 68 (range 38-87; 55% ≥ 65); the median no. of prior therapies was 3 (range 1-9); 48 pts (65%) had received ≥2 prior therapies. Two RP2Ds emerged: a lilotomab pre-dose of 40 mg + 15 MBq/kg Betalutin ("40/15"; Arm 1) and a lilotomab pre-dose of 100 mg/m2 + 20 MBq/kg Betalutin ("100/20"; Arm 4). For all pts, the overall response rate (ORR) was 61%, with 26% complete responses (CR). By subtype, the ORR was 65% (CR 24%) for FL, and 78% (CR 44%) for MZL. FL with ≥2 prior therapies (n=37) had an ORR of 70% (CR 27%). With a median follow-up of 9.1 m (range 4.9-49.5 m), the median duration of response for all pts is 13.3 m (20.5 m for those with a CR); 26 pts (35%) have remained free of disease progression for >12 m [CR(15)/PR(5)/SD(6)].
For the 36 pts receiving the "40/15" regimen, the ORR was 58% (CR 28%), and 64% (CR 28%) for FL (n=25). The ORR was 63% (CR 21%) for 19 pts receiving the "100/20" regimen, and 69% (CR 19%) for FL (n=16).
Betalutinwas well-tolerated. The most common grade (G) 3/4 AEs were neutropenia (53%) and thrombocytopenia (48%); 5 pts (7%) had G3/4 infections (pneumonia, UTI, pharyngitis (G3), 2 G4 sepsis). No febrile neutropenia was reported. Four pts had plt transfusions [low plt count (2), epistaxis (1), hematuria (1)]; 3 received G-CSF. Two pts had infusion reactions; both were related to RTX. SAEs occurred in 14 pts (19%); SAEs in ≥2 pts were atrial fibrillation, thrombocytopenia, lymphoma progression and sepsis (all n=2). Five pts developed transient anti-drug antibodies. One case of CMML occurred 24 m after Betalutin (18 m after subsequent bendamustine-RTX therapy). There were no study drug-related deaths in the treatment period. G3/4 neutropenia and thrombocytopenia occurred in 56%/56% (40/15 regimen) and 47%/42% (100/20 regimen).
Conclusions: Betalutin is well tolerated and has promising antitumor activity in recurrent iNHL, especially in FL and MZL. Use of a higher lilotomab pre-dose resulted in a lower incidence of G3/4 hematologic AEs. With a single administration, Betalutin has the potential to be a novel, safe, and effective therapy for pts with B-cell malignancies. The 2 RP2Ds from Part A of the study are now being compared in a randomized phase 2b cohort (Part B: "PARADIGME") in relapsed, RTX/anti-CD20 refractory FL pts who have received ≥2 prior therapies.

Disclosures
Kolstad: Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche: Research Funding. Illidge:Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria. Hajek:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Jurczak:European Medicines Agency: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Consultancy; Acerta: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Afimed: Research Funding; Bayer: Research Funding; BeiGene: Research Funding; Celgene: Research Funding; Epizyme: Research Funding; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Nordic Nanovector: Research Funding; Merck: Research Funding; Morphosys: Research Funding; Pharmacyclics: Research Funding; Servier: Research Funding; Roche: Research Funding; TG Therapeutics: Research Funding. Rojkjaer:Nordic Nanovector: Employment. Østengen:Nordic Nanovector: Employment.