¹⁷⁷ Lu-Lilotomab Satetraxetan, a Novel CD37-Targeted Antibody-Radionuclide Conjugate in Relapsed Non-Hodgkin's Lymphoma (NHL): Updated Results of an Ongoing Phase I/II Study (LYMRIT 37-01)

The incidence of indolent NHL (iNHL) is increasing, with approximately 63,000 new cases per year in the US. The highest unmet medical need is for rituximab (RTX)-refractory patients (pts), with inferior 5 year overall survival rates for RTX-refractory follicular lymphoma (FL) vs all FL pts (58% vs 87.7%) (Abdollahi S et al. Blood 2008; www.seer.cancer.gov). Many pts develop resistance to RTX or RTX-containing regimens, thus targets other than CD20 are important. CD37 is highly expressed (>90%) in most B-cell NHL, providing an alternative target to CD20. Lutetium (¹⁷⁷Lu) lilotomab satetraxetan (Betalutin^®) is a novel beta-emitting anti-CD37 antibody radionuclide conjugate (ARC) in a ready-to-use formulation that is being evaluated in a phase I/II, open-label, dose-escalation study (LYMRIT 37-01) to determine the safety and preliminary efficacy of Betalutin^® monotherapy in pts with relapsed/refractory NHL, and establish a recommended phase II dose (RP2D). Lilotomab (cold antibody) pre-dosing was determined to be essential to optimize Betalutin^® biodistribution and safety, and dosimetry data indicate less bone marrow (bm) uptake of Betalutin^® with lilotomab pre-dosing with no impact on tumor absorbed dose (Blakkisrud et al. J Nucl Med 2017). Arms 1 and 4 are evaluating 2 different lilotomab pre-doses (Arm 1 - 40 mg; Arm 4 -100mg/m²) with escalating doses of Betalutin^®. We provide here an update on safety/efficacy for the 2 arms.

Methods: Pts with histologically confirmed iNHL (FL grade I-IIIA, mantle cell (MCL), marginal zone (MZL), SLL) with ≥1 prior therapies, <25% bm 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 1) to determine the optimal lilotomab pre-dose and Betalutin^® regimen for further evaluation in an expanded phase II cohort (part 2). All pts received pre-treatment with RTX. Responses were assessed using Cheson IWG response criteria (including CT and PET-CT scans) beginning at week 12.

Results: As of 3 July 2017, 61 pts have been enrolled at 12 centers (55 pts are evaluable for safety having completed 12 weeks of follow-up;55 pts for efficacy). NHL subtypes were FL (n=40; 73%), MCL (n=7; 13%), and MZL (n=8; 14%). Median age was 69; 39 (71%) were ≥ 65. The median no. of prior therapies was 3 (range 1-8); 40 pts (73%) received ≥2 prior therapies, and 31 pts (56%) received ≥2 prior RTX courses. The most common grade (G) 3/4 AEs were hematologic (neutropenia 58% and thrombocytopenia 53%); 4 (7%) pts had ≥ G3 infections. There was no reported G4 neutropenia/thrombocytopenia in Arm 4 compared with 16% for each AE in Arm 1. The median neutrophil and plt nadirs were 0.83/1.00x10⁹/L and 46/50x10⁹/L in Arms 1 and 4 respectively. One pt had a G2 infusion reaction (related to RTX). SAEs occurred in 14 pts; SAEs in ≥2 pts were atrial fibrillation, thrombocytopenia, lymphoma progression and sepsis (all n=2). One pt developed MDS/AML 24 months (m) after Betalutin^® administration (18 m after subsequent bendamustine-RTX therapy). There were no study drug related deaths in the treatment period. The overall response rate (ORR) for all evaluable pts was 64% (CR 24%). For a lilotomab pre-dose of 40 mg (Arm 1), 15 MBq/kg Betalutin^® was the RP2D; 30 pts were subsequently enrolled in a phase II expansion arm. For a lilotomab pre-dose of 100 mg/m² (Arm 4), the RP2D of Betalutin^® was 20 MBq (n=7), and a phase II arm is currently enrolling pts. Thirty-two pts are evaluable for efficacy at the Arm 1 RP2D (21 with FL); the ORR was 69% (CR 28%) for all pts, and 81% (CR 28%) for the FL subset. With a median duration of follow-up of 5.8 m (range 0.6-47.0 m), the median duration of response is 13.3 m (15.0 m for those with a CR), and 15.0 m for the FL pts. 60% of pts with a response (CR or PR) did not show progressive disease. For the seven (phase I) pts who received the Arm 4 RP2D (6 with FL), the ORR was 43% (CR 14%), and 50% (CR 17%) for the FL pts.

Conclusions: Single-agent Betalutin^® is highly active in recurrent iNHL, especially in FL. Most AEs were hematological, all were transient and reversible. Pre-dosing with lilotomab reduces bm uptake of Betalutin^®; preliminary safety and efficacy data using a higher lilotomab pre-dose and Betalutin^® dose in 7 phase I pts from Arm 4 are promising, and updated data will be presented at the meeting. Betalutin^® has the potential to be a novel, safe and effective therapy for B-cell NHL, with an attractive administration regimen.