This study shows a long median and long term survival after liver surgery/RFA for these selected metastatic GEP-NEC patients, particularly for the group with a Ki-67 in the relatively lower G3 range. Our findings indicate a possible role for surgical treatment of liver metastases in the management of this patient population.

Langer and Knigge contributed equally to this work.

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.

International prognostic Index (IPI) is the most widely used clinical prediction model for diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), but may be suboptimal in older patients. We aimed to develop and externally validate a clinical prediction model for older, R-CHOP treated DLBCL patients by examining geriatric assessment and lymphoma-related parameters in real-world cohorts. A population-based training set of 365 R-CHOP treated DLBCL patients ≥70 years was identified through the Cancer Registry of Norway. The external test set consisted of a population-based cohort of 193 patients. Data on candidate predictors was retrieved from the Cancer Registry and through review of clinical records. Cox regression models for 2-year overall survival (OS) were used for model selection. Activities of daily living (ADL), Charlson Comorbidity index (CCI), age, sex, albumin, stage, ECOG and LDH were identified as independent predictors and combined into a Geriatric prognostic index (GPI). The GPI demonstrated good discrimination (optimism-corrected C-index 0.752), and identified a low-, intermediate- and high-risk group with significantly different survival (2-year OS 94%, 65%, 25%). At external validation, the continuous and grouped GPI demonstrated good discrimination (C-index 0.727, 0.710) and the GPI groups had significantly different survival (2- year OS 95%, 65%, 44%). Both the continuous and grouped GPI showed better discrimination than IPI, R-IPI and NCCN-IPI (C-index 0.621, 0.583, 0.670) We have developed and externally validated the GPI for older DLBCL patients treated with RCHOP that outperformed IPI, R-IPI and NCCN-IPI. A web-based calculator is available at https://wide.shinyapps.io/GPIcalculator/.