Phase I/II study of the LAG-3 inhibitor ieramilimab (LAG525) ± anti-PD-1 spartalizumab (PDR001) in patients with advanced malignancies

Combination; Drug therapy; ImmunotherapyCombinació; Teràpia farmacològica; ImmunoteràpiaCombinación; Terapia farmacológica; InmunoterapiaBackground Lymphocyte-activation gene 3 (LAG-3) is an inhibitory immunoreceptor that negatively regulates T-cell activation. This paper presents preclinical characterization of the LAG-3 inhibitor, ieramilimab (LAG525), and phase I data for the treatment of patients with advanced/metastatic solid tumors with ieramilimab ±the anti-programmed cell death-1 antibody, spartalizumab. Methods Eligible patients had advanced/metastatic solid tumors and progressed after, or were unsuitable for, standard-of-care therapy, including checkpoint inhibitors in some cases. Patients received ieramilimab ±spartalizumab across various dose-escalation schedules. The primary objective was to assess the maximum tolerated dose (MTD) or recommended phase II dose (RP2D). Results In total, 255 patients were allocated to single-agent ieramilimab (n=134) and combination (n=121) treatment arms. The majority (98%) had received prior antineoplastic therapy (median, 3). Four patients experienced dose-limiting toxicities in each treatment arm across various dosing cohorts. No MTD was reached. The RP2D on a 3-week schedule was declared as 400 mg ieramilimab plus 300 mg spartalizumab and, on a 4-week schedule (once every 4 weeks; Q4W), as 800 mg ieramilimab plus 400 mg spartalizumab; tumor target (LAG-3) suppression with 600 mg ieramilimab Q4W was predicted to be similar to the Q4W, RP2D schedule. Treatment-related adverse events (TRAEs) occurred in 75 (56%) and 84 (69%) patients in the single-agent and combination arms, respectively. Most common TRAEs were fatigue, gastrointestinal, and skin disorders, and were of mild severity; seven patients experienced at least one treatment-related serious adverse event in the single-agent (5%) and combination group (5.8%). Antitumor activity was observed in the combination arm, with 3 (2%) complete responses and 10 (8%) partial responses in a mixed population of tumor types. In the combination arm, eight patients (6.6%) experienced stable disease for 6 months or longer versus six patients (4.5%) in the single-agent arm. Responding patients trended towards having higher levels of immune gene expression, including CD8 and LAG3, in tumor tissue at baseline. Conclusions Ieramilimab was well tolerated as monotherapy and in combination with spartalizumab. The toxicity profile of ieramilimab in combination with spartalizumab was comparable to that of spartalizumab alone. Modest antitumor activity was seen with combination treatment.This study was sponsored by Novartis Pharmaceuticals Corporation and preliminary results were previously presented at ASCO 2018

Phase I prognostic online (PIPO): A web tool to improve patient selection for oncology early phase clinical trials

Immunotherapy; Phase 1 trials; Prognostic modelInmunoterapia; Ensayos de fase 1; Modelo pronósticoImmunoteràpia; Assajos de fase 1; Model pronòsticPurpose Patient selection in phase 1 clinical trials (Ph1t) continues to be a challenge. The aim of this study was to develop a user-friendly prognostic calculator for predicting overall survival (OS) outcomes in patients to be included in Ph1t with immune checkpoint inhibitors (ICIs) or targeted agents (TAs) based on clinical parameters assessed at baseline. Methods Using a training cohort with consecutive patients from the VHIO phase 1 unit, we constructed a prognostic model to predict median OS (mOS) as a primary endpoint and 3-month (3m) OS rate as a secondary endpoint. The model was validated in an internal cohort after temporal data splitting and represented as a web application. Results We recruited 799 patients (training and validation sets, 558 and 241, respectively). Median follow-up was 21.2 months (m), mOS was 10.2 m (95% CI, 9.3–12.7) for ICIs cohort and 7.7 m (95% CI, 6.6–8.6) for TAs cohort. In the multivariable analysis, six prognostic variables were independently associated with OS – ECOG, number of metastatic sites, presence of liver metastases, derived neutrophils/(leukocytes minus neutrophils) ratio [dNLR], albumin and lactate dehydrogenase (LDH) levels. The phase 1 prognostic online (PIPO) calculator showed adequate discrimination and calibration performance for OS, with C-statistics of 0.71 (95% CI 0.64–0.78) in the validation set. The overall accuracy of the model for 3m OS prediction was 87.2% (95% CI 85%–90%). Conclusions PIPO is a user-friendly objective and interactive tool to calculate specific survival probabilities for each patient before enrolment in a Ph1t. The tool is available at https://pipo.vhio.net/.The research leading to these results has received funding from “la Caixa” Foundation (LCF/PR/CE07/50610001). Cellex Foundation for providing research facilities and equipment. This work was supported by the Accelerator Award (UpSMART) from Fundacion Científica – Asociacion Espanola Contra el Cancer (FC -AECC)/ Associazione Italiana per la Ricerca sul Cancro (AIRC) /Cancer Research United Kingdom (CRUK)