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Phase I/II study of LAG525 ± spartalizumab (PDR001) in patients (pts) with advanced malignancies.
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2018
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Phase I/ii StudyImmunologyPathologyBrain Tumor EdemaPharmacotherapyImmunotherapyOncologyTumor ImmunityAnti-cancer AgentAdvanced MalignanciesLag525 ArmRadiation OncologyCancer ResearchMolecular OncologyCombination ArmLag525 ± SpartalizumabCancer TreatmentPharmacologyMalignant DiseaseImmune Checkpoint InhibitorMedicine
3012 Background: LAG525 and spartalizumab (PDR001), humanized IgG4 mAbs, block binding of LAG-3 to MHC class II and PD-1 to PD-L1 and PD-L2, respectively. Preclinical studies show synergistic anti-tumor activity when blocking PD-1 and LAG-3. Here, we report dose escalation results from a Phase I/II study of LAG525 ± spartalizumab in advanced malignancies (NCT02460224). Methods: LAG525 was dosed Q2W (1–15 mg/kg, or 240/400 mg) or Q4W (3–10 mg/kg, or 400 mg); LAG525 + spartalizumab was dosed at 15 dose levels/schedules from 0.3 mg/kg LAG525 + 1 mg/kg spartalizumab Q2W to 1000 mg LAG525 + 400 mg spartalizumab Q4W. Phase I endpoints (dose-limiting toxicities [DLTs], additional safety, pharmacokinetics, efficacy, and biomarkers) were used along with an adaptive Bayesian logistic regression model guided by escalation with overdose control to support future study dosing. Baseline and on-treatment tumor samples were collected. Results: As of 31 Jul 2017, 115/119 pts (97%) receiving LAG525 and 99/121 pts (82%) receiving LAG525 + spartalizumab had discontinued treatment, primarily due to progressive disease (79% and 67%, respectively). DLTs occurred in 4 pts in each arm (LAG525 arm: Gr 3 intra-abdominal fluid collection, lipase increase, vomiting; Gr 4 acute kidney injury. Combination arm: Gr 3 hyperglycemia, pneumonitis, brain tumor edema, fatigue; Gr 4 autoimmune hepatitis) without clear dose relationship. Common (≥10%) related AEs were fatigue (10%) for LAG525 alone and fatigue (18%), diarrhea (15%), and nausea (12%) for the combination. Gr 3–4 related AEs were reported in 10 pts (8%) in the LAG525 arm and 10 pts (8%) in the combination arm. Approximately dose-proportional increases in LAG525 exposure were seen. No MTD was identified for either arm. LAG525 + spartalizumab led to durable RECIST responses (11 PR, 1 CR) in a variety of solid tumors, including mesothelioma (2/8 pts) and triple-negative breast cancer (TNBC; 2/5 pts). In TNBC tumor biopsies, a trend in conversion of immune-cold to immune-activated biomarker profiles was seen. Conclusions: Treatment was well tolerated with preliminary anti-tumor activity and immune profile modulation observed for LAG525 + spartalizumab. Phase II is ongoing in selected indications. Clinical trial information: NCT02460224.