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

Abstract

BackgroundLymphocyte-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.MethodsEligible 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).ResultsIn 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.ConclusionsIeramilimab 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.Trial registration numberNCT02460224.

Therapeutic targets and biomarkers of tumor immunotherapy: response versus non-response

“… 169 – 172 Coexpression of LAG-3 and PD-1 on intratumor T cells has been observed in several mouse tumor models, and synergistic inhibition of tumor growth was observed when combining the blocking antibodies of these two molecules. 173 – 176 …”

Preclinical Characterization of Relatlimab, a Human LAG-3–Blocking Antibody, Alone or in Combination with Nivolumab

“…Although the focus of this report is the characterization of relatlimab itself, our in vivo results corroborate a large body of existing literature which demonstrates that the combined treatment of mice with blocking antibodies against LAG-3 and PD-1 receptors results in more robust immune responses than either single-agent treatment (9,40). There is a well-developed understanding that the co-blockade of LAG-3 and PD-1 acts to reinvigorate exhausted T cells more robustly than single immune checkpoint blockade, and results in enhanced polyfunctionality (IFNγ and TNFα production, and cytotoxic killing) to potentiate antitumor activity (9,11,(17)(18)(19)(41)(42)(43). Similarly, in the in vitro primary T-cell superantigen stimulation assays reported here, only modest activity was observed from LAG-3 single-agent blockade with relatlimab compared with the substantially enhanced responsiveness in the context of co-blockade of LAG-3 and PD-1 with relatlimab and nivolumab, respectively.…”

Dosing Regimens of Immune Checkpoint Inhibitors: Attempts at Lower Dose, Less Frequency, Shorter Course

“…Previously established methodology of dose-finding in earlystage clinical trials has not progressed with the therapeutic improvements, and the concept of maximally tolerated doses (MTD) has much less instructive for ICIs recommended dose. If the MTD is not reached during dose escalation, the recommended phase 2 dose could be evaluated based on safety profile, pharmacokinetics/pharmacodynamics modelling simulations, early efficacy biomarkers, the variation of immunological composition reflecting immunomodulatory effect, target engagement receptor occupancy model and other new parameters (139)(140)(141)(142)(143). Besides, appropriate extension of the follow-up period may help to reduce the bias brought by unrecognized toxicity.…”