Regeneron Reports 64% Objective Response Rate with Fianlimab Plus Libtayo in PD-(L)1-Naïve Advanced Melanoma Patients

May 23, 2021 /BioonBIOON/ -- Regeneron recently announced clinical data for the first time on the LAG-3 inhibitor fianlimab in combination with the PD-1 inhibitor Libtayo (cemiplimab) for the treatment of advanced melanoma. The results showed that,In advanced patients previously untreated with anti-PD-(L)1 therapy (treatment-naïve)MelanomaIn patients, dual immunotherapy with fianlimab plus cemiplimab demonstrated robust efficacy: the objective response rate (ORR) reached 64%.

Fianlimab and cemiplimab are two high-affinity, fully human, hinge-stabilized IgG4 monoclonal antibodies. In a Phase 1 dose-escalation study, fianlimab in combination with cemiplimab in advanced malignantTumorDemonstrated acceptable safety and some clinical activity in patients.

The data presented herein are from an open-label, dose-escalation, cohort-expansion, first-in-human Phase 1 study (NCT03005782). This study is evaluating fianlimab as monotherapy and the combination of fianlimab plus cemiplimab for the treatment of advancedMelanomasafety, tolerability, efficacy, and pharmacokinetics. In the study, patients who had not previously received anti-PD-(L)1 therapy (treatment-naïve) and those who had received anti-PD-(L)1 therapy within a 3-month screening period (treatment-experienced) received intravenous infusions of 1600 mg of fianlimab and 350 mg of cemiplimab once every 3 weeks.TumorAssessments will be performed every 6 weeks for the first 24 weeks and every 9 weeks thereafter.

Melanoma (Image source: melanoma.org.au)

As of the data cutoff date of January 4, 2021, a total of 48 patients received treatment with fianlimab + cemiplimab, of whom 33 were anti-PD-(L)1 therapy-naive and 15 were anti-PD-(L)1 therapy-experienced.

Investigator-assessed results show that fianlimab + cemiplimab dual immunotherapyThe greatest efficacy was observed in the patient population previously untreated with anti-PD-(L)1 therapy (treatment-naïve).: 21 out of 33 patients experienced remission, i.e.,The objective response rate (ORR) was 64%, of which 3 patients achieved complete response (CR) and 18 partial response (PR), with median progression-free survival (PFS) and median duration of response (DOR) not reached.

whileIn the patient population previously treated with anti-PD-(L)1 therapy, the fianlimab plus cemiplimab regimen demonstrated limited efficacy, with an ORR of 13.3%., among 15 patients, 1 achieved CR and 1 achieved PR.

In this study, the safety profile of the fianlimab plus cemiplimab combination therapy (including immune-related adverse events) was similar to that of anti-PD-1 monotherapy, with one exception. The incidence of adrenal insufficiency was 8.3% (4/48), which was similar to the rate observed with anti-PD-1 plus anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) combination therapy, but higher than that with anti-PD-1 monotherapy. Among the 48 patients receiving the combination of fianlimab and cemiplimab (Libtayo), the most common adverse events (AEs) were fatigue (n=15; 31%) and rash (n=11; 23%). Grade 3 or higher adverse events occurred in 35% (n=17) of patients, with 23% (n=11) classified as serious adverse events. 8% (n=4) of patients discontinued treatment due to adverse events.

Currently, clinical prognostic biomarkers andTumorBiomarker, such as the expression of LAG-3, PD-L1, and major histocompatibility complex class II (MHC-II), is being evaluated. Patient enrollment is also ongoing.

Activating receptors on T cells【Left】and inhibitory receptors【Right】

(Image sourced from literature: DOI:10.3389/fonc.2018.00310)

Fianlimab specifically binds to an inhibitory receptor—lymphocyte-activation gene 3 protein (LAG-3), demonstrating potential immune checkpoint inhibition and anti-TumorActivity. LAG-3 is an inhibitory immune checkpoint on T cells. Similar to PD-1 and CTLA-4, LAG-3 negatively regulates T cell proliferation, activation, and homeostasis. Blocking the LAG-3 signaling pathway can restore effector T cell function.

Following administration, fianlimab binds to LAG-3 expressed on tumor-infiltrating lymphocytes (TILs) and blocks the interaction between LAG-3 and tumor cells expressing major histocompatibility complex class II (MHC-II) molecules. This may activate antigen-specific T lymphocytes and enhance cytotoxic T lymphocyte (CTL)-mediated tumor cell lysis, thereby resulting in slowed tumor growth. LAG-3 is a member of the immunoglobulin superfamily (IgSF) and is expressed on various immune cells; its expression on TILs is associated withTumorassociated with mediated immunosuppression and the negative regulation of cell proliferation and T cell activation.

Currently, multiple immune checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4 have been marketed, and these agents have transformed cancer treatment. However, many patients still fail to derive clinical benefit from them, necessitating the development of novel immune checkpoint inhibitors or the design of new combination immunotherapies leveraging complementary pathways to enhance anti-TumorActivity.

LAG-3 is another highly promising immunotherapy target following PD-1/PD-L1 and CTLA-4, with multiple pharmaceutical companies already advancing pipelines in this space, including Bristol-Myers Squibb,Novartis、Boehringer Ingelheim、Sanofi、Regeneron、GlaxoSmithKline, Roche, etc. In addition to monotherapy, the combination of LAG-3 inhibitors with other immune checkpoint inhibitors (such as PD-(L)1 inhibitors) may yield synergistic anti-TumorActivity. (Bioon.com)

Original source: Clinical activity of fianlimab (REGN3767), a human anti-LAG-3 monoclonal antibody, combined with cemiplimab (anti-PD-1) in patients (pts) with advanced melanoma.