Phase 1 study of fianlimab, a human lymphocyte activation gene-3 (LAG-3) monoclonal antibody, plus cemiplimab in advanced melanoma

Background: Concurrent LAG-3 blockade may enhance efficacy of anti-program cell death-1 (PD-1) therapies such as cemiplimab. We present updated safety and clinical activity data from patients with advanced melanoma treated concurrently with cemiplimab and fianlimab (NCT03005782). Methods: Patients were included with unresectable or metastatic melanoma (excluding uveal melanoma) who were anti-PD-ligand (L) 1 treatment naive (expansion cohort [EC] 6) or anti-PD-(L)1 experienced within 3 months of screening (EC7). Patients received fianlimab 1600 mg + cemiplimab 350 mg intravenously every 3 weeks for 12 months (optional extra 12 months if clinically indicated). Tumours were measured every 6 weeks for 24 weeks, then every 9 weeks. In EC6 (n = 40) and EC7 (n = 15), respectively (data cutoff 9th February 2022), median age was 69.5 and 59.0 years, and median treatment duration was 37.1 and 9.0 weeks. Results: In EC6 and EC7, respectively, incidence of Grade ≥3 treatment-emergent adverse events (TEAEs) were 38% and 47%, incidence of serious TEAEs was 33% and 33%, and 18% and 13% of patients discontinued treatment due to a TEAE. Adrenal insufficiency rate was 13% and 7% in EC6 and EC7, respectively; no instances led to treatment discontinuation. Investigator-assessed objective response rate was63%(six complete responses; 19 partial responses) in EC6 and 13% (two partial responses) in EC7. Kaplan-Meier estimate of median progression-free survival was 14.2 (95% CI: 5.6-not estimated) months in EC6 and 1.4 (95% CI: 1.3-7.7) months in EC7. Median duration of response was not reached in EC6 or EC7. Conclusion: Fianlimab plus cemiplimab in advanced melanoma had a similar safety profile to anti-PD-1 monotherapies. Clinical activity in anti-PD-(L)1-naive patients appeared higher than previously reported for anti-PD-1monotherapy or anti-LAG-3 plus anti-PD-1. A Phase 3 trial (NCT05352672) investigating fianlimab plus cemiplimab in advanced melanoma is ongoing

A study of REGN3767, an antiLAG3 antibody, alone and in combination with cemiplimab (REGN2810), an antiPD1 antibody in advanced cancers

Background: Lymphocyte activation gene 3 (LAG3) is an immune checkpoint receptor with a biological role in Tcell regulation. Analysis of immunecell infiltrates from human tumors show that a subset of CD4+ and/or CD8+ cells coexpress LAG3 and PD1 and may be associated with decreased Tcell effector function and tumor escape (Baitsch, 2011; Jie, 2013). Preclinical models provide evidence that dual inhibition of LAG3 and PD1 blockade offer synergistic antitumor effects and suggest a promising immunotherapy combination that warrants clinical investigation (Woo, 2012). This first in human study will evaluate the safety and efficacy of REGN3767 alone and in combination with cemiplimab in advanced malignancies.Methods: Phase 1 study enrolling patients with advanced malignancies. Dose escalation phase employs a modified 3+3 (4+3) design to assess the tolerability and pharmacokinetics (PK) of REGN3767 monotherapy and in combination with cemiplimab. Monotherapy and combination therapy are exploring multiple escalating REGN3767 dose levels. After tolerability and PK evaluation, doses of REGN3767 will be selected for monotherapy and combination therapy tumorspecific expansion cohorts. Solid tumor expansion cohorts will enroll per Simon\u27s twostage design to evaluate safety and preliminary efficacy. Lymphoma expansion cohorts will enroll 15 patients. Patients who are antiPD1/PDL1 therapy naïve and experienced are eligible for separate cohorts. Patients previously exposed to antiLAG3 therapy are not eligible. The primary objectives are the determination of the recommended dose for expansion (dose escalation) and ORR (dose expansion). Secondary objectives include characterization of PK and immunogenicity in all patients, as well as antitumor efficacy in dose escalation, and safety in dose expansion. This trial is actively enrolling eligible patients in the US, UK, Ireland, and South Korea

790MO Phase I study of fianlimab, a human lymphocyte activation gene-3 (LAG-3) monoclonal antibody, in combination with cemiplimab in advanced melanoma (mel)

Background: Concurrent blockade of LAG-3 may enhance efficacy of anti-programmed cell death-1 (PD-1) therapies. We present updated safety and clinical activity data from patients (pts) with advanced mel treated with concurrent anti-LAG-3 (fianlimab) and anti-PD-1 (cemiplimab). Methods: This phase 1 study included pts with unresectable or metastatic mel (excluding uveal mel) who were anti–PD-(L)1 treatment naïve (expansion cohort [EC] 6) or anti–PD-(L) 1 experienced within 3 months of screening (EC7). Pts received fianlimab 1600 mg + cemiplimab 350 mg intravenously every 3 weeks for 12 months (optional additional 12 months if clinically indicated). Tumour measurements were performed every 6 weeks for 24 weeks, then every 9 weeks. Results: As of the 9 Feb 2022 data cutoff date, 40 EC6 and 15 EC7 pts were enrolled and treated with fianlimab + cemiplimab. For EC6 and EC7 cohorts respectively, median age was 69.5 and 59.0 years, 62.5% and 46.7% were male, 90.0% and 60.0% were White. Median treatment duration was 37.1 weeks (EC6) and 9.0 weeks (EC7). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 37.5% (EC6) and 46.7% (EC7) of pts; serious TEAEs occurred in 32.5% (EC6) and 33.3% (EC7) of pts; 17.5% (EC6) and 13.3% (EC7) of pts discontinued treatment due to a TEAE. Rate of adrenal insufficiency (AI) was 12.5% (EC6) and 6.7% (EC7); none led to treatment discontinuation. Investigator-assessed objective response rate was 62.5% (6 complete responses; 19 partial responses [PRs]) in EC6 and 13.3% (2 PRs) in EC7 pts. Kaplan-Meier estimation of median progression-free survival was 14.2 (95% CI: 5.6–not estimated) months in EC6 and 1.4 (95% CI: 1.3–7.7) months in EC7 pts. Median duration of response had not been reached in both cohorts. LAG-3 and PD-L1 correlative biomarkers analysis will be included in the presentation. Conclusions: Fianlimab + cemiplimab in advanced mel pts had a similar safety profile to anti–PD-1 agents; clinical activity in anti-PD-(L)1-naïve patients appears higher than previously reported for anti-PD-1 monotherapy or anti–LAG-3 + anti–PD-1. A phase 3 trial (NCT05352672) investigating fianlimab + cemiplimab in advanced mel pts is ongoing

First-in-human study of REGN3767 (R3767), a human LAG-3 monoclonal antibody (mAb), ± cemiplimab in patients (pts) with advanced malignancies

Background: We present initial safety, pharmacokinetics (PK), and efficacy from the dose escalation study of R3767, alone (mono) or in combination with cemiplimab (REGN2810), a PD-1 mAb (combo), in pts with advanced malignancies (NCT03005782). Methods: Pts who had progressed on prior therapy(ies) and/or for whom no therapy with clinical benefit was available were enrolled; most pts had received no prior anti-PD-1/PD-L1. Pts received R3767 1, 3, 10, or 20 mg/kg every 3 weeks (Q3W) ± cemiplimab 3 mg/kg or 350 mg Q3W IV for ≤51 weeks. Crossover from mono to combo was allowed at progression. R3767 PK were evaluated. Tumor measurements were performed Q6W for the first 24 weeks and subsequently Q9W. Data cut-off date was Aug 25, 2018. Results: Mono: 27 pts (median age: 66 yr; ECOG PS: 0 [n=4], 1 [n=23]) were treated. There were no dose-limiting toxicities (DLTs). The most common treatment-emergent adverse event (TEAE) was nausea (22.2%). Grade ≥3 immune-related adverse events (irAEs) of increased alanine and aspartate aminotransferases (each 3.7%) were reported. By investigator-assessment (per RECIST 1.1; INV), best response was stable disease in 11 pts. Combo: 42 pts (median age: 60 yr; ECOG PS: 0 [n=15], 1 [n=27]) were treated. One pt treated with R3767 3 mg/kg Q3W + cemiplimab 3 mg/kg Q3W experienced DLT of grade 4 elevated blood creatine phosphokinase, associated with grade 3 myasthenia syndrome and grade 1 elevated troponin. The most common TEAEs were fatigue (33.3%) and nausea (21.4%). Grade 3 irAE of hypothyroidism (2.4%) was also reported. By INV, 2 (both small cell lung cancer) combo pts and 2 (endometrial cancer and cutaneous squamous cell carcinoma) of 12 additional pts who crossed over from mono to combo had partial responses. PK: R3767 concentrations in serum increased in a dose-dependent manner and were unaffected by combo. Conclusions: The safety profile of R3767 ± cemiplimab was generally tolerable; PK was linear. Early efficacy signals were detected despite the difficult-to-treat pt population. Biomarker studies are ongoing. R3767 20 mg/kg or 1600 mg fixed dose equivalent Q3W as mono and combo were selected for further evaluation