Results from a phase II study of eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab in patients with PD-L1 unselected metastatic second-line squamous head and neck carcinoma.

Abstract

6028 Background: Eftilagimod alpha (efti) is a soluble LAG-3 protein that binds to a subset of MHC class II molecules to mediate antigen presenting cell (APC) activation and CD8 T-cell activation. The stimulation of the dendritic cell network and subsequent T cell recruitment with efti may lead to stronger anti-tumor responses in combination than observed with pembrolizumab alone. We hereby report results of the 2nd line metastatic squamous head and neck carcinoma (HNSCC) cohort (part C) of phase II trial (NCT03625323). Methods: Patients (pts) with HNSCC progressed on or after 1st line platinum-based therapy and unselected for PD-L1 expression were recruited into part C. The study used a Simon's 2-stage design (18 pts planned for stage 1 and 19 for stage 2), with objective response rate (ORR) by iRECIST as the primary endpoint (EP). Secondary EPs include tolerability, disease control rate (DCR), progression free survival (PFS), overall survival (OS), pharmacokinetics, pharmacodynamics and immunogenicity. Efti was administered as 30 mg subcutaneous injection every 2 wks for 8 cycles and then every 3 wks for 9 cycles with pembrolizumab (200 mg intravenous infusion every 3 wks for up to 2 yrs). Imaging was performed every 8 weeks. PD-L1 was assessed centrally (22C3 clone). The study was approved by ethics committees and institutional review boards. Results: In total 38 pts were enrolled. The median age was 62 yrs (range 37-84) and 89 % were male. The ECOG PS was 0 and 1 in 34% and 66%, respectively. Primary location at diagnosis was the oral cavity (29%), oropharynx (37%), hypopharynx (18%) and the larynx (16%). All PD-L1 subgroups (CPS < 1 %, ≥ 1 to ≤19; ≥20) were included. All pts were pre-treated with platinum-based chemotherapy. Pts received a median of 3.0 (range 1 – 21) pembrolizumab and 5.0 (range 1-31) efti administrations. Thirty-five (35) pts were evaluated for response (cut-off Jan 2021) with 4 (11 %) pts showing CR, 7 (20 %) pts PR, 3 (9 %) pts SD, 16 (46 %) pts PD with 5 (14 %) pts being not evaluable as per iRECIST. ORR was reported with 31.4 % (95 % CI 16.9 % - 49.3 %) and DCR 40 %Median PFS was 2.1 months and 35 % were progression free at 6 months. Median OS (46 % events) was 12.6 months. There were no adverse reactions leading to treatment discontinuation. The most common ( > 10 %) treatment emergent adverse events were cough (18 %), asthenia (16 %), dyspnea (11 %), fatigue (13 %), diarrhea (11 %), hypothyroidism (11%), upper respiratory tract infection (11%) and back pain (11%). Conclusions: Efti in combination with pembrolizumab is safe and shows encouraging antitumor activity in platinum pre-treated 2nd line HNSCC patients. Clinical trial information: NCT03625323.

Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities

“…In the case of NSCLC, the relatively favorable immune environment in most NSCLC cases 653 suggests that targeting these additional checkpoints could potentially be advantageous. LAG-3 agents have demonstrated efficacy in solid tumor entities such as NSCLC and HNSCC, [52][53][54] and TIGIT agents are currently in several clinical trials in combination with PD-1/PD-L1 agents in NSCLC (Table 1). Exploration of B7 is ongoing across various solid tumors.…”

“… 52 Other combinations like miptenalimab plus ezabenlimab and favezelimab plus pembrolizumab are still under phase I exploration (Table 1 and Supplementary Table 1 ). LAG-3-Ig fusion protein eftilagimod alpha plus pembrolizumab caused an overall response rate (ORR) of 33% and 50% in pembrolizumab-refractory and anti-PD-1 naïve non-small cell lung cancer (NSCLC) patients, respectively, 53 and showed a similarly considerable effect 54 in head and neck squamous cell carcinoma (HNSCC) patients, thus was granted fast track status by FDA for NSCLC and HNSCC. The LAG-3 pathway has thus now been established as the third immune checkpoint pathway that can be inhibited to stimulate anti-tumor immune responses with clinical benefit.…”

Novel Immune Oncology Targets Beyond PD-1/PD-L1 in Head and Neck Cancer

“…Relatlimab is a MoAb that is being investigated either in combination with nivolumab plus ipilimumab or with nivolumab plus an indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor in a phase I/II study in the advanced setting (NCT03459222) (Table 5.2). Eftilagimod alpha is a soluble LAG-3 protein that binds to a subset of major histocompatibility complex (MHC) class II molecules to mediate antigen presenting cell activation and CD8 T-cell activation, that was studied in combination with pembrolizumab in a phase II trial for HNSCC patients who had progressed on or after a first-line platinum-based therapy (NCT03625323) [11]. First reported results showed an encouraging ORR of 31.4% (95% CI: 16.9-49.3%) in patients unselected for PD-L1 tumor expression and deserves further development [11] (Table 5.…”