Background: Eftilagimod alpha (E), a soluble LAG-3 protein, acts as an MHC class II agonist triggering activation of antigen-presenting cells (APC) and CD8 T-cells. Using efti to enhance patients’ immunity may lead to stronger anti-tumor responses than observed with pembrolizumab (P) alone. We report final results from Part C of the TACTI-002 trial (NCT03625323) where 2^nd line metastatic head and neck squamous cell carcinoma (HNSCC) patients (pts) unselected for PD-L1 were treated with E + P. Methods: Pts with metastatic HNSCC, unselected for PD-L1 expression with disease progression on or after 1^st line platinum-based therapy (± cetuximab) were enrolled. Primary endpoint (EP) was objective response rate (ORR) by iRECIST. Other EPs included tolerability, progression free survival (PFS), duration of response (DoR), and overall survival (OS). Pts received E (30 mg SC Q2W for eight 3-week cycles and then Q3W up to 1 yr) with P (200 mg IV Q3W up to 2 yrs). Imaging was performed Q9W. PD-L1 was retrospectively assessed using the IHC 22C3 kit. The study was approved by ethic committees and institutional review boards. Results: 39 pts were enrolled between Mar 2019-Jan 2021 (cut-off Jul 2022) with HNSCC of oropharynx (38%), oral cavity (32%), hypopharynx (19%) and larynx (16%). Median age was 63 yrs (48-84 yrs) and 90% were male. ECOG PS was 0 and 1 in 35% and 65% of pts. Two pts were excluded from efficacy results due to fatal COVID-19 prior to their first post-baseline scan. The primary EP, ORR by iRECIST, was 30% with 14% complete responders (see table). ORR by RECIST 1.1 was comparable (24%). Median PFS by iRECIST was 2.1 mo with 32% of pts progression-free at 6 mo. Median OS was 8.7 mo with 46% alive at 12 mo. Median DoR by iRECIST was not reached with 17 mo min FU. Responses were seen in all PD-L1 subgroups (see table). ORR, 6-mo PFS, 12-mo OS rates for PD-L1 CPS ≥20 were 60%, 53%, 73% with a median OS of 15.5 months. Two pts (5%) discontinued due to adverse events (AE) (fatigue and arthralgia [each grade 2]; pneumonitis [grade 3]) that were related to study treatment (efti and/or pembro). The most common (≥15%) AEs were hypothyroidism (21%), asthenia (21%), cough (18%), anemia (18%), weight decrease (18%), and fatigue (15%). Conclusions: Efti + pembrolizumab is safe, showing encouraging antitumor activity in platinum and partially cetuximab pre-treated, 2nd line HNSCC patients. TACTI-003 (NCT04811027) a randomized study in 1st line HNSCC is currently recruiting. Response by iRECIST: Clinical trial information: NCT03625323.

NR: not reached.