Background: Eftilagimod alpha (efti, IMP321) is a recombinant LAG-3Ig fusion protein that binds to MHC class II and mediates antigen-presenting cell (APC) activation followed by CD8 T-cell activation. Pembrolizumab binds to the PD-1 receptor, blocking both immune-suppressing ligands, PD-L1 and PD-L2, from interacting with PD-1 to help restore effector T-cell responses. The rationale to combine efti and pembrolizumab comes from their complementary mechanisms of action. Efti activates APCs and lead to an increase in activated T cells which effect potentially reduces the number of non-responders to pembrolizumab. Combining an APC activator like efti to pembrolizumab is therefore fundamentally different from many other trials combining two checkpoint inhibitors like an anti-LAG-3 mAb with an anti-PD-1 mAb. In a previous phase I study (NCT 02676869) in metastatic melanoma the combination was found to be safe and well tolerable with encouraging signs of clinical activity. Methods: In the course of this multicenter, open label, Phase II study, patients will be recruited for each of three indications: A: 1st line, PD-X (PD-1 or PD-L1) naïve non-small cell lung cancer (NSCLC); B: 2nd line, PD-X refractory NSCLC; C: 2nd line PD-X naive head and neck squamous cell carcinoma (HNSCC). The study is designed according to Simon's optimal two-stage design, with objective response rate acc to iRECIST as primary endpoint. Secondary endpoints include progression free survival and overall survival. In case there are more responses achieved than a predefined threshold (each part counted separately) in pts recruited in the initial stage (n = 58), additional pts (51) will be recruited in stage 2. Efti will be administered for a maximum of 18 cycles (1 cycle = 3 weeks) as 30 mg subcutaneous injection every 2 weeks for the first 8 and every 3 weeks for the 10 following cycles. Pembrolizumab (200 mg intravenous infusion every 3 weeks) is administered in parallel for up to 35 cycles. Patients are followed up for progression and survival. Clinical trial information: 03625323.