Background: Afatinib and pembrolizumab have demonstrated improvements in the outcomes of pts with SCC of the lung and are approved as monotherapy. Afatinib is a selective and irreversible ErbB family blocker with activity against all homo- and heterodimers formed by ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3, and ErbB4. Pembrolizumab is a humanized IgG4 monoclonal antibody with potent receptor-blocking activity for PD-1. Given the efficacy of these agents as monotherapy in chemo-refractory lung SCC, concurrent inhibition of PD-1 and EGFR pathways represents a promising approach to improve clinical outcomes in lung SCC. Methods: Study 1200.283 (NCT03157089; LUX-Lung IO/Keynote 497) is a phase II, single-arm study (n = 50?62). Eligible pts have stage IIIB/IV lung SCC, progressed during/after first-line platinum-based chemotherapy, and have an ECOG PS 0/1. Prior immune checkpoint inhibitor or EGFR targeted therapy are prohibited. A safety run-in will be performed in 12 pts, using afatinib (starting dose 40 mg/day, with potential dose de-escalation to 30 mg) with pembrolizumab (200 mg every 3 weeks) to assess the safety and confirm the recommended Phase II dose (RP2D) based on dose limiting toxicities observed during the first cycle. In the main trial, afatinib at the RP2D, in combination with pembrolizumab, may be continued for a maximum of 35 cycles. In case of toxicity, afatinib dose reduction to 30/20 mg will be permitted. Primary endpoint is objective response (OR; complete response [CR] or partial response [PR] [RECIST v1.1]). Further endpoints include disease control (CR, PR, stable disease), duration of OR, PFS, OS, and pharmacokinetics. All pts will provide a fresh or archived tumor tissue sample to measure PD-L1 expression and mRNA expression of genes involved in the immune system. Exploratory biomarkers include the evaluation of immune status by determination of tumor infiltrating cells (e.g. CD8+ cells) or TH1-type cytokines, and blood biomarkers related to the emergence of resistance at progression. This study is conducted in the US, Spain, France, Turkey, and Korea. As of January 2018, enrollment in the safety run-in is complete (n = 12). Clinical trial information: NCT03157089