In 2016, immune checkpoint inhibitors entered the therapeutic portfolio of squamous cell carcinoma of the head and neck (SCCHN) in the second-line recurrent and/or metastatic setting, and it took another three years that the long-awaited results of the first-line KEYNOTE-048 trial demonstrated superiority relative to the standard cytotoxic doublet with cetuximab (1-3). As for a brief historical review, the combination of a platinum derivate, preferably cisplatin, and 5-fluorouracil emerged as a reference regimen for recurrent and/or metastatic SCCHN already in 1980s, although its impact on overall survival has rather been assumed on a basis of extrapolations than proved in large randomized trials (4). The major turning point came when the results of the EXTREME trial (Erbitux in firstline treatment of recurrent or metastatic head and neck cancer) were published back in 2008. Adding cetuximab, a monoclonal antibody against the epidermal growth factor receptor (EGFR), to a platinum/5-fluorouracil combination improved overall survival by almost 3 months at acceptable toxicity rates and no cetuximab-related deaths (3). Since then, the 10-month median survival mark achieved by EXTREME has repeatedly been confirmed in several large randomized trials using this regimen in the comparator arm (2, 5, 6). However, this progress related only to the firstline setting in platinum-sensitive patients. At that time, the outcomes of second-line treatment remained bleak with an expected median survival of 3 to 6 months (7).

This changed in 2016. The immune checkpoint inhibitor nivolumab, an immune-modulating monoclonal antibody against programmed cell death protein-1 (PD-1), became the first drug ever to significantly prolong median overall survival to about 8 months in platinumresistant patients enrolled in the CheckMate-141 trial (1). Using pembrolizumab, another anti-PD-1 agent, this benefit was reproduced in the succeeding KEYNOTE-040 trial. Besides that, the latter trial introduced a longawaited predictive biomarker, albeit originating from an exploratory analysis. With a P value for interaction of 0.015, the tumour proportion score (TPS), corresponding with the percentage of tumour cells with membranous staining of the ligand for PD-1 (PD-L1), of 50% or more was associated with improved benefit in comparison to a lower expression, particularly with respect to survival and tumour response (8). Subsequently, high hopes were put into the first-line administration of immune checkpoint inhibitors. The KEYNOTE-048 trial randomly assigned platinumsensitive patients to receive either the standard of care, ie, the EXTREME regimen, or a single-agent pembrolizumab, or a combination of the two, ie, a platinum/5-fluorouracil doublet with pembrolizumab (2). While the primary hypothesis of the two former immunotherapy studies focused solely on the superiority of the respective immune checkpoint inhibitors for overall survival, there were in total 14 primary hypotheses