An Open-label, Randomized, Parallel, Non Comparative, Phase II Trial of Nivolumab Plus Ipilimumab Versus Platinum-based Chemotherapy Plus Nivolumab in Chemonaive Metastatic or Recurrent Squamous-Cell Lung Cancer (SqLC)

Better understanding of the role of the immunological system in tumor control has opened multiple doors to implement different strategies to enhance immune response against cancer cells. It is known that tumor cells elude immune response by several mechanisms. The development of monoclonal antibodies against the checkpoint inhibitor programmed cell death protein 1 (PD-1) and its ligand (PD-L1), on T cells, has led to high activity in cancer patients with long lasting responses. In the KEYNOTE 024 the anti-PD-1 inhibitor Pembrolizumab significantly prolonged progression-free survival (PFS) and overall survival (OS) of patients with advanced NSCLC and high PD-L1 level (\>50% of tumor cells) compared to platinum based chemotherapy, thus becoming a new standard of care in front line setting. However, the trial was not restricted to squamous population, with approximately 18% per arm having this histology. Nivolumab, another PD-1 inhibitor, has been recently approved for the treatment of squamous cell lung cancer patients, given the survival advantage demonstrated in a phase III trial comparing the drug to docetaxel, in second-line setting. Importantly, the benefit produced by the drug was irrespective of PD-L1 expression suggesting that the high mutation burden of squamous-cell lung carcinoma is more relevant than the expression of a single biomarker, at least in pretreated individuals. In addition, recent studies in chemo naive patients with non-squamous histology demonstrated that combination of chemotherapy and immunotherapy is superior to chemotherapy alone in terms of Overall Survival irrespective of PD-L1 expression (Keynote 189 and IMPOWER 150). In addition, the CheckMate 227 study recently showed that, in chemonaive NSCLC, combination of nivolumab and ipilimumab was superior to chemotherapy alone in patients with high tumor mutational burden (TMB), irrespective of PD-L1 expression. A recent press release announced that pembrolizumab plus chemotherapy produced higher response rate when compared to chemotherapy alone in patients with squamous-cell lung cancer (Keynote 407). Nevertheless, no data on Progression-Free Survival and Overall Survival are available. Therefore, considering the lack of data in patients with squamous histology and the lack of information about efficacy of combinations of immune-checkpoints inhibitors versus immune-checkpoint inhibitor plus chemotherapy, there is a strong rationale for conducting a study assessing efficacy of such strategies in patients with advanced, metastatic squamous-cell lung cancer.