Immune checkpoint inhibition in small cell lung cancer: a key to reach an unmet need?

Small cell lung cancer (SCLC), accounting for 13–15% of all lung cancers, is strongly correlated with smoking and it is associated with a poor overall survival (OS) (2-year OS rate: 5%), particularly in patients with extensive disease (1,2). Furthermore, SCLC is one of the solid tumors with a higher mutational burden and an almost universal inactivation of TP53 and Rb1 genes; conversely, potential druggable genome aberrations were very rare (3,4). In the last 30 years, no new effective treatment strategies have emerged and platinum-based chemotherapy represents the standard of care in first-line setting. Despite the high objective response rates (ORR), relapse is an unavoidable event. Recommended salvage second-line chemotherapy is limited to intravenous topotecan and its efficacy depends on the duration of response (DOR) to first-line treatment (5). A treatment-free interval (TFI) shorter than 60 days was identified as a cut-off able to predict patients refractory to second-line chemotherapy and with a poor prognosis (6). Amrubicin is an alternative option in second-line setting, although it is approved only in Japan (7). In contrast to recent milestone changes in the landscape of advanced non-small cell lung cancer (NSCLC) treatment, obtained with the advent of targeted therapies and immune checkpoint inhibitors, SCLC still lacks new effective treatment strategies. In this daunting scenario, Ott and colleagues explored safety and efficacy of pembrolizumab, a highly selective anti-programmed cell death 1 (PD-1) humanized monoclonal IgG4 antibody, in patients with PD-L1 (programmed cell death ligand 1) positive extensive-stage SCLC (8). In this multi-cohort, phase Ib open-label study, 163 patients were screened and only 46 (31.7%) had tumor expressing PD-L1, with a membranous PD-L1 staining cut-off of ≥1% in tumor and associated inflammatory cells or in stroma, evaluated in a central laboratory by using the 22C3 antibody. The primary end points were safety, tolerability and ORR; secondary end-points were progression-free survival (PFS), DOR and OS. Out of 46 patients, only 24 patients were treated with pembrolizumab 10 mg/kg intravenously every 2 weeks for 24 months or until disease progression, unacceptable toxicity or other reasons. Of note, 21 of enrolled patients (87.5%) received ≥2 prior lines of therapy for advanced disease, and 9 of them (37.5%) were heavily pretreated (≥3 lines). All patients were evaluable for tolerability and safety results showed no unexpected adverse events (AEs); most common AEs of any grade were arthralgia, asthemnia and