Clinical use of immune-checkpoint inhibitors: focus on late immune-related adverse events and pseudoprogression

Abstract

Background: Immune-checkpoint inhibitors are changed the treatment's paradigm of Non Small Cell lung cancer in second line setting and for patients with high expression of PD-L1, they play a key role in first-line setting. The immune-based mechanism of action of these drugs determine a spectrum of adverse events called immune-related adverse events (irAEs) and a possibility of atypical response patterns called Pseudoprogression. These treatments require understanding of the management of Immune-related adverse events (irAes) in terms of Incidence and Kinetics of onset and a characterization of atypical response (Pseudoprogression) with Immune-related criteria (irRC). Materials and methods: Sevent-two patients treated with Nivolumab Monotherapy enrolled in Expanded access program and in Clinical Practice were retrospectively studied. Incidence and Kinetics of onset and resolution of irAES (Cutaneous, gastronintestinal, hepatic, endocrine, renal and pulmonary-effects) were evaluated. Late irAEs were defined as irAEs occurred after 12 weeks to start of therapy. Using irRC Pseudoprogression was identified. Results: From August 2015 to May 2017 72 pts are treated with Nivolumab and 43 (60%) pts are elegibile for evaluation of response and later toxicities. The median age at NSCLC diagnosis was 66.5 (55-80) years. Twenty-three pts (76.7%) were male. Twenty-five pts (58.1%) were former smokers, 16 pts (37.2%) were current smokers.Squamous NSCLC was the most common histology (22 pts, 52%). Most pts received Nivolumab in Second-line therapy (31, 72,1%) and 9 (21%) in third line therapy. Median Progression Free Survival(PFS) was 7.2 months (1.75-20.5 months) and in 9 (21%) PFS was superior to 12 months. Incidence of Pseudoprogression was very low (3 pts, 7%) and the treatment in 2 of these pts is ongoing. The Skin events was reported in 4 (9%) of pts and in 1(25%) occurred after 40 weeks of treatment. Gastrointestinal events was reported in 11(25%) of pts and in 5(45%) occurred after 12 weeks, 2(40%) of these occurred after 30 weeks. Endocrine events occurred in 5(11%) pts and in 2 (40%) pts occurred after 12 weeks. Pulmonary events occurred in 3(7%) and 1 of these occurred at 37 weeks. Conclusion: Incidence of atypical response seems a rare events in patients treated whit Nivolumab and seems associated with longer PFS. In our clinical practice the incidence of irAEs is very low but the time to onset is not predictable and some events often occur late.