Key roles of immune-check inhibitors for first- and second line treatment for advanced NSCLC

Abstract

Early development of anti-PD-1/PD-L1 in advanced NSCLC demonstrated long lasting responses translating into long term survival for approximately 15% of patients. Five phase III studies including mainly unselected patients compared anti-PD-1/PD-L1 as single agent with docetaxel in 2nd line setting. Four studies showed a significant OS benefit, doubling 2-year survival rates and a better tolerance profile with around 10% grade 3-4 immune-related adverse events. The lack of PFS improvement and an increase in the early death rates in one trial underscored the need for a better patients selection. PD-L1 expression appears as an enrichment factor correlated with the probability of response and the magnitude of OS benefit. The development of pembrolizumab has established more than 50% of tumor cells expressing PD-L1 as the best cutoff for a high probability of response. Other predictive biomarkers are under investigation, notably the tumor mutational burden. In 1st line setting, the Keynote 024 trial compared pembrolizumab to platinum-based doublet in tumors with high PD-L1 expression and demonstrated a large OS benefit with 30 months median survival compared to 14.2 months in the control arm despite a cross over in 62% of patients, establishing pembrolizumab as the new standard of care for these patients. The 2nd lead combined anti-CTLA4 and anti-PD1/PD-L1 with an announcement of a significant PFS benefit for ipilimumab-nivolumab combination compared to 1st line chemotherapy in case of TMB > 10 mutations/Mb. The 3rd lead in 1st line setting assessed in unselected patients combinations of cytotoxic chemotherapy and anti-PD-1/PD-L1. The addition of atezolizumab to carboplatin-paclitaxel-bevacizumab provided a significant PFS improvement while the combination of pembrolizumab to a platinum-pemetrexed regimen improved both PFS and OS. These new combinations will change the NSCLC treatment algorithm, underscoring the need of predictive biomarkers for patients selection.