Abstract

The combination of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies, two immune checkpoint inhibitors with distinct but complimentary mechanisms of action has shown clinical efficacy across different solid tumors. This concept also has been investigated in a number of randomized trials in patients with advanced NSCLC. In the Mystic trial patients with a PD-L1 expression =/> 25% were randomized to Durvalumab, Durvalumab plus Tremelimumab or platinum based chemotherapy. While clinical efficacy was observed for Durvalumab and the immunotherapy combination no significant improvement for one of the three primary endpoints was reported. In a retrospective analysis a correlation between blood based TMB and efficacy was shown favoring those patients with a high bTMB level. The BR.34 trial compared the combination of Durvalumab/Tremelimumab and chemotherapy with the immunotherapy combination in untreated advanced NSCLC and reported an improvement in PFS but no difference in OS. A prospective evaluation of the combination Nivolumab/Ipilimumab against chemotherapy in two cohorts of untreated patients with PD-L1 expressing or negative tumors was performed in the Checkmate 227 trial. Besides a significant prolongation of PFS in patients with high tissue based TMB also an improvement in the second coprimary endpoint (OS in patients with PD-L1 expressing tumors) was observed. Interestingly the activity of the immunotherapy combination was independent from the PD-L1 expression. In an approach to improve the early tumor control 2 cycles of chemotherapy were added to the combination of Nivolumab/Ipilimumab and were compared to chemotherapy in the Checkmate 9LA trial. OS as the primary endpoint as well as RR and PFS were significantly improved in favor of this combination independent from histology and PD-L1 expression level. The combination of Nivolumab and Ipilimumab with or without chemotherapy represents an active novel first-line treatment opportunity for NSCLC.

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