BACKGROUND: Anti-PD1/PD-L1 directed immune-checkpoint-inhibitors (ICI) are widely used to treat patients with advanced non-small cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction.PATIENTS AND METHODS: We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS) and overall survival (OS) from ICI initiation. The primary endpoint was PFS under ICI. Secondary endpoints were best response (RECIST 1.1) and overall survival (OS) from ICI initiation.RESULTS: We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n=271), EGFR (n=125), BRAF (n=43), MET (n=36), HER2 (n=29), ALK (n=23), RET (n=16), ROS1 (n=7), and multiple drivers (n=1). Median age was 60 years, gender-ratio was 1:1, never/former/current smokers were 28/51/21% respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS=26%, BRAF=24%, ROS1=17%, MET=16%, EGFR=12%, HER2=7%, RET=6%, ALK=0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2).CONCLUSIONS: ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared to the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy.
View details for DOI 10.1093/annonc/mdz167
View details for PubMedID 31125062