The associations between PD-L1 expression, TMB and genomic profiles in metastatic NSCLC: a single centre experience

Introduction Immunotherapy has transformed the landscape of advanced non-small cell lung cancer (NSCLC) treatment (1,2). PD-L1 is the only, but not perfect biomarker approved for patient’s selection for this therapy (3). Further studies revealed, that tumor mutation burden (TMB) and specific molecular alterations, as well as their combinations can also serve as predictive biomarkers (4). Aim To assess associations between PD-L1 expression, TMB and gene alterations in metastatic non-EGFR-altered NSCLC biopsies samples and their association with survival (overall survival (OS) and progression free survival (PFS)) in patients treated with immunotherapy. Methods PD-L1 expression, TMB and gene alterations were assessed in 50 patients with metastatic non-EGFR-altered NSCLC samples. EGFR status was identified using immunohistochemistry. PD-L1 expression was evaluated by tumor proportion score. Tissuebased next-generation sequencing was performed by FoundationOne CDx assay (high TMB was defined as 10 mutations/Mb (mut/Mb)). Results Positive PD-L1 expression was detected in two thirds of cases (n=31, 62%). PD-L1 levels were <1%, 1-49% and ≥50% in 19 (38%), 13 (26%) and 18 (36%) of cases, respectively. The median TMB was 7 mut/Mb. High TMB was detected in one third of cases (n=17, 33.3%). Predominantly higher TMB levels were seen in patients ≥65 years, men, smokers and diagnosed with COPD (p=0.047, p=0.014, p=0.018 and p=0.035, respectively) (Fig. 1). A total of 311 alterations in 111 genes were detected. Targetable mutations (MT) were seen in 33.4% of cases (Fig. 2). Evaluating non-targetable alterations, frequency of TP53 MT was the highest (54.9%), followed by CDKN2A/B (47.1%), MTAP (29.4%), KRAS (other than G12C) (25.5%), and STK11 (21.6%) MT (Fig. 3). Co-occurring MT in KRAS/STK11, KRAS/TP53, STK11/KEAP1 were detected in 12%, 12% and 6% of cases, respectively. TP53 MT was more likely to be found in patients with higher PD-L1 and TMB levels (median 45 vs 0, p=0.005, and 10 vs 4.5, p=0.008, respectively), while STK11 MT – in lover PD-L1 and higher TMB levels (median 0 vs 17.5, p=0.019, and 11.5 vs 6, p=0.047, respectively) (Fig. 4-5). No significant associations between PD-L1 expression, TMB, genetic alterations and DFS or OS were found in patients treated with immunotherapy. Conclusions Positive PD-L1 expression was seen in 2/3 of cases, high TMB - in 1/3 of cases. Targetable MT were detected in 1/3 of cases. Significant associations between molecular alterations, TMB and PD-L1 expression were found.