Correlation of PDL1 Expression with Genomic Alterations in Non-Small Cell Lung Cancer: a 7-month retrospective analysis

Abstract

Abstract Background PD1/PDL1 inhibitors have significantly improved overall survival in non-small cell lung cancer (NSCLC). PDL1 is now a standard biomarker along with molecular testing for therapy selection. Checkpoint therapy is given front-line for patients with high PDL1 and no actionable mutations or fusions, or after progression with any PDL1 expression. Studies comparing PDL1 status in the context of actionable mutations or fusions in NSCLC are sparse. Design All patients undergoing molecular testing for a next-generation sequencing (NGS) lung cancer panel at our institution in a 7-month period were reviewed. This included an NGS DNA panel for actionable/driver genes: EGFR, ERBB2, BRAF, K/NRAS, PIK3CA, and IDH1/2; and a NGS RNA fusion panel for ALK, ROS1, RET, NTRK1/3, NRG1, and MET e14 skipping. PDL1 expression by IHC was scored for tumor proportion score (TPS). Statistical comparison was performed using Fisher’s Exact test. Results 186 patients with NSCLC were included (126 adenocarcinoma, 33 squamous/adeno-squamous, 19 poorly differentiated, and 8 NSCLC-NOS); 162 of those had concurrent PDL1 IHC. 121 (65%) patients had a genomic alteration, most commonly RAS [28%], EGFR [24%], ALK [8%], MET [7%], and BRAF [5%]. Cases with genomic alterations were classified into those with and without RAS mutation/s. The prevalence of high PDL1 expression was greater in RAS-driven tumors: 47% vs 22% with non-RAS bearing genomic alterations (p=0.0173). There was no significant difference in the PDL1 expression between the genomically negative tumors and those with non-RAS bearing mutations. Recently, the FDA granted approval to sotorasib, a KRAS G12C inhibitor, in patients with locally advanced or metastatic NSCLC. However, there was no significant difference in the PDL1 expression between the tumors with RAS G12C mutation and those with other RAS mutations. Conclusion Our data indicate that close to half of RAS-driven NSCLC have high PDL1 expression, an important consideration for front-line therapy selection. The majority of genomically-actionable tumors have at least low-positive expression of PDL1, highlighting the potential importance of immune checkpoint therapy in the resistant-progression setting. In comparison, only about one third of genomically-negative cases have high PDL1 expression, and a significant percent are completely negative. When the actionable KRAS G12C mutation bearing cases were compared to those with other RAS mutations, no significant difference was noted in the PDL1 expression between these two subsets; further investigations and a larger cohort of patients may be helpful in this case to determine whether PDL1 levels are affected by a specific RAS mutation.