Lung sarcomatoid carcinoma (LSC) harbors targetable genomic alterations and high mutational burden as observed by comprehensive genomic profiling (CGP)

Abstract

Background: LSC is a rare, clinically aggressive, heterogeneous and poorly differentiated subtype of non-small cell lung cancer (NSCLC), which is typically difficult to diagnose and resistant to conventional therapies. We queried whether CGP could guide LSC patients to novel targeted therapies. Methods: Hybrid-capture based CGP was performed on 6,923 consecutive FFPE NSCLCs during the course of clinical care and 91 (1.3%) LSCs were identified. Results: In this series the median age was 67 years (range 32-86), 59% were male, and 82% of tumors were stage 4. Overall, 57% of cases involved a genomic alteration (GA) in KRAS (34%) or one of 7 genes now recommended for testing in the NSCLC NCCN guidelines including: MET (8.8%), BRAF (7.7%), EGFR (6.6%), ERBB2 (2.2%) or RET (1.1%). No alterations were detected in ALK or ROS1. BRAF alterations included amplification and mutation at V600 or G469. EGFR alterations included amplification, exon 19 deletion, exon 20 insertion, and activating L858R mutation. Notably, MET exon 14 skipping alterations were enriched in this series (7/91, 7.7%) compared to non-LSC NSCLCs (2.8%). In 39 cases that were wild-type for the 7 NCCN genes and KRAS, potentially actionable GAs were most commonly detected in PTEN (10.3%), PIK3CA (7.7%), FGFR1 (7.7%), and PDGFRA (7.7%). Median tumor mutation burden (TMB) was 8 mutations/megabase (range: 0-165, mean: 14), and 21% (19/91) of cases had high TMB ≥ 20. Clinical outcomes were available for a subset of patients and we report clinical benefit in 4 LSC patients treated with targeted therapy whose tumors harbored alterations in MET, BRAF, and EGFR, as well as an ongoing response to anti-PD-1 therapy in one patient with TMB = 31. Conclusions: Targetable GAs, including MET exon 14 alterations, were found in a majority of LSC patients, some of which occur at greater frequency than that observed in non-LSC NSCLCs. An important portion of LSC cases had high TMB, which has been associated with increased likelihood of response to immunotherapy. Thus, CGP can lead to selection of appropriate targeted therapies in this population of patients, which has historically been poorly characterized and difficult to treat.