Introduction: Therapy directed at molecular actionable variants improves survival in patients with advanced NSCLC and is standard of care. Although there is familiarity with common fusion targets such as ALK, ROS1, and RET, there is growing evidence that emerging rare fusion targets in advanced NSCLC are likely promising targets for matched therapies that also may lead to improved outcomes. Here we report the prevalence of rare BRAF, NRG1, and EGFR fusions, and their co-occurrence with other NCCN recommended actionable NSCLC targets, using concurrent DNA-RNA NGS testing in a real-world patient cohort.

Methods: Deidentified records were extracted from the Tempus multimodal database, consisting of 5,546 advanced (Stage IIIB-IV) patients with a primary diagnosis of adenocarcinoma NSCLC who underwent solid-tumor testing with both DNA-seq and RNA-seq (Tempus xT and xR assays, respectively). Concurrent RNA-NGS and DNA-NGS pipelines were run separately and manually reviewed as part of the Tempus clinical workflow. Fusion partners with the highest read support are reported. NCCN-recommended testing for targeted variants analyzed included ALK, RET, ROS1, and NTRK1/2/3 fusions, MET exon 14 skipping variants, EGFR pathogenic single nucleotide variants (SNVs)/indels (e.g., exon 19 deletions), BRAF V600E, and KRAS G12C.

Results: The overall prevalence of rare fusions in our cohort was 0.6% (n=32): 0.3% (n=18) BRAF, 0.2% (n=9) NRG1, and 0.1% (n=5) EGFR. Fifty percent (n=16) of the rare fusions were detected solely by RNA-seq—including 66.7% (n=12) of BRAF, 22.2% (n=2) of NRG1, and 40% (n=2) of EGFR. Of the 32 NSCLC patients with rare fusions detected, 31% (n=10) harbored an NCCN NSCLC guideline-recommended co-variant. This frequency varied by fusion type: 50% (9/18) of BRAF, 11% (1/9) of NRG1, and 0% of EGFR. All patients with a BRAF fusion and NCCN-recommended co-variant (n=9) had EGFR exon 19 deletions [n=9]; two of these patients had additional T790M variants. Seven out of 8 patients with co-occurrence of BRAF fusions and EGFR SNV/indels, with concomitant treatment information, were treated with EGFR-targeted therapy prior to sequencing, implicating the clonal emergence of BRAF fusions as a possible resistance mechanism to anti-EGFR therapy.

Conclusions: Concurrent DNA-RNA NGS improved the detection rate of emerging rare fusion variants in advanced NSCLC patients compared to DNA-NGS, doubling the number of rare fusions detected and eligible patients that may benefit from targeted therapy. Importantly, co-occurrence of rare fusions and EGFR classical activating mutations in patients pre-treated with anti-EGFR therapy suggests a potential resistance mechanism and consideration of upfront, dual mutation, targeted treatment to improve outcomes. Further clinical studies are needed to validate the best treatment options for these patients with rare fusions.

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