Clinical characteristics and treatment outcome of patients with advanced non-small-cell lung cancer (NSCLC) and FGFR fusions.
Authors: Scharpenseel Heather , Stickelmann Andreas , Siemanowski Janna , Malchers Florian , Scheffler Matthias , Hillmer Axel , Meemboor Sonja , Merkelbach-Bruse Sabine , Scheel Andreas H. , Riedel Richard , Michels Sebastian Yves Friedrich , Eisert Anna , Fischer Rieke Nila , Brodersen Marlene , Thomas Roman K. , Büttner Reinhard , Graeven Ullrich , Kosse Nils , Nogova Lucia , Wolf Juergen 
Published: June 2023

e21139

Background: Activating FGFR fusions are targetable genetic alterations in several solid tumours and hematologic malignancies, but little is known about their frequency in advanced NSCLC patients (pts). Furthermore, clinical characteristics and treatment outcome in NSCLC have not been sufficiently identified yet. Methods: Within Network Genomic Medicine (NGM), we screened advanced NSCLC pts without targetable mutations for genetic fusions using RNA-NGS (ArcherDx FusionPlex) and analysed fusion frequencies, patient characteristics and clinical courses. Results: From 01/2019 to 09/2022, we screened a total of 3309 NSCLC pts. We found 37 pts (1.1%) with FGFR activating fusions. Of these patients, 26 cases had squamous cell carcinoma (70.3%), 10 cases adenocarcinoma (27%), one patient had sarcomatoid differentiation (2.7%). The most common FGFR fusion was FGFR3-TACC3 with 21 cases (56.8%). All patients had UICC stage IIIB or IV at time of diagnosis: 13 were females (35.1%), 24 were males (64.9%); median age at first diagnosis was 69 years (range 36-91), 27 pts were former smokers (72.9%), 8 pts were current smokers (21.6%) and only one patient was a never smoker (2.7%). Co-occurring mutations were identified in 30 pts (81.1%): TP53 co-mutations were the most frequent co-mutation with 27 cases (72.9%), two cases had KEAP1 (5.4%), one case harboured either PTEN (2.7%), PIK3CA (2.7%) or MAP2K1 (2.7%). One patient harboured FGFR2 S587C co-mutation (2.7%). From 37 identified patients, 34 were available for follow-up. The median overall survival (mOS) was 24.87 months (95% confidence interval [CI]: 11.57–38.17). We counted 26 pts who received immunotherapy (either as monotherapy or chemoimmunotherapy) with a mOS of 26.44 months (95% CI: 20.23–32.66) comparing to the median OS of 9.5 months for patients (n = 8) with no immunotherapy (95% CI: 0.0–22.58) (p = 0.037). For three patients there was no information regarding therapy regimen obtainable. Six pts (16.21%) received targeted therapy (Erdafitinib/Rogaratinib) with no improved mOS compared to standard therapy (p = 0.026). Patients with TP53 mutation had longer mOS than pts with TP53 wild type (WT) (mOS 26.45 months [95% CI: 20.06–32.83] vs 9.24 months [95% CI: 1.43–17.06] [p = 0.031]). Conclusions: Activating FGFR fusions in NSCLC are rare events. The majority of patients are elder males with smoking history and predominantly squamous histology. The most frequent co-mutation is TP53 with prolonged OS comparing to TP53 WT patients. In contrast to other NSCLC with targebatle driver mutations, patients with FGFR fusion seem to benefit from immunotherapy, if added to their treatment. Targeted therapy is beneficial, but sufficient long-term data are currently missing.