Clinical utility of liquid biopsy for molecular characterization and resistance detection in patients with advanced NSCLC and ALK, ROS1 or RET fusions

Abstract Introduction Liquid biopsy (LB) is increasingly used in non-small cell lung cancer (NSCLC) for molecular diagnosis or resistance detection. Due to its non-invasive nature, it is often preferred over tissue biopsies, especially when sequential biopsies are warranted. Here, we report the clinical utility of liquid biopsy in patients with advanced NSCLC and ALK, ROS1 or RET fusions and its relevance to detect resistance after targeted therapy. Methods Between December 2020 and June 2022, 597 patients with advanced lung cancer had at least one liquid biopsy assessed by Foundation One CDx Liquid (panel of 324 genes) in a single institution. Plasma collection was performed in treatment-naïve patients and/or at time of progression. Clinical and molecular data were collected from patients with known fusions (ALK, ROS1, RET). LB were defined as “positive” if the fusion or resistance mutations were identified and “negative” in the absence of circulating-tumor DNA. The clinical utility of LB was evaluated as the proportion of positive results. The clinical relevance for resistance detection was defined as the proportion of LB that identified a putative resistance mechanism after targeted therapy. Results A total of 68 patients (29 ALK+, 22 RET+ and 17 ROS1+) with 83 LB were included. Patients were females in 50% of cases, had no smoking history in 58% of cases and had adenocarcinoma in 91% of cases. LB was positive in 55/83 (66%) cases overall, in 14/15 (93%) treatment-naïve patients and in 39/66 (59%) pre-treated patients. Factors significantly associated with a negative LB were limited disease progression (brain- or thoracic-only, p<0.001) and ongoing treatment at time of LB collection (p<0.05). Out of 47 LB performed at progression after targeted therapies, 7 (15%) found on-target resistance, 10 (21%) by-pass resistance, 10 (21%) no explainable resistance and 20 (43%) were negative. By-pass alterations included KRAS p.G12C/A mutations (N=2, ALK+), PIK3CA p.E545K/Q (N=3, ALK+), PTEN splice-site mutation (N=1, RET+), MYC amplifications (N=3, ALK+/RET+) and MET amplification (N=1, ROS1+). Conclusion LB was able to detect resistance mechanisms in one third of NSCLC patients with ALK, RET or ROS1 fusions. However, LB frequently failed to detect circulating-tumor DNA especially in patients with limited disease progression or with ongoing treatment at time of sample collection. Citation Format: Mihaela Aldea, Arianna Marinello, Marco Tagliamento, Filippo Dall'Olio, Damien Vasseur, Arnaud Bayle, Anas Gazzah, Miruna Grecea, Claudio Nicotra, Ludovic Lacroix, Santiago Ponce, Luc Friboulet, Fabrice Barlesi, Fabrice Andre, David Planchard, Etienne Rouleau, Antoine Italiano, Benjamin Besse. Clinical utility of liquid biopsy for molecular characterization and resistance detection in patients with advanced NSCLC and ALK, ROS1 or RET fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1034.