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Abstract 5233: Evolution of therapy resistance through acquired KRAS amplification in ROS1 fusion KRAS G12C double positive NSCLC


 Patients with metastatic non-small cell lung cancer (NSCLC) positive for a ROS proto-oncogene 1 (ROS1) fusion usually experience significant disease response and long-term control while on treatment with a ROS1 targeting tyrosine kinase inhibitor (TKI) but significant clinical heterogeneity exists. The presence of co-occurring genomic alterations likely contribute to this diversity in clinical outcomes. Here, we report on a patient with metastatic NSCLC with a ROS1 fusion and Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutation detected at diagnosis who experienced a short duration of disease control on targeted therapy. The patient was initially treated with entrectinib, a ROS1 TKI, and, at progression, also received sotorasib, a small molecule inhibitor of KRAS G12C, in combination. Using specimens from therapeutically relevant time points including at diagnosis, at time of resistance to entrectinib, and at time of resistance to entrectinib and concurrent sotorasib, we performed broad next generation sequencing and FISH studies to detail the development of therapy resistance. Variant allele frequency of KRAS G12C was increased at each time point (3.2%, 74.2%, and 97%, respectively). A cell line was derived from the patient at time of progression on entrectinib therapy. In vitro testing of the cell line demonstrated increased TKI responsiveness when treated with entrectinib and sotorasib. Signaling pathway analysis of the cell line showed entrectinib inhibited phosphorylation of ROS1 and AKT, but not ERK. Sotorasib alone or in combination with entrectinib resulted in decreased phosphorylation of ERK. In vitro testing suggested efficacy with the combination of entrectinib and sotorasib. However, in clinical follow up the patient’s disease demonstrated progression on the combination, likely related to KRAS G12C amplification. This case supports the need for broad molecular profiling for potential therapeutic and prognostic information to personalize therapy in patients with metastatic NSCLC.
 Citation Format: Katherine Priest, Anh Le, Dara Aisner, Amanuail Gebregzabheir, Hala Nijmeh, Melanie Mandell, Kurtis Davies, Emily O'Donnell, Robert C. Doebele, Liming Bao, Erin L. Schenk. Evolution of therapy resistance through acquired KRAS amplification in ROS1 fusion KRAS G12C double positive NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5233.