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Ref Type Journal Article
PMID (33685866)
Authors Lin JJ, Choudhury NJ, Yoda S, Zhu VW, Johnson TW, Sakhtemani R, Dagogo-Jack I, Digumarthy SR, Lee C, Do A, Peterson J, Prutisto-Chang K, Malik W, Hubbeling HG, Langenbucher A, Schoenfeld AJ, Falcon CJ, Temel JS, Sequist LV, Yeap BY, Lennerz JK, Shaw AT, Lawrence MS, Ou SI, Hata AN, Drilon A, Gainor JF
Title Spectrum of Mechanisms of Resistance to Crizotinib and Lorlatinib in ROS1 Fusion-Positive Lung Cancer.
Journal Vol Issue Date Pages Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research 27 10 2021 May 15 2899-2909 Clin Cancer Res
URL
Abstract Text Current standard initial therapy for advanced, ROS proto-oncogene 1, receptor tyrosine kinase fusion (ROS1)-positive (ROS1+) non-small cell lung cancer (NSCLC) is crizotinib or entrectinib. Lorlatinib, a next-generation anaplastic lymphoma kinase/ROS1 inhibitor, recently demonstrated efficacy in ROS1+ NSCLC, including in crizotinib-pretreated patients. However, mechanisms of lorlatinib resistance in ROS1+ disease remain poorly understood. Here, we assessed mechanisms of resistance to crizotinib and lorlatinib.Biopsies from patients with ROS1 + NSCLC progressing on crizotinib or lorlatinib were profiled by genetic sequencing.From 55 patients, 47 post-crizotinib and 32 post-lorlatinib biopsies were assessed. Among 42 post-crizotinib and 28 post-lorlatinib biopsies analyzed at distinct timepoints, ROS1 mutations were identified in 38% and 46%, respectively. ROS1 G2032R was the most commonly occurring mutation in approximately one third of cases. Additional ROS1 mutations included D2033N (2.4%) and S1986F (2.4%) post-crizotinib and L2086F (3.6%), G2032R/L2086F (3.6%), G2032R/S1986F/L2086F (3.6%), and S1986F/L2000V (3.6%) post-lorlatinib. Structural modeling predicted ROS1L2086F causes steric interference to lorlatinib, crizotinib, and entrectinib, while it may accommodate cabozantinib. In Ba/F3 models, ROS1L2086F, ROS1G2032R/L2086F, and ROS1S1986F/G2032R/L2086F were refractory to lorlatinib but sensitive to cabozantinib. A patient with disease progression on crizotinib and lorlatinib and ROS1 L2086F received cabozantinib for nearly 11 months with disease control. Among lorlatinib-resistant biopsies, we also identified MET amplification (4%), KRAS G12C (4%), KRAS amplification (4%), NRAS mutation (4%), and MAP2K1 mutation (4%).ROS1 mutations mediate resistance to crizotinib and lorlatinib in more than one third of cases, underscoring the importance of developing next-generation ROS1 inhibitors with potency against these mutations, including G2032R and L2086F. Continued efforts are needed to elucidate ROS1-independent resistance mechanisms.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ATR R2425Q missense unknown ATR R2425Q lies within the PI3K/PI4K domain of the Atr protein (UniProt.org). R2425Q has been identified in the scientific literature (PMID: 31748433, PMID: 27693639, PMID: 33685866), but has not been biochemically characterized and therefore, its effect on Atr protein function is unknown (PubMed, Aug 2024).
ROS1 L2000V missense unknown ROS1 L2000V lies within the protein kinase domain of the Ros1 protein (UniProt.org). L2000V has been demonstrated to confer resistance to ROS1 inhibitors in culture (PMID: 33685866), but has not been biochemically characterized and therefore, its effect on Ros1 protein function is unknown (PubMed, Jan 2024). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ROS1 fusion ROS1 S1986F ROS1 L2000V lung non-small cell carcinoma predicted - resistant Lorlatinib Case Reports/Case Series Actionable In a clinical case study, a patient with non-small cell lung cancer harboring a ROS1 fusion who had progressed on Xalkori (crizotinib) was subsequently treated with Lorbrena (lorlatinib) but progression ensued and post treatment biopsy revealed acquisition of ROS1 S1986F and ROS1 L2000V (PMID: 33685866). 33685866