Spectrum of mechanisms of resistance to crizotinib and lorlatinib in ROS1 fusion–positive lung cancer Journal Article
| Authors: | Lin, J. J.; Choudhury, N. J.; Yoda, S.; Zhu, V. W.; Johnson, T. W.; Sakhtemani, R.; Dagogo-Jack, I.; Digumarthy, S. R.; Lee, C.; Do, A.; Peterson, J.; Prutisto-Chang, K.; Malik, W.; Hubbeling, H. G.; Langenbucher, A.; Schoenfeld, A. J.; Falcon, C. J.; Temel, J. S.; Sequist, L. V.; Yeap, B. Y.; Lennerz, J. K.; Shaw, A. T.; Lawrence, M. S.; Ou, S. H. I.; Hata, A. N.; Drilon, A.; Gainor, J. F. |
| Article Title: | Spectrum of mechanisms of resistance to crizotinib and lorlatinib in ROS1 fusion–positive lung cancer |
| Abstract: | Purpose: Current standard initial therapy for advanced, ROS proto-oncogene 1, receptor tyrosine kinase fusion (ROS1)-positive (ROS1þ) non–small cell lung cancer (NSCLC) is crizotinib or entrectinib. Lorlatinib, a next-generation anaplastic lymphoma kinase/ROS1 inhibitor, recently demonstrated efficacy in ROS1þ NSCLC, including in crizotinib-pretreated patients. However, mechanisms of lorlatinib resistance in ROS1þ disease remain poorly understood. Here, we assessed mechanisms of resistance to crizotinib and lorlatinib. Experimental Design: Biopsies from patients with ROS1þ NSCLC progressing on crizotinib or lorlatinib were profiled by genetic sequencing. Results: 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%). Conclusions: 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. © 2021 American Association for Cancer Research. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 27 |
| Issue: | 10 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2021-05-15 |
| Start Page: | 2899 |
| End Page: | 2909 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-21-0032 |
| PUBMED: | 33685866 |
| PROVIDER: | scopus |
| PMCID: | PMC8127383 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2021 -- Source: Scopus |
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46Hubbeling -
40Choudhury -
44Falcon
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