Spectrum of Mechanisms of Resistance to Crizotinib and Lorlatinib in Fusion-Positive Lung Cancer.

Jessica J Lin, Noura J Choudhury, Satoshi Yoda, Viola W Zhu, Ted W Johnson, Ramin Sakhtemani, Ibiayi Dagogo-Jack, Subba R Digumarthy, Charlotte Lee, Andrew Do, Jennifer Peterson, Kylie Prutisto-Chang, Wafa Malik, Harper G Hubbeling, Adam Langenbucher, Adam J Schoenfeld, Christina J Falcon, Jennifer S Temel, Lecia V Sequist, Beow Y Yeap, Jochen K Lennerz, Alice T Shaw, Michael S Lawrence, Sai-Hong Ignatius Ou, Aaron N Hata, Alexander Drilon, Justin F Gainor

Journal: Clinical cancer research : an official journal of the American Association for Cancer Research 2022;27(10):2899-2909

PMID: 33685866

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Abstract

PURPOSE

Current standard initial therapy for advanced, ROS proto-oncogene 1, receptor tyrosine kinase fusion ()-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.

EXPERIMENTAL DESIGN

Biopsies from patients with ROS1 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, mutations were identified in 38% and 46%, respectively. G2032R was the most commonly occurring mutation in approximately one third of cases. Additional 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 ROS1 causes steric interference to lorlatinib, crizotinib, and entrectinib, while it may accommodate cabozantinib. In Ba/F3 models, ROS1, ROS1, and ROS1 were refractory to lorlatinib but sensitive to cabozantinib. A patient with disease progression on crizotinib and lorlatinib and L2086F received cabozantinib for nearly 11 months with disease control. Among lorlatinib-resistant biopsies, we also identified amplification (4%), G12C (4%), amplification (4%), mutation (4%), and mutation (4%).

CONCLUSIONS

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.

Address: Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.; Department of Medicine, University of California Irvine, Orange, California.; Pfizer Worldwide Research and Development, La Jolla, California.; Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.; Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts. [email protected].; Harvard Medical School, Boston, Massachusetts.

DOI: 10.1158/1078-0432.CCR-21-0032