Details

Autor(en) / Beteiligte

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

Titel

Spectrum of Mechanisms of Resistance to Crizotinib and Lorlatinib in ROS1 Fusion-Positive Lung Cancer

Ist Teil von

• Clinical cancer research, 2021-05, Vol.27 (10), p.2899-2909

Ort / Verlag

United States

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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, 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%). 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.