Clin Cancer Res. 2021 Mar 08. pii: clincanres.0032.2021. [Epub ahead of print]
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 H,
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.
PURPOSE: Current standard initial therapy for advanced, ROS1 fusion-positive (ROS1+) non-small cell lung cancer (NSCLC) is crizotinib or entrectinib. Lorlatinib, a next-generation ALK/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 ROS1+ NSCLC patients 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 common occurring in approximately a third of cases. Additional ROS1 mutations included: D2033N (2.4%) and S1986F (2.4%) post-crizotinib; 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 over 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.