PURPOSE: The ROS1 tyrosine kinase is activated through ROS1 gene rearrangements in 1-2% of non-small cell lung cancer (NSCLC), conferring sensitivity to treatment with the ALK/ROS1/MET inhibitor crizotinib. Currently, insights into patterns of metastatic spread and mechanisms of crizotinib resistance among ROS1-positive patients are limited. PATIENTS AND METHODS: We reviewed clinical and radiographic imaging data of patients with ROS1- and ALK-positive NSCLC in order to compare patterns of metastatic spread at initial metastatic diagnosis. To determine molecular mechanisms of crizotinib resistance, we also analyzed repeat biopsies from a cohort of ROS1-positive patients progressing on crizotinib. RESULTS: We identified 39 and 196 patients with advanced ROS1- and ALK-positive NSCLC, respectively. ROS1-positive patients had significantly lower rates of extrathoracic metastases (ROS1 59.0%, ALK 83.2%, P=0.002), including lower rates of brain metastases (ROS1 19.4%, ALK 39.1%; P = 0.033), at initial metastatic diagnosis. Despite similar overall survival between ALK- and ROS1-positive patients treated with crizotinib (median 3.0 versus 2.5 years, respectively; P=0.786), ROS1-positive patients also had a significantly lower cumulative incidence of brain metastases (34% vs. 73% at 5 years; P<0.0001). Additionally, we identified 16 patients who underwent a total of 17 repeat biopsies following progression on crizotinib. ROS1 resistance mutations were identified in 53% of specimens, including 9/14 (64%) non-brain metastasis specimens. ROS1 mutations included: G2032R (41%), D2033N (6%), and S1986F (6%). CONCLUSIONS: Compared to ALK rearrangements, ROS1 rearrangements are associated with lower rates of extrathoracic metastases, including fewer brain metastases, at initial metastatic diagnosis. ROS1 resistance mutations, particularly G2032R, appear to be the predominant mechanism of resistance to crizotinib, underscoring the need to develop novel ROS1 inhibitors with activity against these resistant mutants.
PURPOSE: The ROS1 tyrosine kinase is activated through ROS1 gene rearrangements in 1-2% of non-small cell lung cancer (NSCLC), conferring sensitivity to treatment with the ALK/ROS1/MET inhibitor crizotinib. Currently, insights into patterns of metastatic spread and mechanisms of crizotinib resistance among ROS1-positive patients are limited. PATIENTS AND METHODS: We reviewed clinical and radiographic imaging data of patients with ROS1- and ALK-positive NSCLC in order to compare patterns of metastatic spread at initial metastatic diagnosis. To determine molecular mechanisms of crizotinib resistance, we also analyzed repeat biopsies from a cohort of ROS1-positive patients progressing on crizotinib. RESULTS: We identified 39 and 196 patients with advanced ROS1- and ALK-positive NSCLC, respectively. ROS1-positive patients had significantly lower rates of extrathoracic metastases (ROS1 59.0%, ALK 83.2%, P=0.002), including lower rates of brain metastases (ROS1 19.4%, ALK 39.1%; P = 0.033), at initial metastatic diagnosis. Despite similar overall survival between ALK- and ROS1-positive patients treated with crizotinib (median 3.0 versus 2.5 years, respectively; P=0.786), ROS1-positive patients also had a significantly lower cumulative incidence of brain metastases (34% vs. 73% at 5 years; P<0.0001). Additionally, we identified 16 patients who underwent a total of 17 repeat biopsies following progression on crizotinib. ROS1 resistance mutations were identified in 53% of specimens, including 9/14 (64%) non-brain metastasis specimens. ROS1 mutations included: G2032R (41%), D2033N (6%), and S1986F (6%). CONCLUSIONS: Compared to ALK rearrangements, ROS1 rearrangements are associated with lower rates of extrathoracic metastases, including fewer brain metastases, at initial metastatic diagnosis. ROS1 resistance mutations, particularly G2032R, appear to be the predominant mechanism of resistance to crizotinib, underscoring the need to develop novel ROS1 inhibitors with activity against these resistant mutants.
Authors: Justin F Gainor; Leila Dardaei; Satoshi Yoda; Luc Friboulet; Ignaty Leshchiner; Ryohei Katayama; Ibiayi Dagogo-Jack; Shirish Gadgeel; Katherine Schultz; Manrose Singh; Emily Chin; Melissa Parks; Dana Lee; Richard H DiCecca; Elizabeth Lockerman; Tiffany Huynh; Jennifer Logan; Lauren L Ritterhouse; Long P Le; Ashok Muniappan; Subba Digumarthy; Colleen Channick; Colleen Keyes; Gad Getz; Dora Dias-Santagata; Rebecca S Heist; Jochen Lennerz; Lecia V Sequist; Cyril H Benes; A John Iafrate; Mari Mino-Kenudson; Jeffrey A Engelman; Alice T Shaw Journal: Cancer Discov Date: 2016-07-18 Impact factor: 39.397
Authors: Aria Vaishnavi; Laura Schubert; Uwe Rix; Lindsay A Marek; Anh T Le; Stephen B Keysar; Magdalena J Glogowska; Matthew A Smith; Severine Kako; Natalia J Sumi; Kurtis D Davies; Kathryn E Ware; Marileila Varella-Garcia; Eric B Haura; Antonio Jimeno; Lynn E Heasley; Dara L Aisner; Robert C Doebele Journal: Cancer Res Date: 2017-04-20 Impact factor: 12.701
Authors: Kristin Bergethon; Alice T Shaw; Sai-Hong Ignatius Ou; Ryohei Katayama; Christine M Lovly; Nerina T McDonald; Pierre P Massion; Christina Siwak-Tapp; Adriana Gonzalez; Rong Fang; Eugene J Mark; Julie M Batten; Haiquan Chen; Keith D Wilner; Eunice L Kwak; Jeffrey W Clark; David P Carbone; Hongbin Ji; Jeffrey A Engelman; Mari Mino-Kenudson; William Pao; A John Iafrate Journal: J Clin Oncol Date: 2012-01-03 Impact factor: 44.544
Authors: Curtis R Chong; Magda Bahcall; Marzia Capelletti; Takayuki Kosaka; Dalia Ercan; Taebo Sim; Lynette M Sholl; Mizuki Nishino; Bruce E Johnson; Nathanael S Gray; Pasi A Jänne Journal: Clin Cancer Res Date: 2016-07-01 Impact factor: 12.531
Authors: Klarisa Rikova; Ailan Guo; Qingfu Zeng; Anthony Possemato; Jian Yu; Herbert Haack; Julie Nardone; Kimberly Lee; Cynthia Reeves; Yu Li; Yerong Hu; Zhiping Tan; Matthew Stokes; Laura Sullivan; Jeffrey Mitchell; Randy Wetzel; Joan Macneill; Jian Min Ren; Jin Yuan; Corey E Bakalarski; Judit Villen; Jon M Kornhauser; Bradley Smith; Daiqiang Li; Xinmin Zhou; Steven P Gygi; Ting-Lei Gu; Roberto D Polakiewicz; John Rush; Michael J Comb Journal: Cell Date: 2007-12-14 Impact factor: 41.582
Authors: Matteo Canale; Luigi Pasini; Giuseppe Bronte; Angelo Delmonte; Paola Cravero; Lucio Crinò; Paola Ulivi Journal: Transl Lung Cancer Res Date: 2019-11
Authors: Tejas Patil; Derek E Smith; Paul A Bunn; Dara L Aisner; Anh T Le; Mark Hancock; William T Purcell; Daniel W Bowles; D Ross Camidge; Robert C Doebele Journal: J Thorac Oncol Date: 2018-07-05 Impact factor: 15.609
Authors: Jessica J Lin; Ginger Y Jiang; Nencyben Joshipura; Jennifer Ackil; Subba R Digumarthy; Sandra P Rincon; Beow Y Yeap; Justin F Gainor; Alice T Shaw Journal: J Thorac Oncol Date: 2018-12-07 Impact factor: 15.609
Authors: D G Bebb; J Agulnik; R Albadine; S Banerji; G Bigras; C Butts; C Couture; J C Cutz; P Desmeules; D N Ionescu; N B Leighl; B Melosky; W Morzycki; F Rashid-Kolvear; Clin Lab; H S Sekhon; A C Smith; T L Stockley; E Torlakovic; Z Xu; M S Tsao Journal: Curr Oncol Date: 2019-08-01 Impact factor: 3.677