Bob T Li1, Egbert F Smit1, Yasushi Goto1, Kazuhiko Nakagawa1, Hibiki Udagawa1, Julien Mazières1, Misako Nagasaka1, Lyudmila Bazhenova1, Andreas N Saltos1, Enriqueta Felip1, Jose M Pacheco1, Maurice Pérol1, Luis Paz-Ares1, Kapil Saxena1, Ryota Shiga1, Yingkai Cheng1, Suddhasatta Acharyya1, Patrik Vitazka1, Javad Shahidi1, David Planchard1, Pasi A Jänne1. 1. From Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York (B.T.L.); the Netherlands Cancer Institute, Amsterdam (E.F.S); the National Cancer Center Hospital, Tokyo (Y.G.), Kindai University Hospital, Osaka (K.N.), and the National Cancer Center East, Kashiwa (H.U.) - all in Japan; Centre Hospitalier Universitaire, Toulouse (J.M.), Centre Léon Bérard, Lyon (M.P.), and the Department of Medical Oncology, Thoracic Group, Gustave Roussy, Villejuif (D.P.) - all in France; Karmanos Cancer Institute, Detroit (M.N.); the University of California, San Diego, Moores Cancer Center, San Diego (L.B.); Moffitt Cancer Center, Tampa, FL (A.N.S.); Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona (E.F.); University of Colorado, Aurora (J.M.P.); Hospital Universitario 12 de Octubre, H12O-Centro Nacional de Investigaciones Oncológicas (CNIO) Lung Cancer Clinical Research Unit, and Complutense University, Madrid (L.P.-A.); Daiichi Sankyo, Basking Ridge, NJ (K.S., R.S., Y.C., S.A., P.V., J.S.); and Dana-Farber Cancer Institute and the Belfer Center for Applied Cancer Science, Boston (P.A.J.).
Abstract
BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have not been approved for patients with non-small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody-drug conjugate, in patients with HER2-mutant NSCLC have not been investigated extensively. METHODS: We conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed. RESULTS: A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification. CONCLUSIONS: Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number, NCT03505710.).
BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have not been approved for patients with non-small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody-drug conjugate, in patients with HER2-mutant NSCLC have not been investigated extensively. METHODS: We conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed. RESULTS: A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification. CONCLUSIONS: Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number, NCT03505710.).
Authors: Y-L Wu; D Planchard; S Lu; H Sun; N Yamamoto; D-W Kim; D S W Tan; J C-H Yang; M Azrif; T Mitsudomi; K Park; R A Soo; J W C Chang; A Alip; S Peters; J-Y Douillard Journal: Ann Oncol Date: 2019-02-01 Impact factor: 32.976
Authors: Michael Offin; Daniel Feldman; Ai Ni; Mackenzie L Myers; W Victoria Lai; Elena Pentsova; Adrienne Boire; Mariza Daras; Emmet J Jordan; David B Solit; Maria E Arcila; David R Jones; James M Isbell; Kathryn Beal; Robert J Young; Charles M Rudin; Gregory J Riely; Alexander Drilon; Viviane Tabar; Lisa M DeAngelis; Helena A Yu; Mark G Kris; Bob T Li Journal: Cancer Date: 2019-08-30 Impact factor: 6.860
Authors: Mark G Kris; Bruce E Johnson; Lynne D Berry; David J Kwiatkowski; A John Iafrate; Ignacio I Wistuba; Marileila Varella-Garcia; Wilbur A Franklin; Samuel L Aronson; Pei-Fang Su; Yu Shyr; D Ross Camidge; Lecia V Sequist; Bonnie S Glisson; Fadlo R Khuri; Edward B Garon; William Pao; Charles Rudin; Joan Schiller; Eric B Haura; Mark Socinski; Keisuke Shirai; Heidi Chen; Giuseppe Giaccone; Marc Ladanyi; Kelly Kugler; John D Minna; Paul A Bunn Journal: JAMA Date: 2014-05-21 Impact factor: 56.272
Authors: U Gatzemeier; G Groth; C Butts; N Van Zandwijk; F Shepherd; A Ardizzoni; C Barton; P Ghahramani; V Hirsh Journal: Ann Oncol Date: 2004-01 Impact factor: 32.976
Authors: Jacqulyne P Robichaux; Yasir Y Elamin; R S K Vijayan; Monique B Nilsson; Lemei Hu; Junqin He; Fahao Zhang; Marlese Pisegna; Alissa Poteete; Huiying Sun; Shuai Li; Ting Chen; Han Han; Marcelo Vailati Negrao; Jordi Rodon Ahnert; Lixia Diao; Jing Wang; Xiuning Le; Funda Meric-Bernstam; Mark Routbort; Brent Roeck; Zane Yang; Victoria M Raymond; Richard B Lanman; Garrett M Frampton; Vincent A Miller; Alexa B Schrock; Lee A Albacker; Kwok-Kin Wong; Jason B Cross; John V Heymach Journal: Cancer Cell Date: 2019-10-03 Impact factor: 31.743
Authors: Junji Tsurutani; Hiroji Iwata; Ian Krop; Pasi A Jänne; Toshihiko Doi; Shunji Takahashi; Haeseong Park; Charles Redfern; Kenji Tamura; Trisha M Wise-Draper; Kaku Saito; Masahiro Sugihara; Jasmeet Singh; Takahiro Jikoh; Gilles Gallant; Bob T Li Journal: Cancer Discov Date: 2020-03-25 Impact factor: 39.397
Authors: Bob T Li; Flavia Michelini; Sandra Misale; Emiliano Cocco; Laura Baldino; Yanyan Cai; Sophie Shifman; Hai-Yan Tu; Mackenzie L Myers; Chongrui Xu; Marissa Mattar; Inna Khodos; Megan Little; Besnik Qeriqi; Gregory Weitsman; Clare J Wilhem; Alshad S Lalani; Irmina Diala; Rachel A Freedman; Nancy U Lin; David B Solit; Michael F Berger; Paul R Barber; Tony Ng; Michael Offin; James M Isbell; David R Jones; Helena A Yu; Sheeno Thyparambil; Wei-Li Liao; Anuja Bhalkikar; Fabiola Cecchi; David M Hyman; Jason S Lewis; Darren J Buonocore; Alan L Ho; Vicky Makker; Jorge S Reis-Filho; Pedram Razavi; Maria E Arcila; Mark G Kris; John T Poirier; Ronglai Shen; Junji Tsurutani; Gary A Ulaner; Elisa de Stanchina; Neal Rosen; Charles M Rudin; Maurizio Scaltriti Journal: Cancer Discov Date: 2020-03-25 Impact factor: 38.272
Authors: Anna Michelotti; Marco de Scordilli; Elisa Bertoli; Elisa De Carlo; Alessandro Del Conte; Alessandra Bearz Journal: Int J Mol Sci Date: 2022-06-17 Impact factor: 6.208