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.).
N Engl J Med. 2022 Jan 20;386(3):241-251. doi: 10.1056/NEJMoa2112431. Epub 2021 Sep 18.
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 -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 -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 mutation subtypes, as well as in patients with no detectable HER2 expression or amplification. CONCLUSIONS: Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated -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.).
背景：人表皮生长因子受体 2（HER2）靶向治疗尚未被批准用于非小细胞肺癌（NSCLC）患者。HER2 抗体药物偶联物曲妥珠单抗 deruxtecan（以前称为 DS-8201）在 -突变型 NSCLC 患者中的疗效和安全性尚未广泛研究。
方法：我们进行了一项多中心、国际、2 期研究，在该研究中，曲妥珠单抗 deruxtecan（每公斤体重 6.4 毫克）用于转移性 -突变型 NSCLC 患者，这些患者对标准治疗有抗药性。主要终点是独立中心评估的客观缓解。次要终点包括缓解持续时间、无进展生存期、总生存期和安全性。评估了 HER2 改变的生物标志物。
结果：共纳入 91 例患者。中位随访时间为 13.1 个月（0.7 至 29.1）。中心确认的客观缓解率为 55%（95%CI，44 至 65）。缓解持续时间的中位数为 9.3 个月（95%CI，5.7 至 14.7）。中位无进展生存期为 8.2 个月（95%CI，6.0 至 11.9），中位总生存期为 17.8 个月（95%CI，13.8 至 22.1）。安全性概况与以往研究一致；46%的患者发生 3 级或更高级别的药物相关不良事件，最常见的事件是中性粒细胞减少症（19%）。经判定与药物相关的间质性肺病在 26%的患者中发生，并导致 2 例患者死亡。在不同的 突变亚型以及无 HER2 表达或扩增的患者中均观察到了应答。
结论：曲妥珠单抗 deruxtecan 在先前治疗的 -突变型 NSCLC 患者中显示出持久的抗癌活性。安全性概况包括两例致命的间质性肺病。观察到的毒性作用与先前报道的研究基本一致。（由 Daiichi Sankyo 和 AstraZeneca 资助；DESTINY-Lung01 ClinicalTrials.gov 编号，NCT03505710.）。
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