背景：T-dxd 是人源化抗 her2 抗體與拓撲異構酶 I 抑製劑通過可切割的連接體結合的抗體-藥物結合物。DES-TINY-CRC01（DS8201-A-J203；NCT03384940），一項 2 期、開放標記、多中心的 T-dxd 在表達 Her2 的 MCRC 患者中的研究顯示了良好的抗腫瘤活性和可控的安全性（隊列 a 中位隨訪[FU]，27.1 周；錫耶納 SASCO 2020）。我們提供了最新的長期療效和安全性數據。
Background: T-DXd is an antibody–drug conjugate of a humanized anti-HER2 antibody bound to a topoisomerase I inhibitor by a cleavable linker. The primary analysis of DESTINY-CRC01 (DS8201-A-J203; NCT03384940), a phase 2, open-label, multicenter study of T-DXd in pts with HER2-expressing mCRC showed promising antitumor activity and a manageable safety profile (cohort A median follow-up [FU], 27.1 weeks; Siena S, ASCO 2020). We present updated longer-term efficacy and safety data.
方法：Ptshad 集中證實 Her2 表達，RAS 野生型 MCRC，在 2 次治療後進展。在 3 個隊列（A:HER2 HC3+或 HC2+/SH+B:HC2+/ISH-）中，每 3 周給藥 6.4mg/kg T-dxd（Q3W）；C:HC1+。原發性腰背痛通過獨立的中心回顧證實為客觀有效率（ORR）。次要終點為疾病控製率（DCR）；CR+PR+SD）、反應持續時間（DOR）、無進展生存期（PFS）和總生存期（OS）。
Methods: Pts had centrally confirmed HER2-expressing, RAS wild-type mCRC that progressed after ≥2 prior regimens. 6.4 mg/kg of T-DXd was administered every 3 weeks (Q3W) in 3 cohorts (A: HER2 IHC3+ or IHC2+/ISH+; B: IHC2+/ISH-; C: IHC1+). The primary end point was confirmed objective response rate (ORR) by independent central review in cohort A. Secondary end points were disease control rate (DCR; CR+PR+SD), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
結果：Atdata cutoff（2020 年 12 月 28 日），86 分（A，53 分；B，15 歲；C，18）收到T-dxd。中位年齡 58.5 歲（27-79 歲），53.5%為男性，90.7%為左半結腸癌或直腸癌。轉移性疾病的中位既往治療方案為 4（範圍 2-11）。所有患者均接受普瑞力諾替康治療；30 . 隊列A 中有 2%曾接受過抗 HER2 治療。中位（m）治療時間（所有 pts）為 3.0 個月（95%Cl，2.1-4.1 ; A 組，5.1 個月[95%氯，3。9-7 . 6 ) . A 組（中位 FU，62。4 周），證實 ORR 為 45。3%（24/53 分；95%CI31.6～59.6）DCR 為 83.0%（44/53 分）；95%Cl，70.2-91.9），MDOR為 7.0 mo（95%Cl，5。8-9 . ) , MPFS 為 6.9 個月（95%cl，4.5%）。1-8 . 7）與 37（69。8%）PFS 事件和 mos 為 15.5 個月（95%Cl，8。8-20 . 8）與 36（67。9%）操作係統事件。這些結果與初步分析一致。8%（7/16 分；95%cl，19.8-70 . 1）在接受過抗 HER2 治療的患者中，57.5%（23/40 分；95%cl，40.973。0）有 HC3+狀態者，占 7.7%（1/13）；95%cl，0。 2-36 . 0）在具有 IHC2-+/SH+狀態的 pts 中。在 B 組和 C 組中，MPFS 為 2.1 個月（95%置信區間，1。4-4 . 1）和 1.4mo（95%Cl，1.3-2.1）：mos 為 7.3mo（95%Cl，3。0-ne）和7.7mo（95%Cl，2.213.9）。65 例患者發生（G）=3 級的治療性不良事件（TEAE）。1%的患者（56/86）；最常見的 TEAE 是血液學和胃腸道。TEAES 導致停藥 13 例（15 例）。1 % ) . 8 分（9.3%的患者有間質性肺病（LD），由一個獨立委員會判定與 T-dxd 有關（4 G2；1 G3；3 G5）。
Results: At data cutoff (Dec 28, 2020), 86 pts (A, 53; B, 15; C, 18) received T-DXd. Median age was 58.5 y (range, 27-79), 53.5% were male, and 90.7% had left colon or rectum cancer. Median prior regimens for metastatic disease was 4 (range, 2-11). All pts had prior irinotecan; 30.2% in cohort A had prior anti-HER2 therapy. Median (m) treatment duration (all pts) was 3.0 mo (95% CI, 2.1-4.1; cohort A, 5.1 mo [95% CI, 3.9-7.6]). In cohort A (median FU, 62.4 weeks), confirmed ORR was 45.3% (24/53 pts; 95% CI, 31.6-59.6), DCR was 83.0% (44/53 pts; 95% CI, 70.2-91.9), mDOR was 7.0 mo (95% CI, 5.8-9.5), mPFS was 6.9 mo (95% CI, 4.1-8.7) with 37 (69.8%) PFS events, and mOS was 15.5 mo (95% CI, 8.8-20.8) with 36 (67.9%) OS events. These results are consistent with the primary analysis. Confirmed ORR was 43.8% (7/16 pts; 95% CI, 19.8-70.1) in pts with prior anti-HER2 therapy, 57.5% (23/40 pts; 95% CI, 40.9-73.0) in pts with IHC3+ status, and 7.7% (1/13 pts; 95% CI, 0.2-36.0) in pts with IHC2+/ISH+ status. In cohorts B and C, mPFS was 2.1 mo (95% CI, 1.4-4.1) and 1.4 mo (95% CI, 1.3-2.1); mOS was 7.3 mo (95% CI, 3.0-NE) and 7.7 mo (95% CI, 2.2-13.9), respectively. Treatment-emergent adverse events (TEAEs) of grade (G) ≥3 occurred in 65.1% of pts (56/86); the most common TEAEs were hematologic and gastrointestinal. TEAEs leading to drug discontinuation occurred in 13 pts (15.1%). 8 pts (9.3%) had interstitial lung disease (ILD) adjudicated by an independent committee as related to T-DXd (4 G2; 1 G3; 3 G5).
結論：6.4mg/kgq3w 的 T-dxd 在該患者中顯示出良好的活性和長期服用 FU 的持久性。安全性與先前的結果一致；ILD 仍然被認為是一種重要的確定風險，需要根據需要進行仔細的監測和幹預。這些結果支持在 Her2 過度表達的 MCRC 患者中繼續探索。
Conclusions: T-DXd at 6.4 mg/kg Q3W showed promising activity and durability with longer-term FU in this pt population. The safety profile was consistent with prior results; ILD continues to be recognized as an important identified risk that requires careful monitoring and intervention as needed. These results support continued exploration of T-DXd in pts with HER2-overexpressing mCRC.
