肿瘤

曲妥珠单抗 deruxtecan(T-DXd;DS-8201)在表达 HER2 的转移性 结直肠(mCRC)患者(pts)中的应用:来自一项 2 期、多中心、开放标签研究 (DESTINY-CRC01)的最终结果

作者:会飞的大胖纸 来源:医学论坛网 日期:2021-06-30
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         背景:T-dxd 是人源化抗 her2 抗体与拓扑异构酶 I 抑制剂通过可切割的连接体结合的抗体-药物结合物。DES-TINY-CRC01(DS8201-A-J203;NCT03384940),一项 2 期、开放标记、多中心的 T-dxd 在表达 Her2 的 MCRC 患者中的研究显示了良好的抗肿瘤活性和可控的安全性(队列 a 中位随访[FU],27.1 周;锡耶纳 SASCO 2020)。我

关键字:  肿瘤 

背景:T-dxd 是人源化抗 her2 抗体与拓扑异构酶 I 抑制剂通过可切割的连接体结合的抗体-药物结合物。DES-TINY-CRC01(DS8201-A-J203;NCT03384940),一项 2 期、开放标记、多中心的 T-dxd 在表达 Her2 的 MCRC 患者中的研究显示了良好的抗肿瘤活性和可控的安全性(队列 a 中位随访[FU],27.1 周;锡耶纳 SASCO 2020)。我们提供了最新的长期疗效和安全性数据。

 

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 集中证实 Her2 表达,RAS 野生型 MCRC,在 2 次治疗后进展。在 3 个队列(A:HER2 HC3+或 HC2+/SH+B:HC2+/ISH-)中,每 3 周给药 6.4mg/kg T-dxd(Q3W);C:HC1+。原发性腰背痛通过独立的中心回顾证实为客观有效率(ORR)。次要终点为疾病控制率(DCR);CR+PR+SD)、反应持续时间(DOR)、无进展生存期(PFS)和总生存期(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).

 

结果:Atdata cutoff(2020 年 12 月 28 日),86 分(A,53 分;B,15 岁;C,18)收到T-dxd。中位年龄 58.5 岁(27-79 岁),53.5%为男性,90.7%为左半结肠癌或直肠癌。转移性疾病的中位既往治疗方案为 4(范围 2-11)。所有患者均接受普瑞力诺替康治疗;30 . 队列A  中有 2%曾接受过抗 HER2 治疗。中位(m)治疗时间(所有 pts)为 3.0 个月(95%Cl,2.1-4.1 ; A 组,5.1 个月[95%氯,3。9-7 . 6 ) . A 组(中位 FU,62。4 周),证实 ORR 为 45。3%(24/53 分;95%CI31.6~59.6)DCR 为 83.0%(44/53 分);95%Cl,70.2-91.9),MDOR为 7.0 mo(95%Cl,5。8-9 . ) , MPFS 为 6.9 个月(95%cl,4.5%)。1-8 . 7)与 37(69。8%)PFS 事件和 mos 为 15.5 个月(95%Cl,8。8-20 . 8)与 36(67。9%)操作系统事件。这些结果与初步分析一致。8%(7/16 分;95%cl,19.8-70 . 1)在接受过抗 HER2 治疗的患者中,57.5%(23/40 分;95%cl,40.973。0)有 HC3+状态者,占 7.7%(1/13);95%cl,0。 2-36 . 0)在具有 IHC2-+/SH+状态的 pts 中。在 B 组和 C 组中,MPFS 为 2.1 个月(95%置信区间,1。4-4 . 1)和 1.4mo(95%Cl,1.3-2.1):mos 为 7.3mo(95%Cl,3。0-ne)和7.7mo(95%Cl,2.213.9)。65 例患者发生(G)=3 级的治疗性不良事件(TEAE)。1%的患者(56/86);最常见的 TEAE 是血液学和胃肠道。TEAES 导致停药 13 例(15 例)。1 % ) . 8 分(9.3%的患者有间质性肺病(LD),由一个独立委员会判定与 T-dxd 有关(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).

 

结论:6.4mg/kgq3w 的 T-dxd 在该患者中显示出良好的活性和长期服用 FU 的持久性。安全性与先前的结果一致;ILD 仍然被认为是一种重要的确定风险,需要根据需要进行仔细的监测和干预。这些结果支持在 Her2 过度表达的 MCRC 患者中继续探索。

 

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.

 

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