Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study

Shitara, Kohei; Iwata, Hiroji; Takahashi, Shunji; Tamura, Kenji; Park, Haeseong; Modi, Shanu; Tsurutani, Junji; Kadowaki, Shigenori; Yamaguchi, Kensei; Iwasa, Satoru; Saito, Kaku; Fujisaki, Yoshihiko; Sugihara, Masahiro; Shahidi, Javad; Doi, Toshihiko

doi:10.1016/s1470-2045(19)30088-9

Cited by 168 publications

(128 citation statements)

References 26 publications

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“…In addition to NSCLC, the current results demonstrated preliminary activity for T-DXd in other HER2-expressing Treatment with T-DXd resulted in an acceptable safety profile that was observed to be consistent across other study cohorts (patients with HER2-positive breast cancer and gastric cancer), as described previously (19,20). Our experience of pulmonary toxicity draws parallels with many EGFRtargeting agents, which have also been associated with an increased risk of drug-induced ILD, yet the specific mechanism remains unknown.…”

Section: Discussionsupporting

confidence: 84%

“…During the dose-expansion phase, T-DXd demonstrated promising antitumor activity with an acceptable safety profile in patients with HER2-positive breast cancer or gastric cancer treated with 5.4 or 6.4 mg/kg doses [investigator-assessed confirmed objective response rates (ORR) of 59.5% and 43.2%, respectively; refs. 19,20]. In the HER2-expressing non-breast/ non-gastric or HER2-mutant solid tumor cohort, the MTD during dose escalation was 6.4 mg/kg intravenously once every 3 weeks, and this dose was chosen for dose expansion in this cohort based on the principle of highest tolerated dose without dose-limiting toxicities (18).…”

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confidence: 99%

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Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors

et al. 2020

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HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or HER2-mutant solid tumors from a phase I trial (NCT02564900). Most common (>50%) treatment-emergent adverse events (TEAE) were nausea, decreased appetite, and vomiting. Two drug-related TEAEs were associated with fatal outcomes. The confirmed objective response rate (ORR) was 28.3% (17/60). Median progression-free survival (PFS) was 7.2 [95% confidence interval (CI), 4.8-11.1] months. In HER2-mutant non-small cell lung cancer (NSCLC), ORR was 72.7% (8/11), and median PFS was 11.3 (95% CI, 8.1-14.3) months. Confirmed responses were observed in six tumor types, including HER2-expressing NSCLC, colorectal cancer, salivary gland cancer, biliary tract cancer, endometrial cancer, and HER2-mutant NSCLC and breast cancer. Results suggest T-DXd holds promise for HER2-expressing/mutant solid tumors. SIGNIFICANCE: T-DXd demonstrated promising activity in a heterogeneous patient population with heavily pretreated HER2-expressing or HER2-mutant solid tumors, especially HER2-mutant NSCLC. The safety profile was generally acceptable. Interstitial lung disease can be severe and requires prompt monitoring and intervention.

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Section: Discussionsupporting

confidence: 84%

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confidence: 99%

Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors

et al. 2020

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“…A dose-escalation and dose-expansion phase I trial was conducted for trastuzumab deruxtecan in patients with AGC [61]. A total of 44 patients pretreated with HER2-positive AGC received at least one dose of trastuzumab deruxtecan (5.4 or 6.4 mg/kg) every three weeks.…”

Section: Trastuzumab Deruxtecan (Ds-8201a)mentioning

confidence: 99%

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Mitani

Kawakami

2020

Cancers

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Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody-drug conjugates that are under development and have shown promising antitumor activity in early studies. basis of these results, trastuzumab was approved for AGC with a high HER2 expression level, and trastuzumab-containing regimens are now a standard option for the first-line treatment of such patients, who accounted for 7% to 17% of all individuals with gastric cancer [3-5]. Derivatives of the ToGA Regimen in the First-Line SettingThe ToGA trial adopted a regimen of cisplatin combined with either 5-fluorouracil (5-FU) or capecitabine, whereas subsequent prospective studies found similar treatment outcomes with regimens containing oxaliplatin or tegafur-gimeracil-oteracil (S-1). In a single-arm, nonrandomized phase II trial (HER2-based strategy in stomach cancer (HERBIS)-1) performed in Japan [6], trastuzumab in combination with S-1 plus cisplatin yielded a confirmed ORR of 68%, with a median OS and a median PFS of 16.0 and 7.8 months, respectively, in HER2-positive AGC patients with measurable lesions, with these results being similar to those of the ToGA trial [2]. Similar efficacy was also apparent in AGC patients without measurable lesions (HERBIS-1B study) [7]. Three phase II studies that assessed the combination of trastuzumab with capecitabine plus oxaliplatin reported a median OS, a median PFS, and an ORR of 13.8 to 21.0 months, 7.1 to 9.8 months, and 46.7% to 67.3%, respectively [8][9][10]. Trastuzumab in combination with S-1 plus oxaliplatin was also shown to provide a similar treatment outcome in a phase II study, with a median OS, a median PFS, and an ORR of 18.1 months, 8.8 months, and 70.7%, respectively [11]. A meta-analysis of data from these trials revealed that S-1 or oxaliplatin can substitute effectively for capecitabine or 5-FU or for cisplatin, respectively [12].Immune checkpoint inhibitors such as antibodies to programmed cell death-1 (PD-1) have recently revolutionized treatment strategies for advanced cancer. Given that trastuzumab was found to stimulate T cell responses [13], the combination of trastuzumab-containing regimens with antibodies to PD-1 is receiving attention. A phase II study including 37 patients with HER2-positive AGC treated in the first-line setting with capecitabine, oxaliplatin, and trastuzumab in combination with the anti-PD-1 antibody pembrolizumab reported an ORR of 83%, with a median PFS of 11.4 months and a median ...

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“…Indeed, previous landmark clinical trials reported that ado-trastuzumab emtansine (T-DM1), an anti-human epidermal growth factor receptor 2 (anti-HER2) monoclonal antibody linked to the cytotoxic antimicrotubule agent DM1, was clearly superior to conventional cytotoxic chemotherapies in HER2-expressing breast cancer (15,16). Furthermore, a recent early clinical trial of DS-8201a, an anti-HER2 ADC carrying the highly potent topoisomerase I inhibitor DXd, demonstrated a promising result for HER2-positive solid cancers (17)(18)(19). With these results, ADC may be considered as a replacement for conventional cytotoxic chemotherapies, at least in advanced HER2-positive cancers.…”

Section: Introductionmentioning

confidence: 99%

U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation

Haratani¹,

Yonesaka²,

Takamura³

et al. 2019

Journal of Clinical Investigation

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Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study

Cited by 168 publications

References 26 publications

Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors

Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation

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