Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial

Siena, Salvatore; Bartolomeo, Maria Di; Raghav, Kanwal; Masuishi, Toshiki; Loupakis, Fotios; Kawakami, Hisato; Yamaguchi, Kensei; Nishina, Tomohiro; Fakih, Marwan; Élez, Elena; Rodríguez, Javier; Ciardiello, Fortunato; Komatsu, Yoshito; Esaki, Taito; Chung, Ki Young; Wainberg, Zev A.; Sartore‐Bianchi, Andrea; Saxena, Kapil; Yamamoto, E.; Bako, Emarjola; Okuda, Yasuyuki; Shahidi, Javad; Grothey, Axel; Yoshino, Takayuki; investigators, Destiny-Crc

doi:10.1016/s1470-2045(21)00086-3

Cited by 280 publications

(186 citation statements)

References 27 publications

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“…Indeed, immune checkpoint inhibitors blocking the PD-1/PD-L1 interaction have shown remarkable results in cancer therapy (7). Most recently, the therapeutic effect of trastuzumab deluxtecan (DS-8201), which is an antibodydrug conjugate, was reported in patients with CRC (8). It showed strong and durable anti-tumor activity in patients with HER2positive metastatic CRC following two or more previous therapies (8).…”

Section: Introductionmentioning

confidence: 99%

“…Most recently, the therapeutic effect of trastuzumab deluxtecan (DS-8201), which is an antibodydrug conjugate, was reported in patients with CRC (8). It showed strong and durable anti-tumor activity in patients with HER2positive metastatic CRC following two or more previous therapies (8). Furthermore, PD-L1 is expressed in various normal tissues and maintains immune homeostasis (9).…”

Section: Introductionmentioning

confidence: 99%

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The Enhanced Inhibitory Effect of Estrogen on PD-L1 Expression Following Nrf2 Deficiency in the AOM/DSS Model of Colitis-Associated Cancer

et al. 2021

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Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a dual role in carcinogenesis. We previously reported that Nrf2 deficiency enhances the anti-tumorigenic effect of 17β-estradiol (E2) in an azoxymethane (AOM)/dextran sodium sulfate (DSS) model of colitis-associated cancer (CAC). Herein, we aimed to determine a possible explanation for our recent work and investigated the immune microenvironment represented by programmed death-ligand 1 (PD-L1) expression. One week after the AOM injection, mice were administered with DSS in drinking water for seven days; daily E2 injections were intraperitoneally administered during this period. The mice were sacrificed 16 weeks after AOM injection and analyzed for PD-L1 expression in the distal colon tissues using Western blotting and immunohistochemistry (IHC). Based on Western blotting results, PD-L1 expression was reduced in Nrf2 knockout (KO) female and E2-treated male mice when compared with their wild-type counterparts, following AOM/DSS treatment; this supports the association of PD-L1 expression with tumor progression. Additionally, this finding was in good agreement with the IHC results for PD-L1. Furthermore, we observed that PD-L1 is predominantly expressed in stromal cells rather than on epithelial cells in the colon. Western blotting revealed that PD-L1 expression in the colon positively correlates with expressions of inducible nitric oxide synthase (iNOS) (male, P = 0.002; female, P <0.001) and cyclooxygenase-2 (COX-2) (male, P <0.001; female, P <0.001). Collectively, our findings indicate that estrogen ameliorates the immune microenvironment represented by PD-L1 expression and enhances its effect in the absence of Nrf2.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Enhanced Inhibitory Effect of Estrogen on PD-L1 Expression Following Nrf2 Deficiency in the AOM/DSS Model of Colitis-Associated Cancer

et al. 2021

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“…published the results of the DESTINY-CRC01 phase II study which shows promising and durable activity of trastuzumab deruxtecan (DS-8201) in patients with refractory HER2-positive mCRC; notably, this activity was evident even in those patients who had previously received HER2-targeted therapies. In particular, in cohort A (including HER2 IHC 3+ or IHC2+ and ISH-positive mCRC patients), the authors documented the regression of target lesions, as well as lasting responses; this ultimately resulted in PFS and OS benefits [144]. Table 2 describes the main features of the principal ongoing trials on HER2 in aCRC (Table 2).…”

Section: Ongoing Trials On Anti-her2 Targeted Therapies In Acrcmentioning

confidence: 99%

Beyond RAS and BRAF: HER2, a New Actionable Oncotarget in Advanced Colorectal Cancer

Guarini

Grassi²,

Pezzicoli

et al. 2021

IJMS

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The human epidermal growth factor receptor 2 (HER2) is a well-established oncogenic driver and a successful therapeutic target in several malignancies, such as breast and gastric cancers. HER2 alterations, including amplification and somatic mutations, have also been detected in a small but not negligible subset of patients affected by advanced colorectal cancer (aCRC). However, to date, there are no available oncotargets in this malignancy beyond RAS and BRAF that are available. Here we present an overview on the present predictive and prognostic role of HER2 expression in aCRC, as well as on its consequent potential therapeutic implications from preclinical investigations towards ongoing trials testing anti-HER2 agents in aCRC. While HER2′s role as a molecular predictive biomarker for anti-EGFR therapies in CRC is recognized, HER2 prognostic value remains controversial. Moreover, thanks to the impressive and growing body of clinical evidence, HER2 is strongly emerging as a new potential actionable oncotarget in aCRC. In conclusion, in the foreseeable future, HER2-targeted therapeutic strategies may integrate the algorithm of aCRC treatment towards an increasingly tailored therapeutic approach to this disease.

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“…The DESTINY-CRC01 trial enrolled 78 RAS/BRAF wild-type mCRC patients refractory to standard treatments. Previous anti-HER2 therapy was not an exclusion criterion [67,68]. Patients were divided into three cohorts based on the degree of HER2 overexpression/amplification: cohort A (N = 53) immunohistochemistry (IHC)3+/IHC2+ and in situ hybridization (ISH) positive; cohort B (N = 15) IHC2+ and ISH negative; cohort C (N = 18) IHC1+.…”

Section: Targeting Her2mentioning

confidence: 99%

Tackling Refractory Metastatic Colorectal Cancer: Future Perspectives

Personeni

Smiroldo

Giunta

et al. 2021

Cancers

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Substantial improvements have characterized the systemic treatment of metastatic colorectal cancer (mCRC) over the past 20 years. Besides strong evidence that supports the use of RAS and BRAF status as prognostic and predictive indicators of disease and response, novel technologies have made possible the incorporation of emerging biomarkers for the management of mCRC. On one hand, the discovery of point mutations, amplifications, fusions, and gene expression profiles highlights the genomic and dynamic complexity of CRC. On the other, such discoveries are leading to newer biomarker-driven strategies that add to existing anti-epidermal growth factor receptor (EGFR) and anti-angiogenic approaches. In addition, the availability of a wide molecular profiling has relevant implications for patient prognosis and treatment benefits. Here, we will review the molecular underpinnings and clinical data supporting novel targeted treatments under development for refractory mCRC harboring BRAF mutations, KRAS G12C mutations, HER2 amplification, and less common molecular alterations, such as the re-arrangements of NTRK, ALK, and ROS1. Additionally, we will discuss novel strategies driving the rechallenge of EGFR antibodies and the incorporation of newer anti-angiogenic agents in the therapeutic armamentarium.

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Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial

Cited by 280 publications

References 27 publications

The Enhanced Inhibitory Effect of Estrogen on PD-L1 Expression Following Nrf2 Deficiency in the AOM/DSS Model of Colitis-Associated Cancer

The Enhanced Inhibitory Effect of Estrogen on PD-L1 Expression Following Nrf2 Deficiency in the AOM/DSS Model of Colitis-Associated Cancer

Beyond RAS and BRAF: HER2, a New Actionable Oncotarget in Advanced Colorectal Cancer

Tackling Refractory Metastatic Colorectal Cancer: Future Perspectives

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