Debio 1143 and high-dose cisplatin chemoradiotherapy in high-risk locoregionally advanced squamous cell carcinoma of the head and neck: a double-blind, multicentre, randomised, phase 2 study

Sun, Xu-Shan; Tao, Yungan; Tourneau, Christophe Le; Pointreau, Y.; Siré, C.; Kaminsky, Marie‐Christine; Coutté, Alexandre; Alfonsi, M.; Boisselier, P.; Martin, Laurent; Miroir, J.; Ramée, Jean-François; Delord, Jean‐Pierre; Clatot, Florian; Rolland, Frédéric; Villa, Julie; Magné, Nicolas; Eliçin, Olgun; Gherga, Elisabeta; Nguyen, F.; Lafond, C.; Béra, G.; Calugaru, Valentin; Geoffrois, Lionnel; Chauffert, Bruno; Zubel, Angela; Zanna, Claudio; Brienza, S.; Crompton, Philippa; Rouits, Elisabeth; Gollmer, Kathrin; Szyldergemajn, Sergio; Bourhis, Jean

doi:10.1016/s1470-2045(20)30327-2

Cited by 98 publications

(75 citation statements)

References 20 publications

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“…Published results report that weekly oral doses of LCL161 was well-tolerated and efficacious in treating patients with advanced solid tumors, supporting further investigation [ 167 ]. Two publications have arisen from clinical evaluation of AT-406 (aka DEBIO1143, SM-406) against metastatic solid tumors [ 171 ] and head and neck cancers [ 172 ]. The recent Phase 2 study concluded that the addition of AT-406 augmented standard-of-care therapy with manageable safety, warranting Phase 3 investigation [ 172 ].…”

Section: Small-molecule Inhibitors Targeting the Upsmentioning

confidence: 99%

Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors

LaPlante

Zhang

2021

Cancers

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The ubiquitin-proteasome system (UPS) is a critical regulator of cellular protein levels and activity. It is, therefore, not surprising that its dysregulation is implicated in numerous human diseases, including many types of cancer. Moreover, since cancer cells exhibit increased rates of protein turnover, their heightened dependence on the UPS makes it an attractive target for inhibition via targeted therapeutics. Indeed, the clinical application of proteasome inhibitors in treatment of multiple myeloma has been very successful, stimulating the development of small-molecule inhibitors targeting other UPS components. On the other hand, while the discovery of potent and selective chemical compounds can be both challenging and time consuming, the area of targeted protein degradation through utilization of the UPS machinery has seen promising developments in recent years. The repertoire of proteolysis-targeting chimeras (PROTACs), which employ E3 ligases for the degradation of cancer-related proteins via the proteasome, continues to grow. In this review, we will provide a thorough overview of small-molecule UPS inhibitors and highlight advancements in the development of targeted protein degradation strategies for cancer therapeutics.

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Section: Small-molecule Inhibitors Targeting the Upsmentioning

confidence: 99%

Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors

LaPlante

Zhang

2021

Cancers

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“…Furthermore, our sampling was performed 24-72 hours post-treatment which is after the time when peak chemotherapy-induced apoptosis may reasonably be expected and may explain the absence of a signal in these samples (13). In previous studies Debio 1143 has successfully demonstrated anti-tumor activity in preclinical cancer models including SCCHN (7),(8), (9), and also in patients with SCCHN (11). However, it should be noted that the focus of this window study was not efficacy but the application of a clinical model to support the mode of action of Debio 1143, potentially leading to efficacy in SCCHN clinical trials.…”

Section: Accepted Articlementioning

confidence: 99%

“…The recommended phase II dose (RP2D) of Debio 1143 was 200 mg/day for 14 days three weekly (q3w) when combined with concomitant q3w high-dose cisplatin (100 mg/m 2 ) chemoradiotherapy. In addition, Debio 1143 improved locoregional control compared with chemoradiation alone (11).…”

Section: Accepted Articlementioning

confidence: 99%

“…These concentrations largely exceed the IC 50 for the cIAP-1 and -2 and XIAP targets by 100 to 1000-fold. Furthermore, systemic Debio 1143 PK disposition was broadly similar between the monotherapy and combination cohorts, further evidence supporting the utility of Debio 1143 200 mg/day in combination with standard cisplatin based chemoradiotherapy in this refractory population.Results from a phase II trial of daily Debio 1143 at this same dose in combination with cisplatin based chemoradiotherapy, in patients with high-risk LA-SCCHN were recently published(11).…”

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confidence: 99%

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Exploratory window‐of‐opportunity trial to investigate the tumor pharmacokinetics/pharmacodynamics of the IAP antagonist Debio 1143 in patients with head and neck cancer

Gomez‐Roca

Even

Tourneau

et al. 2021

Clinical Translational Sci

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Inhibitor of apoptosis proteins (IAPs) regulate apoptosis and modulate NF-κB signalling thereby driving expression of genes involved in immune/inflammatory responses. The orally available IAP antagonist Debio 1143 has potential to enhance tumor response to chemoradiotherapy and/or immunotherapy. Patients with pre-operative squamous cell carcinomas of the head and neck (SCCHN) received: Debio 1143 monotherapy (200 mg/day D1-15 +/-2); Debio 1143 (200 mg/day D1-15 +/-2) plus cisplatin (40 mg/m 2 D-1 and 8); cisplatin alone (40 mg/m 2 D-1 and 8) (EudraCT: 2014-004655-31). Pharmacokinetic/pharmacodynamic effects were assessed in plasma and resected tumors. Primary endpoint; effect of Debio 1143 on cellular IAP-1 (cIAP-1). Levels of cIAP-1/-2, X-linked inhibitor of apoptosis protein (XIAP), tumor infiltrating lymphocytes (TILs) including CD8+ T cells, programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) and gene expression were also analyzed. Twenty-three of 26 patients completed treatment. In the Debio 1143 monotherapy cohort (n=13), mean tumor concentrations of Debio 1143 were 18-fold (maximum 55.2-fold) greater than in Accepted Article This article is protected by copyright. All rights reserved plasma, exceeding the IC 50 for cIAPs and XIAP by 100 to 1000-fold, with significant engagement/degradation of cIAP-1 (p <0.05). Overall, levels of CD8+ TILs, PD-1 and PD-L1 positive immune cells increased significantly (p <0.05) following Debio 1143 treatment. Changes were observed in the expression of genes related to NF-κB signalling. Treatments were well tolerated. Debio 1143 penetrated SCCHN tumors, engaged cIAP-1 and induced immune inflammatory changes in the tumor microenvironment. Based on the mode of action demonstrated here and in previous studies, these data support future combinations of Debio 1143 with immune-checkpoint agents.

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“…At present, the treatment of CESC and HNSC is surgery combined with adjuvant radiotherapy or radical radiation therapy ( 5 ). However, the five-year progression-free survival rate of CESC patients treated with radiotherapy and the two-year progression-free survival rate of HNSC patients treated with combined radiotherapy and cisplatin are only 43.6 ( 6 ) and 41% ( 7 ), respectively. Relapse, which causes radiotherapy failure in CESC and HNSC, is primarily attributed to radioresistance.…”

Section: Introductionmentioning

confidence: 99%

FSCN1 Promotes Radiation Resistance in Patients With PIK3CA Gene Alteration

Huang

Wang

et al. 2021

Front. Oncol.

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Radiotherapy is one of the standard treatments for cervical cancer and head and neck cancer. However, the clinical efficacy of this treatment is limited by radioresistance. The discovery of effective prognostic biomarkers and the identification of new therapeutic targets have helped to overcome the problem of radioresistance. In this study, we show that in the context of PIK3CA mutation or amplification, high expression of fascin actin-bundling protein 1 (FSCN1) (using the median as the cut-off value) is associated with poor prognosis and radiotherapy response in cancer patients. Silencing FSCN1 enhances radiosensitivity and promotes apoptosis in cancer cells with PIK3CA alterations, and this process may be associated with the downregulation of YWHAZ. These results reveal that FSCN1 may be a key regulator of radioresistance and could be a potential target for improving radiotherapy efficacy in cervical cancer and head and neck cancer patients with PIK3CA alterations.

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Debio 1143 and high-dose cisplatin chemoradiotherapy in high-risk locoregionally advanced squamous cell carcinoma of the head and neck: a double-blind, multicentre, randomised, phase 2 study

Cited by 98 publications

References 20 publications

Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors

Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors

Exploratory window‐of‐opportunity trial to investigate the tumor pharmacokinetics/pharmacodynamics of the IAP antagonist Debio 1143 in patients with head and neck cancer

FSCN1 Promotes Radiation Resistance in Patients With PIK3CA Gene Alteration

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