Double-blind randomized phase II results comparing concurrent high-dose cisplatin chemorradiation (CRT) plus debio 1143 or placebo in high-risk patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN): A GORTEC study

Bourhis, Jean; Sun, Xiaoqun; Pointreau, Y.; Siré, C.; Tourneau, C. Le; Kaminsky-Forrett, M.-C.; Alfonsi, M.; Boisselier, P.; Martin, L.; Delord, Jean Pierre; Clatot, Florian; Miroir, J.; Rolland, F.; Crompton, Philippa; Brienza, S.; Szyldergemajn, Sergio; Even, C.; Tao, Yoshiaki

doi:10.1093/annonc/mdz394.062

Cited by 4 publications

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“…8 This designation was based on positive clinical data from a phase 2 study presented at the 2019 annual meeting of the European Society for Medical Oncology. 9 Ninety-six patients with high-risk squamous cell carcinoma of the head and neck were randomized to receive either standard of care radiation with concurrent cisplatin plus placebo or the standard of care plus Debio 1143. The primary end point of locoregional control at 18 months was met with an improvement of 21% (odds ratio, 2.69; 95% CI, 1.13-6.42; P = .03).…”

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“…The primary end point of locoregional control at 18 months was met with an improvement of 21% (odds ratio, 2.69; 95% CI, 1.13-6.42; P = .03). 9 Breakthrough therapy designation is similar to fast track, but requires preliminary clinical evidence of a treatment effect that may represent a substantial improvement over available therapies. 6 While these actions by the FDA are encouraging, it is important to note that fast track and breakthrough therapy are merely designations, not market approvals.…”

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confidence: 99%

“…On February 27, 2020, the FDA granted Debiopharm breakthrough therapy designation for Debio 1143 for the treatment of patients with previously untreated, unresectable locally advanced squamous cell carcinoma in combination with cisplatin-based concomitant chemoradiation . This designation was based on positive clinical data from a phase 2 study presented at the 2019 annual meeting of the European Society for Medical Oncology . Ninety-six patients with high-risk squamous cell carcinoma of the head and neck were randomized to receive either standard of care radiation with concurrent cisplatin plus placebo or the standard of care plus Debio 1143.…”

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Drug-Radiotherapy Combinations in 2020—A Landmark Year?

2021

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Oncology drug development is a multibillion-dollar industry. Since 2013, cancer drug expenditures as a percentage of total prescription spending in the US has increased to almost 60%. 1 The number of US Food and Drug Administration (FDA) drug approvals each year is a reflection of this growth. In 2019 alone, the FDA Oncology Center of Excellence approved 11 new drugs or biologics and 30 supplemental applications. 2 The good news is that it appears we are making progress in cancer outcomes. A recent report from the American Cancer Society stated that the US cancer death rate fell by 2.2% in 2017, the biggest single-year drop ever recorded. 3 But the most important question for patients with cancer who are taking these recently approved drugs is: Will I be cured of my disease? And the sobering answer remains, probably not.Only 2 of the 30 approvals in patients with solid malignant neoplasms in 2019 were approved in the upfront or adjuvant setting where patients are considered potentially curable. 2 Despite the development of promising cancer drugs and the pharmaceutical industry clamoring for a share of the oncology market, almost all FDAlabeled indications for oncology drugs remain in the metastatic or palliative setting. This lack of drug development in the curative setting is corroborated by a recent publication by Zaorsky and colleagues 4 that reported an exceedingly low number of patients enrolling in clinical trials as a first course of therapy (0.1%). Even among those patients, most had metastatic disease. In other words, this approval trend is unlikely to change in the near future, and the cure rate will not increase.Patient-focused drug development is central to the 21st Century Cures Act (https://www.govinfo.gov/app/ details/PLAW-114publ255). The Act applies to improved collection, interpretation, and reporting of patientreported outcomes, as well as advancing the science surrounding assessments of clinical outcomes. But we believe the Act also should comprise a concerted effort to maximize the benefit of definitive-potentially curative-therapies, including radiation therapy.About half of patients who are cured of cancer will receive radiation therapy as a component of their care. Although radiation therapy is considered a local therapy, it is important to acknowledge that in tumors with high metastatic potential, an improvement in locoregional control can improve survival. Furthermore, many patients living with metastatic disease are diagnosed at an early stage, and later develop distant disease. While radiation is delivered with concurrent chemotherapy in many disease sites treated with curative intent, recurrence rates with standard cytotoxic agents (eg, cisplatin, mitomycin, etoposide) remain suboptimal. For example, fewer than 60% of patients with stage III

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Drug-Radiotherapy Combinations in 2020—A Landmark Year?

2021

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“…Compound 9 is currently being evaluated in Phase I/II in a combination therapy by Debiopharm for squamous cell carcinoma of the head and neck (NCT02022098) . The study recently achieved statistical significance on their primary end point of locoregional control rate with 21% improvement at 18 months after chemoradiotherapy …”

Section: Single Protein Ring E3 Ubiquitin Ligasesmentioning

confidence: 99%

“…34 The study recently achieved statistical significance on their primary end point of locoregional control rate with 21% improvement at 18 months after chemoradiotherapy. 35 In 2004, a serendipitous discovery by the groups of Prof. Xiaodong Wang and Prof. Patrick Harran at the University of Texas introduced a new class of IAP antagonists. They found that a dimer of a Smac mimetic surpassed its momomeric congener at inducing apoptosis in human cancer cells.…”

Section: Single Protein Ring E3 Ubiquitin Ligasesmentioning

confidence: 99%

Medicinal Chemistry of Inhibiting RING-Type E3 Ubiquitin Ligases

Blaquière¹,

Villemure²,

Staben³

2020

J. Med. Chem.

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The ubiquitin proteasome system (UPS) presents many opportunities for pharmacological intervention. Key players in the UPS are E3 ubiquitin ligases, responsible for conjugation of ubiquitin to specific cognate substrates. Numbering more than 600 members, these ligases represent the most selective way to intervene within this physiologically important system. This Perspective highlights some of the dedicated medicinal chemistry efforts directed at inhibiting the function of specific single-protein and multicomponent RING-type E3 ubiquitin ligases. We present opportunities and challenges associated with targeting this important class of enzymes.

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