ArticlesDebio 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
Introduction
The broad geographical variation in the incidence of squamous cell carcinoma of the head and neck is predominantly attributable to regional patterns of tobacco and alcohol use and, together, these habits contribute to the development of almost 80% of cases worldwide.1 Human papillomavirus (HPV) infection status has become increasingly important in the epidemiology and prognosis of squamous cell carcinoma of the head and neck.2 Most patients diagnosed with squamous cell carcinoma of the head and neck present with the locoregionally advanced form of disease.3 Although potentially curable, the management of patients with locoregionally advanced squamous cell carcinoma of the head and neck poses a complex challenge due to the requirement for combined-modality therapy.4 In patients with an unresectable form of this disease, three-weekly high-dose cisplatin (100 mg/m2) with concurrent radiotherapy is a standard treatment. More than half of patients with locoregionally advanced squamous cell carcinoma of the head and neck relapse or have treatment failure, the majority locoregionally and within 2 years of completing treatment.5 Treatment resistance remains a major challenge, especially in those with HPV-negative oropharyngeal cancers.6 HPV status is a strong, independent prognostic indicator in patients with oropharyngeal cancer, with 5-year survival rates of 75–80% in patients with HPV-positive disease, compared with 45–50% for those with HPV-negative cancers.7 Currently, no therapies are indicated specifically for patients with HPV-negative oropharyngeal cancers, and these patients, usually heavy tobacco smokers, have the poorest prognoses and represent an unmet medical need.
In numerous cancer types, including squamous cell carcinoma of the head and neck, regulation of programmed cell death is impaired, allowing cancer cells to evade apoptosis in response to potentially lethal standard chemoradiotherapy exposure, thereby contributing to the emergence of treatment-resistant clones.8 Inhibitor of apoptosis proteins (IAPs), including X chromosome-linked IAP (XIAP), cellular IAP1 (cIAP1; also known as BIRC2), and cIAP2, are a class of proteins that can negatively regulate apoptosis, modulate immune and inflammatory responses, and affect a multitude of other cellular processes that are frequently deregulated in human cancers. IAPs are highly expressed in several human tumours, including squamous cell carcinoma of the head and neck.7, 9 Squamous cell carcinomas of the head and neck are among the cancers with the highest frequency of deregulation in genes encoding constituents of the cell death pathway, with more than 40% of HPV-negative and more than 30% of HPV-positive cases showing deregulation of FADD, cIAP1, CASP8, and TRAF3.7 Direct binding of IAPs with inhibitory agents has been shown to moderate their anti-apoptotic effects through promotion of apoptosis and restoration of treatment sensitivity.10, 11 cIAP1 and cIAP2 are also modulators of NF-κB signalling, which plays an important part in T-cell activation and proliferation, and inhibition of cIAP1 and cIAP2 with IAP antagonists has resulted in antitumour activity through modulation of innate and adaptive immunity.12
Debio 1143 (also known as AT-406 and SM-406) is an orally available, small-molecule antagonist of IAPs, including XIAP, cIAP1, and cIAP2. Debio 1143 has been shown to enhance the effect of chemoradiotherapy in several preclinical models of cancer, including squamous cell carcinoma of the head and neck, sensitising for radiotherapy and improving the effects of platinum derivatives in multiple squamous cell carcinoma of the head and neck tumour models.13, 14, 15, 16 Furthermore, the antitumour host immune system was shown to contribute to the radiosensitisation effect of Debio 1143, and was dependent on CD8 cells, TNF, and IFNγ.14 In a window-of-opportunity study, high concentrations of Debio 1143 were achieved in squamous cell carcinoma of the head and neck tumours (up to 55 times those found in plasma), largely exceeding the half maximal inhibitory concentration for XIAP and cIAPs by 100 to 1000 times, resulting in cIAP1 target engagement and downstream effects on CD8 tumour-infiltrating lymphocytes.16
In the phase 1 part of this study, the safety profile of Debio 1143 in combination with standard chemoradiotherapy was largely consistent with that of chemoradiotherapy alone in 14 patients with locoregionally advanced squamous cell carcinoma of the head and neck.17 In this setting, we established the safety profile, dose-limiting toxicities, maximum tolerated dose, pharmacokinetics, pharmacodynamics, and preliminary antitumour activity of Debio 1143. The recommended phase 2 dose (RP2D) of Debio 1143 (200 mg once daily, administered on days 1–14 of 21-day cycles) was also defined (detailed findings will be reported elsewhere). Here, we aimed to investigate the efficacy and safety of Debio 1143 at the RP2D in combination with standard chemoradiotherapy in patients with high-risk locoregionally advanced squamous cell carcinoma of the head and neck.
Section snippets
Study design and participants
This double-blind, multicentre, randomised, phase 2 study (GORTEC 2015-03) was run by the French Head and Neck Radiotherapy Oncology Group (GORTEC) at 19 hospitals in France and Switzerland. Patients were eligible to participate if they were aged 18–75 years with a histologically confirmed diagnosis of previously untreated locoregionally advanced squamous cell carcinoma of the head and neck (stage III, IVa, and IVb, limited to T ≥2, N0–3, and M0 [according to the 2010 American Joint Committee
Results
Between Jan 25, 2016, and April 24, 2017, 96 patients were enrolled and randomly assigned to the Debio 1143 group (n=48) or the placebo group (n=48); these patients constituted the intention-to-treat population. One patient from the placebo group did not receive study treatment; thus, 95 patients were included in the safety population (figure 1). Baseline characteristics are in table 1. Eight (17%) of 48 patients in the Debio 1143 group versus two (4%) of 48 patients in the placebo group had
Discussion
The key findings from our placebo-controlled, randomised study provide, to our knowledge, the first proof of concept that the addition of Debio 1143 to standard-of-care chemoradiotherapy resulted in superior clinical outcomes, compared with chemoradiotherapy alone, in a cohort of patients with non-resected, high-risk locoregionally advanced squamous cell carcinoma of the head and neck. Our results in this poor prognostic population suggest that inhibition of IAPs is a novel and promising
Data sharing
Availability of the data underlying this publication will be determined according to Debiopharm's commitment to the European Federation of Pharmaceutical Industries and Associations–Pharmaceutical Research and Manufacturers of America principles for responsible clinical trial data sharing. This pertains to scope, timepoint, and process of data access. As such, Debiopharm commits to sharing, upon request from qualified scientific and medical researchers, patient-level clinical trial data,
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Lead authors and contributed equally to this work