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

Summary

Background

Debio 1143 is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumour activity of cisplatin and radiotherapy. The radiosensitising effect of Debio 1143 is mediated through caspase activation and TNF, IFNγ, CD8 T cell-dependent pathways. We aimed to investigate the efficacy and safety of Debio 1143 in combination with standard chemoradiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck.

Methods

This double-blind, multicentre, randomised, phase 2 study by the French Head and Neck Radiotherapy Oncology Group (GORTEC) was run at 19 hospitals in France and Switzerland. Eligible patients were aged 18–75 years with locoregionally advanced, squamous cell carcinoma of the head and neck (characterised as non-metastatic, measurable stage III, IVa, or IVb [limited to T ≥2, N0–3, and M0] disease), Eastern Cooperative Oncology Group performance status of 0 or 1, a history of heavy tobacco smoking (>10 pack-years) with no previous or current treatment for invasive head and neck cancer, and no previous treatment with inhibitor of apoptosis protein antagonists. Patients were randomly assigned (1:1) to receive oral Debio 1143 (200 mg per day on days 1–14 of 21-day cycles, for three cycles) or oral placebo (20 mg/mL, administered at the same dosing schedule) using a stochastic minimisation technique according to node involvement and primary tumour site, and HPV-16 status in patients with an oropharyngeal primary tumour site. All patients received standard high-dose cisplatin chemoradiotherapy. The primary endpoint was the proportion of patients with locoregional control 18 months after chemoradiotherapy, analysed in the intention-to-treat population (primary analysis), and repeated in the per-protocol population. Responses were assessed according to Response Evaluation Criteria in Solid Tumors (version 1.1). This trial is registered with ClinicalTrials.gov, NCT02022098, and is still active but not recruiting.

Findings

Between Jan 25, 2016, and April 24, 2017, 48 patients were randomly assigned to the Debio 1143 group and 48 to the placebo group (one patient in the placebo group did not receive the study drug and was not included in the safety analysis). Median duration of follow-up was 25·0 months (IQR 19·6–29·4) in the Debio 1143 group and 24·2 months (6·6–26·8) in the placebo group. Locoregional control 18 months after chemoradiotherapy was achieved in 26 (54%; 95% CI 39–69) of 48 patients in the Debio 1143 group versus 16 (33%; 20–48) of 48 patients in the placebo group (odds ratio 2·69 [95% CI 1·13–6·42], p=0·026). Grade 3 or worse adverse events were reported in 41 (85%) of 48 patients in the Debio 1143 group and in 41 (87%) of 47 patients in the placebo group. The most common grade 3–4 adverse events were dysphagia (in 24 [50%] patients in the Debio 1143 group vs ten [21%] in the placebo group), mucositis (in 15 [31%] vs ten [21%]), and anaemia (in 17 [35%] vs 11 [23%]). Serious treatment-emergent adverse events were recorded in 30 (63%) of 48 patients in the Debio 1143 group and 28 (60%) of 47 in the placebo group. In the placebo group, two (4%) deaths were due to adverse events (one multiple organ failure and one asphyxia; neither was considered to be related to treatment). No deaths due to adverse events occurred in the Debio 1143 group.

Interpretation

To our knowledge, this is the first treatment regimen to achieve superior efficacy in this disease setting against a high-dose cisplatin chemoradiotherapy comparator in a randomised trial. These findings suggest that inhibition of inhibitor of apoptosis proteins is a novel and promising approach in this poor prognostic population and warrant confirmation in a phase 3 study with the aim of expanding the therapeutic options for these patients.

Funding

Debiopharm.

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.