In a French Head and Neck Radiotherapy Oncology Group phase II trial reported in The Lancet Oncology, Sun et al found that the addition of Debio 1143 (a small-molecule antagonist of inhibitor of apoptosis proteins) to high-dose cisplatin chemoradiation improved locoregional disease control in patients with high-risk locoregionally advanced squamous cell carcinoma of the head and neck.
Study Details
The double-blind trial included 96 patients who had received no prior treatment for invasive disease from sites in France and Switzerland. Patients were randomly assigned between January 2016 and April 2017 to receive oral Debio 1143 at 200 mg per day on days 1 to 21 of 3-week cycles for three cycles (n = 48) or placebo (n = 48) in combination with standard high-dose cisplatin chemoradiotherapy. The primary endpoint was the proportion of patients with locoregional control 18 months after chemoradiotherapy in the intention-to-treat population.
Locoregional Control
Median duration of follow-up was 25.0 months in the Debio 1143 group and 24.2 months in the placebo group. Locoregional control 18 months after chemoradiotherapy was achieved in 26 (54%; 95% confidence interval [CI] = 39%–69%) of 48 patients in the Debio 1143 group vs 16 (33%; 95% CI = 20%–48%) of 48 patients in the placebo group (odds ratio [OR] = 2.69, 95% CI = 1.13–6.42, P = .026). The median duration of locoregional control was not reached in either group (hazard ratio [HR] = 0.53, 95% CI = 0.22–1.30, P = .165).
Median progression-free survival was not reached in the Debio 1143 group vs 16.9 months in the placebo group (HR = 0.37, 95% CI = 0.18–0.76, P = .0069). Overall survival at 24 months was 73% (95% CI = 58%–84%) in the Debio 1143 group vs 65% (95% CI = 48%–77%) in the placebo group (HR = 0.65, 95% CI = 0.32–1.33, P = .243).
Adverse Events
Grade ≥ 3 adverse events occurred in 85% of patients in the Debio 1143 group and 87% of those in the placebo group, with the most common in the Debio 1143 group being dysphagia (50% vs 21%), mucositis (31% vs 21%), and anemia (35% vs 23%). Serious adverse events occurred in 63% vs 60% of patients; the most common were mucositis (8%), pyrexia (6%), and malnutrition (6%) in the Debio 1143 group, and acute kidney injury (11%), pyrexia (9%), and polyuria (6%) in the placebo group. None of the patients in the Debio 1143 group experienced adverse events that led to death; however, two patients in the placebo group did (due to multiple organ failure and asphyxia). No deaths were considered related to treatment.
The investigators concluded, “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 randomized 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 III study with the aim of expanding the therapeutic options for these patients.”
Jean Bourhis, MD, CHUV, Service de Radio-oncologie, Bâtiment Hospitalier, Lausanne, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Debiopharm. For full disclosures of the study authors, visit thelancet.com.
