Debio 1143 plus chemoradiotherapy improved head and neck squamous cell carcinoma disease control.
Major Finding: Debio 1143 plus chemoradiotherapy improved head and neck squamous cell carcinoma disease control.
Concept: Debio 1143 is a small-molecule antagonist of overexpressed inhibitors of apoptosis proteins (IAP).
Impact: This randomized, double-blind, phase II trial shows that Debio 1143 merits further investigation.
In half of patients with unresectable head and neck squamous-cell carcinoma (HNSCC), standard-of-care treatment with high-dose cisplatin plus radiotherapy is ineffective or is initially effective but then gives way to relapse. The prognosis for human papillomavirus (HPV)–negative HNSCC, which is most often caused by smoking tobacco and/or drinking alcohol, is worse than that for HPV-positive HNSCC, and there are no therapeutic agents specifically targeting HPV-negative HNSCC. In a multicenter, randomized, double-blind, phase II clinical trial enrolling 96 patients with locoregionally advanced (stage III, IVa, or IVb) HNSCC and a history of heavy smoking (≥10 pack-years), Sun, Tao, and colleagues investigated the utility of Debio 1143 (also known as AT-406 and SM-406), an orally available small-molecule antagonist of inhibitor of apoptosis proteins (IAP), which are overexpressed in HNSCC and suppress cell death. Forty-eight patients were randomized to receive Debio 1143 plus high-dose cisplatin and concurrent radiotherapy, and the other 48 patients were randomized to receive placebo plus high-dose cisplatin and concurrent radiotherapy. At 18 months, 54% of patients in the Debio 1143 group and 33% of patients in the placebo group experienced ongoing locoregional disease control. The median duration of locoregional disease control was not reached in either group, and the median progression-free survival was not reached in the Debio 1143 group and was 16.9 months in the placebo group. At 24 months, there was no significant difference in overall survival between the Debio 1143 group and the placebo group (78% versus 63%, respectively); however, median overall survival was not reached, preventing firm conclusions about survival differences. The safety profile of Debio 1143 was similar to that of high-dose cisplatin and radiotherapy alone, with the most common side effects being dysphagia, mucositis, and anemia. In summary, the results of this trial support the notion that Debio 1143 is generally safe in this patient population, with evidence of activity against smoking-related HNSCC, a disease with poor prognosis and no approved targeted agents.
Sun XS, Tao Y, Le Tourneau C, Pointreau Y, Sire C, Kaminsky MC, et al. 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. Lancet Oncol 2020;21:1173–87.
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