Addition Of Apoptosis Inhibitor Antagonist May Improve Locally Advanced SCCHN Outcomes

Author: By Shreeya Nanda, Senior medwireNews Reporter 

medwireNews: Phase II trial data show improved outcomes with the addition of Debio 1143, an antagonist of inhibitor of apoptosis proteins (IAPs), to chemoradiotherapy in treatment-naïve patients with high-risk locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN).

The investigators explain in The Lancet Oncology that impaired regulation of programmed cell death is a feature of various tumours, including SCCHN, and IAPs – “a class of proteins that can negatively regulate apoptosis” – are highly expressed in several tumours.

They therefore evaluated the addition to high-dose cisplatin chemoradiotherapy of a small-molecule antagonist of IAPs, Debio 1143, which the team hypothesises has “the potential to enhance the antitumour activity of cisplatin and radiotherapy.”

In the double-blind GORTEC 2015-03 trial, 96 patients with previously untreated stage III, IVa or IVb (T≥2, N0–3 and M0) disease were randomly assigned to receive three cycles of oral Debio 1143 at a dose of 200 mg or placebo on days 1–14 of each 21-day cycle alongside chemoradiotherapy.

The primary endpoint of locoregional control at 18 months was achieved and ongoing in 54% of the 48 patients given Debio 1143 and 33% of their 48 counterparts given placebo, a significant difference equating to a 2.69-fold increased likelihood of locoregional control favouring the experimental agent.

By contrast, the Kaplan–Meier analysis of locoregional control did not demonstrate a significant between-group difference at 18 months, with rates of 78% and 67% for the Debio 1143 and placebo groups, respectively, but the researchers point out that “the study was not powered to detect differences” in this endpoint.

Treatment with Debio 1143 was associated with a significantly prolonged progression-free survival (PFS) relative to placebo, with the median unreached and 16.9 months, respectively, and a hazard ratio for progression or death of 0.37. The corresponding 24-month PFS rates were 72% and 41%.

There was no significant improvement in overall survival, however, with the addition of Debio 1143 to chemoradiotherapy; the median was unreached in both study arms at 24 months, and a comparable 73% of Debio 1143-treated participants and 65% of those given placebo were alive at this timepoint.

But the authors highlight that “[t]he overall survival data are not yet mature enough to be interpreted robustly”, and note that follow-up is ongoing.

In terms of toxicity, the incidence of treatment-emergent adverse events (TEAEs) of grade 3 or worse was comparable between the Debio 1143 and placebo groups, at 85% and 87%, respectively, as was the rate of serious TEAEs, at 63% versus 60%.

Jean Bourhis, from Bâtiment Hospitalier in Lausanne, Switzerland, and co-researchers comment that “Debio 1143 treatment did not increase the frequency or severity of cisplatin-associated adverse events”, and TEAEs “more frequently observed in the Debio 1143 group than in the placebo group were generally related to radiotherapy”.

Specifically, patients treated with Debio 1143 were more likely than those given placebo to experience grade 3 or 4 dysphagia (50 vs 21%), mucositis (31 vs 21%) and anaemia (35 vs 23%).

And the team concludes: “These findings suggest that inhibition of [IAPs] 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.”

The author of a linked commentary says that in spite of “its limitations as a phase 2 study with a surrogate primary endpoint,” GORTEC 2015-03 provides “compelling data indicating the potential superiority of Debio 1143 added to chemoradiotherapy” in a setting with a “paucity of therapeutic breakthroughs” over the past two decades.

Jens Voortman, from Cancer Center Amsterdam in the Netherlands, cautions, however, that “[t]he findings should be interpreted in the context of a population of patients with HPV-negative squamous cell carcinoma of the head and neck since only eight (8%) of all 96 patients had HPV-positive disease.”

References

• Sun X-S, Tao Y, Le Tourneau C, 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; Advance online publication 3 August 2020. doi: 10.1016/S1470-2045(20)30327-2 
• Voortman J. Chemoradiotherapy plus a SMAC mimetic for locally advanced squamous cell carcinoma of the head and neck. Lancet Oncol; Advance online publication 3 August 2020. doi: 10.1016/S1470-2045(20)30383-1