1432 - Double-blind Randomized Phase 2 Results Comparing Concurrent High-dose Cisplatin Chemorradiation (CRT) plus Debio 1143 or Placebo In High-risk Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN): A GORTEC Study

Background

Debio 1143 is an antagonist of Inhibitor of Apoptosis Proteins (IAP) with the potential to enhance the antitumor activity of cisplatin and radiotherapy (RT) through a radiosensitizing effect that is mediated via caspase activation and TNFα-, IFNγ-, CD8+ T-cell dependent pathways.

Methods

This phase II, double-blind, randomized controlled study was conducted by the GORTEC group at 19 sites in France and Switzerland to compare efficacy and safety of Debio 1143 at 200 mg/day (A), oral once daily D1–14 q3w (3 cycles), with matching placebo (B) when added to standard high-dose cisplatin chemoradiation (CRT). Eligible patients had locally advanced, squamous cell carcinoma of the head and neck (SCCHN) and heavy smoking history. Data cut-off was after a minimum 2-year follow-up.

Results

96 patients were randomized and 95 treated (A: 48, B: 47). Median age was 58, with 81% male, 56% ECOG 0, 84% were stage IV, 67% oropharynx primary (88% HPV p16-), 59% consuming alcohol; median smoking history was 40 pack-years, all balanced across arms. Median dose was 70 Gy for RT and 288mg/m2 for cisplatin in both arms. The primary endpoint, locoregional control (LRC) rate at 18 months after CRT end, was improved by 21%; (OR = 2.69, 95% CI: 1.13-6.42, p = 0.026). Overall and complete response rates 6 months after CRT (A vs B) were 67% vs 48% and 52 vs 38% respectively. Median PFS was 16.9 months in arm B and not yet reached in arm A (HR = 0.37, 95% CI: 0.18-0.76, p = 0.007). Median OS was not yet reached (HR = 0.65, 95% CI: 0.32-1.33, p = 0.243). AEs and severe AEs (grades 3/4) were comparable across arms except for grade 3 mucositis, dysphagia and anemia that occurred more often in arm A and two grade 5 AEs reported in arm B.

Conclusions

The primary endpoint was met. LRC rate and PFS significantly improved when Debio 1143 was added to standard CRT in high-risk SCCHN patients. A trend in OS improvement was observed and additional follow-up will provide more mature OS/PFS data. Debio 1143 addition was feasible, safe and did not compromise backbone therapy. These promising results need to be confirmed in a larger phase III study.

Clinical trial identification

EudraCT: 2013-000044-25.

Editorial acknowledgement

Marina Leroy and Berit Sund, from Weber Shandwick.

Legal entity responsible for the study

GORTEC group and Debiopharm International SA GORTEC and Debiopharm International SA.

Funding

Debiopharm International.

Disclosure

J. Bourhis: Advisory / Consultancy: Merck; Advisory / Consultancy: MSD; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS. X. Sun: Honoraria (self): Novartis; Honoraria (self): Merck. Y. Pointreau: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: MSD; Advisory / Consultancy: EMD Serono. C. Le Tourneau: Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: BMS; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Amgen. A. Coutte: Honoraria (self): Merck; Honoraria (self): Takeda; Honoraria (self): BMS; Honoraria (self): Roche; Honoraria (self): Sanofi. M. Kaminsky-Forrett: Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Merck; Advisory / Consultancy: EMD Serono; Honoraria (self): AstraZeneca. M. Alfonsi: Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: BMS; Advisory / Consultancy: EMD Serono. P. Boisselier: Honoraria (self): Merck-Serono; Honoraria (self): BMS; Honoraria (self): Roche; Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: MSD. L. Martin: Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Merck; Advisory / Consultancy: BMS; Advisory / Consultancy: EMD Serono. J. Delord: Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Research grant / Funding (institution): MSD; Advisory / Consultancy: EMD Serono; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech. F. Clatot: Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Elly Lilly. J. Miroir: Honoraria (self): Novartis; Honoraria (self): Merck. F. Rolland: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Travel / Accommodation / Expenses: Ipsen; Honoraria (self): Merck; Advisory / Consultancy: BMS; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Astellas; Travel / Accommodation / Expenses: AstraZeneca. P. Crompton: Full / Part-time employment, employee: Debiopharm; Shareholder / Stockholder / Stock options: GSK. S. Brienza: Advisory / Consultancy, Full / Part-time employment, consultant: Debiopharm; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: BMS; Advisory / Consultancy: EMD Serono. S.A. Szyldergemajn: Full / Part-time employment, employee: Debiopharm. C. Even: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck-Serono; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Innate Pharma. Y. Tao: Research grant / Funding (institution): Debiopharm; Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Research grant / Funding (self), Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Merck Serono. All other authors have declared no conflicts of interest.