Xevinapant, an investigational inhibitor of apoptosis proteins (IAP) blocker, prolonged overall survival when added to standard chemoradiotherapy for locally advanced head and neck squamous cell carcinoma, according to an updated analysis of a randomized, placebo-controlled phase II study presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.1
At a median follow-up of 36 months, median overall survival was not reached in the group receiving xevinapant in addition to cisplatin-based chemoradiotherapy vs 36.1 months in the group receiving placebo plus chemoradiotherapy (P = .0261), representing a 51% reduction in the risk of death favoring the investigational agent. The 3-year overall survival rate was 66% vs 51%, respectively.
“This is probably the first time in 30 years that such an overall survival benefit is seen when compared with cisplatin radiotherapy in advanced head and neck squamous cell carcinoma.”— Jean Bourhis, MD
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“This is a clinically meaningful survival improvement. This is probably the first time in 30 years that such an overall survival benefit is seen when compared with cisplatin radiotherapy in advanced head and neck squamous cell carcinoma,” said lead author Jean Bourhis, MD, of the Lausanne University Hospital, Switzerland. “Safety was manageable, with no increases in severe toxicity.”
Formerly known as Debio 1143, xevinapant is a first-in-class oral IAP blocker with immunomodulatory properties, making it a natural candidate for combination with immune checkpoint inhibitors. In addition, this and other agents in its class promote apoptosis of cancer cells by mimicking the activity of the natural second mitochondrial-derived activator of caspase (SMAC). Xevinapant is thought to be chemo- and radiosensitizing through its dual mode of action, and the drug is being studied in combination with chemoradiotherapy in head and neck squamous cell carcinoma, in combination with immunotherapy in non–small cell lung cancer, and with radiotherapy in ovarian cancer.
Xevinapant received Breakthrough Therapy status for the front-line treatment of head and neck squamous cell carcinoma from the U.S. Food and Drug Administration in September 2020.
Study Details
The phase II, double-blind, placebo-controlled study randomly assigned 96 cisplatin-eligible patents with previously treated unresectable stage III or IV head and neck squamous cell carcinoma. They were treated with high-dose chemoradiotherapy (100 mg/m2 of cisplatin every 3 weeks, plus intensity-modulated radiation at a dose of 70 Gy over 7 weeks) plus xevinapant on days 1 to 14 every 3 weeks vs placebo. Patients were stratified according to nodal status and oropharyngeal vs nonoropharyngeal tumors. Baseline characteristics were well balanced between the two treatment arms.
All patients were considered to be at high risk and were heavy smokers; more than 80% had stage IV head and neck squamous cell carcinoma, and more than 80% of oropharyngeal cancers were human papillomavirus (HPV)-negative. “Heavy smokers and those with HPV-negative cancers are at high risk. About 50% will relapse in 5 years,” explained Dr. Bourhis.
Updated Results
As previously reported at the ESMO Congress 2019,2 with a median follow-up of 18 months, the trial met its primary endpoint of improving the rate of locoregional tumor control with xevinapant vs placebo: 54% vs 33%. Xevinapant also improved progression-free survival (P = .007).
The updated analysis presented by Dr. Bourhis confirmed these findings at 3 years of follow-up. Progression-free survival was not reached with xevinapant vs 16.9 months with placebo (P = .0023), which represents a 66% improvement with xevinapant. The probability of progression-free survival at 36 months was improved to 72% with xevinapant vs 36% with placebo.
KEY POINTS
- An overall survival benefit was observed with xevinapant added to chemoradiotherapy in locally advanced head and neck squamous cell cancer.
- This is the first survival benefit seen in this group of patients over cisplatin-based chemoradiotherapy in 30 years.
- Phase III confirmatory trials are planned.
- Xevinapant is a first-in-class IAP inhibitor that is thought to be chemotherapy and radiotherapy-sensitizing.
The duration of progression-free survival was significantly better with xevinapant: not yet reached with xevinapant vs a median of 16.9 months with placebo. The duration of overall survival was significant in the xevinapant arm vs placebo (P = .0261). With the extended analysis, median locoregional tumor control was not met in either arm; the local tumor control rate was 78% vs 56%, respectively.
Safety Profile
Cisplatin chemoradiotherapy is associated with toxicities that are often irreversible, including hearing loss and renal failure. “Of note, the addition of xevinapant [to chemoradiotherapy] resulted in a good safety profile, which did not compromise the standard of chemoradiotherapy delivery,” Dr. Bourhis said.
The treatment-emergent adverse events were unchanged from the 2-year analysis. At extended follow-up, a small increase in grade 1 and 2 late toxicities was observed in the xevinapant arm, but there was no difference from the previous analysis in grade 3 and 4 late toxicities in the xevinapant arm.
Grade 1 or 2 toxicity occurred in 50.1% of the xevinapant arm vs 40.4% of the placebo arm; grade 3 toxicities, 16.7% vs 17%, respectively; grade 4 toxicities, 6.3% vs 6.4%, respectively. The most common grade 1 and 2 adverse events were dry mouth (25% vs 19.1), dysgeusia (14.6% vs 8.5%), fibrosis (12.5% vs 8.5%), dysphagia (8.3% vs 6.4%), dysphonia (8.3% vs 14.9%), and deafness/hypoacusis (8.3% vs 8.5%).
In the xevinapant arm, grade 3 adverse events were dry mouth (6.3%), dysphagia (4.2%), dysgeusia (2.1%), and deafness (2.1%). Grade 4 dysphagia was reported in one patient (2.1%). For the placebo arm, grade 3 adverse events were dysphagia (6.4%), dry mouth (4.3%), dysgeusia (4.3%), deafness/hypoacusis (4.3%), and fibrosis (2.1%).
Up Next
The phase II participants will be followed for 5 years, said Dr. Bourhis.
TrilynX, a confirmatory phase III trial, is planned to enroll 700 patients with locally advanced head and neck squamous cell carcinoma. They will be randomly assigned to chemoradiotherapy plus xevinapant vs xevinapant or placebo for three cycles, followed by two cycles of monotherapy with xevinapant or placebo.
DISCLOSURE: The study was funded by Debiopharm. Dr. Bourhis has served as an advisor or consultant to Debiopharm, AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, and Merck KGaA.
REFERENCES
1. Bourhis J Sun X, Le Tourneau C, et al: 3-Years follow-up of double-blind randomized phase II trial comparing concurrent high-dose cisplatin chemo-radiation plus xevinapant or placebo in high-risk patients with locally advanced squamous cell carcinoma of the head and neck. ESMO Virtual Congress 2020. Abstract LBA39. Presented September 19, 2020.
2. Bourhis J, Sun X, Le Tourneau C, et al: Double-blind randomized phase 2 results comparing concurrent high-dose cisplatin chemoradiation plus Debio 1143 or placebo in high-risk patients with locally advanced squamous cell carcinoma of the head and neck: A GORTEC study. ESMO Congress 2019. Abstract LBA65. Presented September 30, 2019.
