Xevinapant in combination with standard cisplatin-based chemoradiation therapy (CRT) reduces the risk of death in high-risk patients with locally advanced head and neck cancer by 50%. This first-in-class molecule showed it could improve long-term outcomes in hard-to-treat patients, becoming the first in decades to demonstrate a survival benefit in this group.
The drug, previously known as Debio 1143, is a potent, orally available inhibitor of IAPs (inhibitor of apoptosis proteins) in development at Debiopharm, a private biopharmaceutical company based in Switzerland and the recent winner of the Swiss Biotech Success Story Award 2020.
The company showed the potential of the drug last year when they presented positive two-year data from a phase 2 randomized placebo-controlled trial at ESMO 2019, a study that enrolled 96 patients at 19 sites. Patients received xevinapant or placebo over three 3-week cycles in combination with standard of care CRT.
The three-year follow-up data presented at the ESMO Virtual Congress 2020 showed that adding xevinapant to CRT clinically and statistically significantly halved the risk of death (HR=0.49) compared to the standard of care alone, whilst safety was predictable and manageable without increases in severe toxicities. After three years, the overall survival (OS) rate in the xevinapant arm was 66%, compared to 51% in the control cohort. The median OS in the xevinapant arm has not yet been reached. CRT achieved a median OS of 36.1 months.
Xevinapant had positive effects on other outcomes, too, with the phase 2 linking the drug candidate to improved progression-free survival (PFS). The probability of three-year PFS in the xevinapant arm was 72%, compared to 36% in the standard of care cohort. Xevinapant is improving outcomes in the hardest to treat SCCHN patients, specifically people who are classed as high risk due to being heavy smokers or suffering from HPV-negative oropharyngeal cancer.
The first-in-class drug triggered those improvements without causing unexpected or unmanageable safety or tolerability problems. CRT is associated with both acute toxicities and adverse events that only emerge more than 30 days after the end of treatment.
Debiopharm’s three year-data confirms the sustainability of the promising two-year outcomes recently published in Lancet, by demonstrating continued, statistically significant improvements across all other major endpoints including the doubling of the progression free survival rate along with superior duration of response.
When CRT damages a cancer cell, apoptosis can be triggered via the activation of caspases. However, IAPs, proteins that are often overexpressed in SCCHN, block caspases and, in doing so, prevent cell death. The interaction between xevinapant and IAPs blocks the route tumor cells use to escape from the controlled pathway and survive damage caused by CRT. As well as enhancing the effect of CRT by acting as a chemo-radio sensitizer, preclinical studies suggest the inhibition of IAPs directly boosts T lymphocyte activation, promoting anti-tumor immunity.
Addressing a major unmet need
The validation of the chemo-radio sensitizing effect of xevinapant by the three-year data marks a big moment for the treatment of high-risk, locally advanced SCCHN. It is now decades since the field has had a major breakthrough in terms of improved overall survival, despite widespread recognition of the unmet medical needs of a significant proportion of SCCHN patients.
More than half of these patients relapse after receiving standard of care CRT. The high rate of relapse translates into poor long-term prospects. The disease is the sixth most common cancer type globally, meaning the lack of effective therapies affects many thousands of patients annually.
There are 740,000 new cases of SCCHN and 400,000 deaths due to the disease every year. Even if patients survive, they can experience changes to how they look, talk, eat and breathe that have a negative effect on the quality of their lives and social interactions. A new standard of care is needed.
Having validated xevinapant with three-year phase 2 data, Debiopharm is now racing to bring the drug to more patients. Debiopharm recently dosed the first subject in a phase 3 trial of xevinapant (TrilynX), which is enrolling 700 patients with high-risk LA SCCHN to conclusively show the effect of the candidate on event-free survival.
The FDA signalled its interest in getting xevinapant to patients as quickly as possible when it designated the drug as a breakthrough therapy in February. Breakthrough status, which is reserved for drugs that drive substantial improvements in serious or life-threatening conditions, enables the FDA to expedite development and review