Xevinapant plus CRT Improves Survival in Patients with Locally Advanced HNSCC

TON - December 2020, Vol 13, No 6 - Emerging Therapies

Xevinapant, an investigational antagonist of IAPs (inhibitor of apoptosis proteins), prolonged overall survival (OS) in patients with locally advanced head and neck squamous-cell carcinoma (HNSCC) when added to chemoradiotherapy (CRT), according to an updated analysis of a phase 2 clinical trial that was presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

The analysis was based on a 3-year follow-up and confirmed the earlier results from an 18-month follow-up that were reported at ESMO 2019. In the updated analysis, the median OS was not reached in the group receiving xevinapant plus cisplatin-based CRT compared with 36.1 months in the group receiving placebo plus CRT (P = .0261). The 3-year OS rates were 66% and 51%, respectively.

“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 to cisplatin-radiotherapy in advanced HNSCC,” noted lead investigator Jean Bourhis, MD, PhD, Radiation Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. “Safety was manageable, with no increases in severe toxicity.”

“There is finally hope on the horizon that we can increase the cure rate of our patients, if these data are confirmed in a phase 3 study,” commented formal discussant Sjoukje Oosting, MD, PhD, Medical Oncologist, University Medical Center Groningen, Netherlands.

First-in-Class IAPs Antagonist

Based on the results reported at ESMO 2019, in February 2020, the FDA granted xevinapant a breakthrough therapy designation for the first-line treatment of patients with HNSCC.

Xevinapant is an oral, first-in-class potent antagonist of IAPs, with immunomodulatory properties; as such, it is a natural candidate for combination therapy with immune checkpoint inhibitors. In addition, antagonists of IAPs promote the apoptosis of cancer cells by mimicking the activity of the natural second mitochondrial-derived activator of caspases (which are the central regulators of the apoptic mechanism in cancer cells).

Xevinapant is chemo- and radiosensitizing by its dual mechanisms of action. The drug is currently under investigation for use, in combination with CRT, in patients with HNSCC; in combination with immunotherapy in patients with non–small-cell lung cancer; and with radiotherapy in patients with ovarian cancer.

Improved Survival

As was reported at ESMO 2019, at 18 months of follow-up, treatment with xevinapant significantly improved locoregional control (the primary end point) compared with placebo (54% vs 33%, respectively), as well as progression-free survival (PFS). These results were further confirmed by the updated results reported at ESMO 2020.

“Last year at ESMO we heard about the significant benefit [of xevinapant] in locoregional control and progression-free survival observed in this phase 2 trial. Today we learned that improvement in locoregional control is confirmed, and with longer follow-up, the overall survival is significantly better in the xevinapant arm, with limited late toxicity,” Dr Oosting emphasized.

The phase 2, double-blind, placebo-controlled study randomized 94 cisplatin-eligible patients with previously treated unresectable stage III or IV HNSCC. The patients received high-dose CRT and were randomized to receive xevinapant or matching placebo on days 1 to 14 every 3 weeks. The patients were stratified according to nodal status and tumor localization (oropharyngeal vs nonoropharyngeal tumors).

The patients enrolled in the trial were deemed high-risk and were heavy smokers; more than 80% had stage IV HNSCC, and more than 80% of oropharyngeal cancers were negative for human papillomavirus infection.

3-Year Follow-Up Results

The results of the updated 3-year analysis were promising. At 3 years, PFS was not reached in the xevinapant arm and was 16.9 months in the placebo arm (P = .0023), reducing the risk for disease progression or death by 66% in patients who received xevinapant, and the probability of PFS by 36 months was 72% with xevinapant compared with 36% with placebo.

The 3-year OS was significantly longer in the xevinapant arm than in the placebo arm (P = .0261). With the extended analysis, the median locoregional control was not met in either arm; the local control rates were 78% and 56%, respectively.

“The addition of xevinapant [to chemoradiotherapy] resulted in a good safety profile, which did not compromise the standard of chemoradiotherapy delivery,” Dr Bourhis observed.

The rates of treatment-emergent adverse events were unchanged from the previous analysis. At the extended follow-up, a small increase in grade 1 and grade 2 late adverse events was observed in the xevinapant arm, but there was no change in grade 3 or grade 4 late adverse events in the xevinapant arm.

A confirmatory phase 3 clinical trial of xevinapant plus CRT versus CRT alone is planned. The TrilynX study plans to enroll 700 patients with locally advanced HNSCC.

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Last modified: July 22, 2021