Xevinapant Plus Chemoradiotherapy Improves OS in Locally Advanced Head and Neck Cancer

Jean Bourhis, MD, PhD

Xevinapant plus chemoradiotherapy more than halved the risk of death vs placebo plus chemoradiotherapy without increasing toxicity in patients with unresectable, locally advanced head and neck squamous cell carcinoma (HNSCC), according to 5-year findings from a phase 2 study (NCT04459715) that were presented at the 2022 ESMO Congress.¹

The results showed that xevinapant plus chemoradiotherapy (n = 48) nearly doubled the 5-year overall survival (OS) rate vs chemoradiotherapy alone (n = 48), at 53% vs 28%, respectively. At a median follow-up of 60.1 months (range, 7.1-70.5) in the xevinapant arm and 39.2 months (range, 4.8-71.2) in the placebo arm, the median OS was not reached (95% CI, 40.3-not estimable [NE]) vs 36.1 months (95% CI, 21.8-46.7), respectively (HR, 0.47; 95% CI, 0.27-0.84; P = .0101).

“This is the first study in decades to improve the cure rate by adding a new treatment to standard-of-care cisplatin and radiotherapy,” lead study author Jean Bourhis, MD, PhD, of the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, and coauthors, wrote in the presentation.

Xevinapant is a first-in-class, potent, oral, small molecule IAP inhibitor believed to restore cancer cell sensitivity to apoptosis, leading to improved efficacy with chemoradiotherapy.

The study enrolled patients with unresected, locally advanced, stage III, IVA, or IVB HNSCC of the oral cavity, oropharynx, or larynx who had a greater than 10 pack-year smoking history. Per the TNM staging system, patients had to have a tumor score of at least 2, node score between 0 and 3, and a metastasis score of 0.

Patients were randomly assigned to 200 mg/day of oral xevinapant on days 1 through 14 plus 100 mg/m² of intravenous cisplatin every 3 weeks for 3 cycles and 70 Gy of intensity-modulated radiation therapy (IMRT) administered at 2 Gy/day, 5 days a week for 7 weeks, or matched placebo plus cisplatin and IMRT in the same schedule.

The primary end point was the 18-month local-regional control (LRC) rate from the end of chemoradiotherapy. Secondary end points included progression-free survival (PFS), OS, duration of response (DOR), and safety.

Prior findings showed a significant improvement in the 18-month LRC rate with xevinapant vs placebo, meeting the primary end point of the study (odds ratio, 2.74; 95% CI, 1.15-6.53; P = .0232). Additionally, the 3-year PFS rate favored the use of xevinapant over placebo, at 72% vs 36%, respectively (HR, 0.33; 95% CI, 0.17-0.67; P = .0019).^2,3

Notably, findings from the updated analysis showed that xevinapant improved OS and DOR across all prespecified subgroups, including nodal involvement (N0-N1 vs N2-N3), primary tumor type (oropharynx vs hypopharynx vs larynx vs oral cavity), TNM stage (III vs IVA vs IVB), smoking history (former vs current), and alcohol consumption (current vs none).

Additional findings showed that xevinapant prolonged DOR, leading to a median DOR that was not reached (95% CI, NE-NE) compared with 17.3 months (95% CI, 5.0-NE) with chemoradiotherapy. The 3-year DOR rate was 79% with xevinapant vs 36% with chemoradiotherapy (HR, 0.21; 95% CI, 0.08-0.54; P = .0011).

Responses with xevinapant consisted of 31 complete remissions (CRs) and 6 partial remissions (PRs) vs 26 CRs and 9 PRs with chemoradiotherapy alone.

A total of 16 (33.3%) patients in the xevinapant arm received subsequent anticancer therapy vs 19 (40.4%) in the placebo arm, consisting of surgery (31.3% vs 31.6%), radiotherapy (37.5% vs 21.1%), or systemic therapy (75.0% vs 84.2%).

With regard to systemic therapy, most patients in the xevinapant arm received cetuximab (Erbitux) with (66.7%) or without chemotherapy (66.7%) compared with a checkpoint inhibitor (41.7%). Most patients in the placebo arm received cetuximab with or without chemotherapy (68.8%) or a checkpoint inhibitor (62.5%) compared with chemotherapy (50.0%).

In keeping with prior findings, the safety profile, including late-onset adverse effects (AEs), was comparable between arms. The rate of all-grade and grade 3 or greater late-onset AEs was 81.3% and 27.1% with xevinapant vs 70.2% and 25.5% with placebo.

Toxicities in order of frequency included dry mouth, dysgeusia, trismus, fibrosis, dysphagia, ear pain, chronic kidney disease, tinnitus, laryngeal edema, weight decrease, anemia, dysphonia, mucosal inflammation, deafness, lymphedema, edema, hypoacusis, and odynophagia.

No patients in the xevinapant arm died because of treatment-related AEs vs 2 (4.3%) patients in the placebo arm, resulting from asphyxia and multiple organ dysfunction syndrome.

Early treatment discontinuation occurred in 8 patients (16.7%) in the xevinapant arm vs 7 patients (14.6%) in the placebo arm.

Based on these results, the confirmatory phase 3 TrilynX trial (NCT04459715) will move forward as planned, enrolling patients with unresected, locally advanced HNSCC.

References

1. Bourhis J, Tourneau CL, Calderon B, et al. 5-year overall survival (OS) in patients (pts) with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) treated with xevinapant + chemoradiotherapy (CRT) vs placebo + CRT in a randomized, phase 2 study. Ann Oncol. 2022;33(suppl 7):S1400. doi:10.1016/j.annonc.2022.08.030
2. 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. 2020;21(9):1173-1187. doi:10.1016/S1470-2045(20)30327-2
3. Bourhis J, Sun X, Le Tourneau C, et al. 3-years follow-up of double-blind randomized phase II 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. Ann Oncol. 2020;31(suppl 4):S1168. doi:10.1016/j.annonc.2020.08.2269