Five-year data from Xevinapant shows survival rate nearly doubles in patients with unresected SCCHN when added to standard of care

ROCKLAND, Mass.–(BUSINESS WIRE)–EMD Serono, the healthcare business of Merck KGaA, Darmstadt, Germany, USA and Canada, today announced that the IAP (inhibitor of apoptosis protein) inhibitor xevinapant (formerly known as Debio 1143) plus chemoradiotherapy (CRT) has significantly improved long-term efficacy outcomes in patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN ) compared to placebo plus CRT. Adding xevinapant more than halved the five-year risk of death compared to placebo. These late-breaking data from the 96-patient phase II trial will be presented during the Head and Neck Cancer Oral Mini-Session on September 10, 2022 at 10:55 a.m. CEST (Abstract #LBA33) at the European Society of Medical Oncology Congress 2022.

“There is a clear need for improved treatment options for patients with unresected locally advanced head and neck cancer. Chemoradiotherapy has served as the standard of care in this setting for decades, yet half of patients treated with CRT see their cancer come back, either locally or as metastatic disease,” said Professor Jean Bourhis, MD. , Ph.D., Head of the Radiation Oncology Department at Lausanne University Hospitals and principal investigator of the study. “The five-year results of this randomized phase II study are the first to show improved efficacy outcomes compared to standard of care for these patients and suggest the potential of xevinapant to increase the proportion of patients who achieve healing after definitive treatment.

In this analysis, overall survival (OS) was assessed five years after the last patient was randomized; the median follow-up was 60.1 months (range, 7.1-70.5 months) in the xevinapant arm and 39.2 months (range, 4.8-71.2 months) in the placebo arm. The data shows:

  • Xevinapant more than halved the risk of death over five years of follow-up compared to placebo (adjusted RR, 0.47 [95% CI, 0.27-0.84]; nominal p = 0.0101).

  • Median OS was prolonged with xevinapant (median not reached; 95% CI, 40.3 months – not evaluable) compared to placebo (36.1 months; 95% CI, 21.8-46.7 months ).

  • Treatment with xevinapant almost doubled OS, with a 53% (95% CI, 37-66%) survival probability after five years, compared to 28% (95% CI, 15-42%) with placebo .

As previously reported, the addition of xevinapant to CRT was well tolerated and consistent with the safety profile of CRT alone with a follow-up of approximately two years. Grade 3 or higher adverse events were reported in 41 (85%) of 48 patients in the xevinapant group and 41 (87%) of 47 patients in the placebo group. The most common grade 3 or higher treatment-emergent adverse events in patients who received xevinapant plus CRT and occurring in more than 15% of patients were dysphagia (50%), anemia (35%), mucositis ( 31%) and neutropenia (23%).1 Three-year follow-up analysis showed similar safety.2

“Head and neck cancer is a devastating disease that often has a profound impact on a patient’s ability to eat, communicate and even sleep, yet there have been few advances in treatment over the past 20 years. years,” said Amanda Hollinger, Executive Director, Leader and Neck Cancer Alliance. “We hope these findings will pave the way for a new approach that may improve outcomes.”

Previously reported results from the randomized, double-blind phase II study showed that the addition of xevinapant to standard CRT provided a statistically significant improvement in locoregional control rate at 18 months, the primary endpoint, by versus placebo and CRT in unresected patients. THE SCCHN (54% [95% CI, 39 to 69] against 33% [95% CI, 20 to 48]; odds ratio 2.69 [95% CI, 1.13 to 6.42]; p=0.026). The first results of the study have been published in The Lancet Oncology.1

“The opportunity to develop an oncology drug in a curative setting is a rare privilege, especially for a difficult-to-treat disease such as locally advanced head and neck cancer, where many patients cannot undergo surgery,” said Victoria Zazulina, MD, Head of Development Unit Oncology, Merck KGaA, Darmstadt, Germany. “Based on these Phase II results, we are committed to exploring the potential value of xevinapant in the locally advanced setting through our ongoing Phase III program, as we pioneer the study of the pathway apoptotics as a new treatment modality.

Based on the promising efficacy and safety profile observed in the phase II trial and the urgent need for new treatments, xevinapant is being evaluated in two ongoing phase III clinical trials. The first is the international, randomized, double-blind, placebo-controlled TrilynX study (NCT04459715) to evaluate the efficacy and safety of xevinapant versus placebo when added to definitive CRT in patients with an unresected SCCHN LA. The second is XRay Vision (NCT05386550), a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of xevinapant versus placebo when added to adjuvant postoperative radiotherapy in patients with of resected SCCHN who are at high risk for relapse and are not eligible for cisplatin. TrilynX and XRay Vision are currently recruiting.

In February 2020, the United States Food and Drug Administration granted Breakthrough Therapy Designation to xevinapant (formerly under development with Debiopharm as Debio 1143) for the treatment of patients with previously untreated SCCHN, in combination with current standards of care, based on the results of the phase II trial.

About head and neck cancer

Worldwide, head and neck cancer accounts for more than 870,000 cases and 440,000 deaths per year,3 making it the 8th most common type of cancer. SCCHN is a very debilitating disease that can lead to difficulty breathing, swallowing and speaking as it progresses. Despite treatment with curative intent using standard CRT, approximately 50% of patients with SCCHN develop local recurrence and/or distant metastases,4 which are usually detected within the first two years after the end of the standard treatment, which highlights the need to identify new therapeutic approaches.

About Xevinapant

Xevinapant (formerly known as Debio 1143) is a potent investigational oral small molecule IAP (inhibitor of apoptosis protein) inhibitor for the treatment of SCCHN. In preclinical studies, xevinapant restored susceptibility to apoptosis in cancer cells, enhancing the effects of chemotherapy and radiation therapy. Xevinapant, the most clinically advanced IAP inhibitor, has improved efficacy outcomes in combination with chemoradiotherapy (CRT), including three-year progression-free survival and five-year survival, by versus placebo plus CRT in a phase II study in patients with unresected LA SCCHN. In March 2021, Merck KGaA, Darmstadt, Germany, obtained exclusive rights from Debiopharm to develop and commercialize xevinapant worldwide. Xevinapant is not approved for any use worldwide.

About EMD Serono, Inc.

EMD Serono – the healthcare business of Merck KGaA, Darmstadt, Germany in the United States and Canada – aspires to create, improve and extend the lives of people living with difficult-to-treat conditions such as infertility, multiple sclerosis and cancer. The company imagines the future of healthcare by striving to translate molecule discovery into potentially meaningful outcomes for people with serious unmet medical needs. EMD Serono’s global roots go back over 350 years with Merck KGaA, Darmstadt, Germany. Today, the company has approximately 1,500 employees across the country with commercial, clinical and research operations in Massachusetts. www.emdserono.com.

About Merck KGaA, Darmstadt, Germany

Merck KGaA, Darmstadt, Germany, a leading science and technology company, operates in the fields of life sciences, healthcare and electronics. Approximately 60,000 employees work every day to make a positive difference in the lives of millions of people by creating more enjoyable and sustainable lifestyles. From advancing gene-editing technologies, to discovering unique ways to treat the toughest diseases, to enabling device intelligence, the company is everywhere. In 2021, Merck KGaA, Darmstadt, Germany, achieved sales of €19.7 billion in 66 countries.

The company owns the global rights to the “Merck” name and trademark internationally. The only exceptions are the United States and Canada, where the business areas of Merck KGaA, Darmstadt, Germany, operate as MilliporeSigma in life sciences, EMD Serono in healthcare, and EMD Electronics in electronics. Since its founding in 1668, scientific exploration and responsible entrepreneurship have been at the heart of the company’s technological and scientific advancements. To this day, the founding family remains the majority shareholder of the listed company.

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1 Sun XS Tao Y, Le Tourneau C, et al. Debio 1143 and high-dose cisplatin chemoradiotherapy in high-risk locoregional advanced squamous cell carcinoma of the head and neck: a phase 2, multicenter, randomized, double-blind study. Lancet Oncol. 2020 Sep;21(9):1173-1187. doi: 10.1016/S1470-2045(20)30327-2. Published online August 3, 2020.

2 Bourhis J, Sun XS, Le Tourneau C, et al. 3-year follow-up results of randomized, double-blind phase II trial comparing concurrent high-dose cisplatin radiotherapy plus xevinapant (Debio 1143) or placebo in high-risk patients with locally advanced squamous cell carcinoma of head and neck. Oral presentation at: 2020 Virtual ESMO Congress.

3 Sung H, Ferlay J, Siegel RL, et al. World Cancer Statistics 2020: GLOBOCAN estimates of worldwide incidence and mortality for 36 cancers in 185 countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Published online February 4, 2021.

4 Choong N, Vokes E. Growing role of the medical oncologist in the management of head and neck cancer. CA Cancer J Clin. 2008 Jan-Feb;58(1):32-53. doi: 10.3322/CA.2007.0004. Published online December 20, 2007.

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