Extended follow-up of a phase 2 trial of xevinapant plus chemoradiotherapy in high-risk locally advanced squamous cell carcinoma of the head and neck: a randomised clinical trial

Tao, Yungan; Sun, Xu-Shan; Pointreau, Y.; Tourneau, Christophe Le; Siré, C.; Kaminsky, Marie‐Christine; Alfonsi, M.; Calderon, Benôit; Boisselier, P.; Martin, Laurent; Miroir, J.; Ramée, Jean-François; Delord, Jean‐Pierre; Clatot, Florian; Rolland, Frédéric; Villa, Julie; Magné, Nicolas; Eliçin, Olgun; Gherga, Elisabeta; Nguyen, F.; Lafond, C.; Béra, G.; Calugaru, Valentin; Geoffrois, Lionnel; Chauffert, Bruno; Damstrup, Lars; Crompton, Philippa; Ennaji, Abdallah; Gollmer, Kathrin; Nauwelaerts, Heidi; Bourhis, Jean

doi:10.1016/j.ejca.2022.12.015

Cited by 19 publications

(9 citation statements)

References 39 publications

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“…Due to its modality of action, it is reasonable that the addition of this agent could exert its activity also in HPV-positive cancers with an history of smoking. However, so far, only 3 out of 48 patients allocated in the experimental arm of the aforementioned randomized phase 2 trial were HPV positive ( 25 ), thus no clinical evidence supports the biologic assumption of activity in this patient population, for the time being.…”

Section: Discussionmentioning

confidence: 99%

“…Xevinapant, a first-in-class, potent, oral, small-molecule, targeting inhibitor of apoptosis protein (IAP) is emerging as a promising compound. Extended follow up data of the phase 2 trial recently published confirms xevinapant's activity, efficacy, and safety profile in high risk locally advanced HPV negative head and neck squamous cell carcinoma combined with standard cisplatin based RT (25). Due to its modality of action, it is reasonable that the addition of this agent could exert its activity also in HPV-positive cancers with an history of smoking.…”

Section: Compare Trial (Comparing Alternative Regimens For Escalating...mentioning

confidence: 93%

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Human Papilloma Virus (HPV) driven oropharyngeal cancer in current or previous heavy smokers: should we look for a different treatment paradigm?

Lorini,

Bossi,

Psyrri

et al. 2024

Front. Oncol.

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IntroductionHuman papillomavirus Virus (HPV)-associated oropharyngeal squamous cell carcinoma (OSCC) has increased in incidence in recent decades and represents a heterogeneous disease entity in the context of Head and Neck Squamous Cell Carcinoma (HNSCC), in terms of disease prognosis. Treatment of locoregionally advanced OSCC is mainly based on concurrent chemoradiotherapy. Given the younger age of patients, if compared with HPV-negative counterparts, and the high cure rates, the acute- and long-term toxicity in survivors represents a field of interest. However, patient selection for de-escalation trials remains a major challenge due to the lack of robust validated prognostic indicators within the HPV-associated OSCC.DiscussionThe impact of smoking status on HPV-associated OSCC prognosis has been demonstrated in the majority of studies. However, the magnitude of the association is unclear due to variability in smoking metrics and study outcomes. Smoking status has been identified as a potential confounding factor in HPV-positive de-escalation trials. Smokers with HPV-positive OSCC have a worse prognosis in most studies than non-smokers and may require different and more aggressive therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Compare Trial (Comparing Alternative Regimens For Escalating...mentioning

confidence: 93%

Human Papilloma Virus (HPV) driven oropharyngeal cancer in current or previous heavy smokers: should we look for a different treatment paradigm?

Lorini,

Bossi,

Psyrri

et al. 2024

Front. Oncol.

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“…For instance, addition of Xevinapant, an inhibitor of the antiapoptotic proteins XIAP and cIAP1/2, to this combination led to improved efficacy [ 90 ]. A follow-up showed improved 5-year OS and 3-year PFS, and was deemed safe [ 91 ].…”

Section: New Combinatorial Approaches For Oral Cancer Treatmentmentioning

confidence: 99%

Combination Therapy as a Promising Way to Fight Oral Cancer

et al. 2023

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Oral cancer is a highly aggressive tumor with invasive properties that can lead to metastasis and high mortality rates. Conventional treatment strategies, such as surgery, chemotherapy, and radiation therapy, alone or in combination, are associated with significant side effects. Currently, combination therapy has become the standard practice for the treatment of locally advanced oral cancer, emerging as an effective approach in improving outcomes. In this review, we present an in-depth analysis of the current advancements in combination therapies for oral cancer. The review explores the current therapeutic options and highlights the limitations of monotherapy approaches. It then focuses on combinatorial approaches that target microtubules, as well as various signaling pathway components implicated in oral cancer progression, namely, DNA repair players, the epidermal growth factor receptor, cyclin-dependent kinases, epigenetic readers, and immune checkpoint proteins. The review discusses the rationale behind combining different agents and examines the preclinical and clinical evidence supporting the effectiveness of these combinations, emphasizing their ability to enhance treatment response and overcome drug resistance. Challenges and limitations associated with combination therapy are discussed, including potential toxicity and the need for personalized treatment approaches. A future perspective is also provided to highlight the existing challenges and possible resolutions toward the clinical translation of current oral cancer therapies.

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“…In the phase II study, xevinapant plus CRT significantly improved locoregional control (LRC) at 18 months after the end of CRT (primary end point) vs. placebo plus CRT in patients with unresected LA SCCHN 27 . In a follow‐up analysis, 3‐year progression‐free survival (PFS) and 5‐year overall survival (OS) were also markedly improved with xevinapant plus CRT vs. placebo plus CRT 28,29 . Based on the encouraging phase II data, two phase III studies have been initiated ( Figure ).…”

Section: Figurementioning

confidence: 99%

“…27 In a follow-up analysis, 3-year progression-free survival (PFS) and 5-year overall survival (OS) were also markedly improved with xevinapant plus CRT vs. placebo plus CRT. 28,29 Based on the encouraging phase II data, two phase III studies have been initiated (Figure 1). The randomized, double-blind, international TrilynX study (NCT04459715) is assessing the efficacy and safety of xevinapant in combination with CRT in patients with unresected LA SCCHN.…”

mentioning

confidence: 99%

Model‐Informed Selection of the Recommended Phase III Dose of the Inhibitor of Apoptosis Protein Inhibitor, Xevinapant, in Combination with Cisplatin and Concurrent Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Vugmeyster,

Ravula,

Rouits

et al. 2023

Clin Pharma and Therapeutics

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Xevinapant, an oral inhibitor of apoptosis protein (IAP) inhibitor, demonstrated efficacy in combination with chemoradiotherapy in a randomized phase 2 study (NCT02022098) in patients with locally advanced squamous cell carcinoma of the head and neck at 200 mg/day on days 1‐14 of a 3‐week cycle. To confirm 200 mg/day as the recommended phase 3 dose (RP3D), we integrated preclinical, clinical, pharmacokinetic/pharmacodynamic (PK/PD), and exposure‐response modeling results. Population PK/PD modeling of IAP inhibition in peripheral blood mononuclear cells in 21 patients suggested the pharmacologically active dose range was 100‐200 mg/day, with a trend for more robust inhibition at the end of the dosing interval at 200 mg/day based on an indirect response model. Additionally, the unbound average plasma concentration at 200 mg/day was similar to that associated with efficacy in preclinical xenograft models. Logistic regression exposure‐response analyses of data from 62 patients in the phase 2 study showed exposure‐related increases in probabilities of locoregional control at 18 months (primary endpoint), overall response, complete response, and the radiosensitization mechanism‐related composite safety endpoint “mucositis and/or dysphagia” (p<0.05). Exposure‐response relationships were not discernible for 12 of 13 evaluated safety endpoints, incidence of dose reductions, and time to first dose reduction. Quantitative integration of all available data, including model‐derived target inhibition profiles, positive exposure‐efficacy relationships, and lack of discernible exposure‐safety relationships for most safety endpoints, supports selection of xevinapant 200 mg/day on days 1‐14 of a 3‐week cycle as the RP3D, allowing for successive dose reductions to 150 and 100 mg/day to manage adverse events.

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Extended follow-up of a phase 2 trial of xevinapant plus chemoradiotherapy in high-risk locally advanced squamous cell carcinoma of the head and neck: a randomised clinical trial

Cited by 19 publications

References 39 publications

Human Papilloma Virus (HPV) driven oropharyngeal cancer in current or previous heavy smokers: should we look for a different treatment paradigm?

Human Papilloma Virus (HPV) driven oropharyngeal cancer in current or previous heavy smokers: should we look for a different treatment paradigm?

Combination Therapy as a Promising Way to Fight Oral Cancer

Model‐Informed Selection of the Recommended Phase III Dose of the Inhibitor of Apoptosis Protein Inhibitor, Xevinapant, in Combination with Cisplatin and Concurrent Radiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck

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