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For locally advanced (LA) squamous cell carcinoma of the head and neck (HNSCC), the standard of care is chemoradiation therapy (CRT) or surgery followed by radiation, with or without chemotherapy. However, despite this multimodal treatment, the 5-year overall survival (OS) rate for patients with HPV-negative stage III/IV HNSCC remains low, around 50%. Pembrolizumab and nivolumab, two monoclonal antibodies (mAbs) targeting programmed cell death protein-1 (PD-1), improve the overall survival of patients with inoperable recurrent and/or metastatic (R/M) HNSCC). Integrating those immune checkpoint inhibitors (ICI) with the multimodal curative treatment is still under investigation. These combinations are explored in different settings: as de-escalation option for good prognosis patients, as alternative to chemotherapy for cisplatin-unfit patients, or as treatment intensification for poor prognosis patients. Strategies such as better patient selection (PD-L1 expressing tumors), ICI post chemoradiation, or neoadjuvant ICI before surgery are being explored. Concerns also arise regarding the neutralizing effect of large irradiation field on immune competent cells. Beyond immunotherapy, compounds like xevinapant, an antagonist of inhibitor of apoptosis proteins (IAP), are investigated in LA-HNSCC. For example, xevinapant in combination with chemoradiation has shown promising results in improving survival in unresected LA-HNSCC in a randomized phase II trial. Other novel non-immunologic molecules such as targeted therapies, drugs targeting the DNA damage response pathways, and NBTXR3 are also under investigation for enhancing the effects of radiotherapy with or without chemotherapy.

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Immunotherapy and Novel Agents in Locoregionally Advanced HNSCC

  • 章节

  • 出版模式：

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  • 发表日期：

    2025年

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  • Séverine Carlier,
  • Jean-Pascal Machiels

摘要

For locally advanced (LA) squamous cell carcinoma of the head and neck (HNSCC), the standard of care is chemoradiation therapy (CRT) or surgery followed by radiation, with or without chemotherapy. However, despite this multimodal treatment, the 5-year overall survival (OS) rate for patients with HPV-negative stage III/IV HNSCC remains low, around 50%. Pembrolizumab and nivolumab, two monoclonal antibodies (mAbs) targeting programmed cell death protein-1 (PD-1), improve the overall survival of patients with inoperable recurrent and/or metastatic (R/M) HNSCC). Integrating those immune checkpoint inhibitors (ICI) with the multimodal curative treatment is still under investigation. These combinations are explored in different settings: as de-escalation option for good prognosis patients, as alternative to chemotherapy for cisplatin-unfit patients, or as treatment intensification for poor prognosis patients. Strategies such as better patient selection (PD-L1 expressing tumors), ICI post chemoradiation, or neoadjuvant ICI before surgery are being explored. Concerns also arise regarding the neutralizing effect of large irradiation field on immune competent cells. Beyond immunotherapy, compounds like xevinapant, an antagonist of inhibitor of apoptosis proteins (IAP), are investigated in LA-HNSCC. For example, xevinapant in combination with chemoradiation has shown promising results in improving survival in unresected LA-HNSCC in a randomized phase II trial. Other novel non-immunologic molecules such as targeted therapies, drugs targeting the DNA damage response pathways, and NBTXR3 are also under investigation for enhancing the effects of radiotherapy with or without chemotherapy.