Role of Targeted and Immunotherapy in Metastatic Head and Neck Cancer

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What is the role of targeted therapy and Immunotherapy in the treatment of advanced-stage Head and Neck Cancer (HNC)?

HNC is a group of heterogeneous neoplasms involving several anatomical structures in the head and neck region, such as oral cavity, oropharynx, larynx, hypopharynx, nasopharynx, nasal cavity, and salivary glands. Most HNCs are squamous cell carcinoma that arises from the cells in the surface epithelium lining the above anatomical structures. The prognosis of advanced-stage or recurrent HNC is generally poor with overall survival ranging from 6 months to 12 months in most patients.

Following are the two targeted drugs approved for the treatment of advanced/recurrent HNC:

Cetuximab

It is an inhibitor of epidermal growth factor receptor (EGFR), a protein that has been observed to be overexpressed in more than 90% of the cases of HNC. EGFR has been reported to regulate the growth and proliferation of cancer cells. Thus, cetuximab helps in inhibiting the EGFR driven growth of cancer cells.

Along with concurrent radiotherapy, cetuximab has been approved for the treatment of newly diagnosed advanced (stage III to IV) HNC (preferable for oropharynx, hypopharynx, and larynx and can be employed for other sites). Single-agent cetuximab treatment can be employed both as first-line or second-line therapy for patients with advanced-stage (metastatic) or recurrent HNC except the nasopharyngeal cancer. Cetuximab has also been approved in combination with platinum-based chemotherapy as first-line and subsequent-line therapy for patients with advanced-stage or recurrent HNC.

Side effects of cetuximab include an acne-like rash that generally itches, fatigue, headache, fever, nausea, vomiting, diarrhea, weight loss.

Nimotuzumab

It is another EGFR inhibitor that is approved for the treatment of advanced-stage HNC in various countries including India, Argentina, Colombia, Ukraine, Peru, and Sri Lanka. It is also approved in China for the treatment of advanced-stage nasopharyngeal cancer. However, it has not received US FDA approval yet. Nimotuzumab is recommended for the treatment of patients with advanced-stage HNC as an add-on therapy to standard chemo-radiation therapy regimen.

The safety profile of nimotuzumab is favorable with significantly less severe associated side-effects compared to that of cetuximab. Side-effects associated with nimotuzumab include chills, fever, nausea, vomiting, mucositis, hyperpigmentation, and pruritus.

Afatinib

It is a multi-functional kinase inhibitor targeting several tyrosine kinases, the intracellular enzymes that trigger the growth and proliferation of cells. It is recommended as a second-line therapy for patients with non-nasopharyngeal HNC that has progressed on or after platinum-containing chemotherapy. Adverse events associated with the treatment of afatinib may include skin rash, diarrhea, mouth sores, and fatigue.

 

What is the role of immunotherapy for the treatment of advanced-stage HNC?

Immunotherapy acts by stimulating the body’s immune system to kill or retard the growth of cancer cells. The introduction of immunotherapeutic drugs has revolutionized the management of advanced-stage or recurrent HNC. Immunotherapy is now being considered as the fourth modality treatment after surgery, radiotherapy, and chemotherapy.

Following two immunotherapeutic drugs are currently approved for the treatment of advanced-stage or recurrent HNC:

Nivolumab

It is an immune-checkpoint inhibitor that selectively blocks the interaction of programmed death receptor-1 (PD-1) expressed on activated T cells with its ligands (PD-L1 and similar) expressed on normal cells and tumor cells. It is recommended for the treatment of patients with advanced-stage (metastatic) or recurrent HNC that have progressed on or after platinum-based chemotherapy.

Pembrolizumab

It is another immune-checkpoint inhibitor designed to block the interaction of PD-1 expressed on activated T cells with its ligands (PD-L1 and similar) expressed on normal cells and tumor cells. It is recommended for the treatment of patients with advanced or recurrent non-nasopharyngeal HNC that has progressed on or after a platinum-based chemotherapy; and advanced or recurrent nasopharyngeal HNC that express >/=1% of PD-L1 surface protein. It was found to be effective against both HPV-positive and negative disease.

Immunotherapy has resulted into a significant improvement in survival but the benefits were not observed in all patients. Researchers are also testing immunotherapy in combination with other modalities for the treatment of advanced-stage HNC. It was found that radiotherapy can upregulate the PD-L1 expression within 24 to 48 hours. Thus, immunotherapy can be a good option after radiotherapy.

Similarly, another immune-checkpoint (cytotoxic T-lymphocyte antigen 4 [CTLA-4]) was found to be upregulated in patients with locally advanced HNC who received cetuximab. Thus, immune-checkpoint inhibitor, Ipilimumab can be combined with cetuximab for a better outcome.

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