Merck's Cetuximab Nears New Indication Approval in China for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma

By DOPINE

On February 14, the status of Merck KGaA’s marketing application for cetuximab injection (Acceptance No.: JXSS1900014) with the National Medical Products Administration (NMPA) was updated to “Under Review.” It is anticipated that cetuximab will soon gain an additional indication in China. Based on ongoing clinical trials, the indication under review is speculated to be recurrent and/or metastatic squamous cell carcinoma of the head and neck.

Cetuximab (Erbitux) is a chimeric human-mouse IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR), developed by ImClone. As the first anti-EGFR monoclonal antibody approved globally, it has received regulatory approval in more than 100 countries worldwide and is primarily indicated for the treatment of RAS wild-type metastatic colorectal cancer and squamous cell carcinoma of the head and neck.

EGFR is a member of the epidermal growth factor receptor family within the receptor tyrosine kinases (RTKs). It is widely distributed on the surface of various mammalian cells, including epithelial cells, fibroblasts, glial cells, and keratinocytes, and serves as an important transmembrane receptor. Studies have shown that EGFR is overexpressed or abnormally expressed in many types of solid tumor cells, including those of head and neck cancer, breast cancer, bladder cancer, ovarian cancer, renal cancer, colorectal cancer, and non-small cell lung cancer (NSCLC), particularly in lung cancer. Currently, a series of drugs with diverse mechanisms of action targeting EGFR have been developed. These EGFR-targeted therapies can be categorized into two classes: small-molecule inhibitors, such as erlotinib, gefitinib, and icotinib; and monoclonal antibodies, such as cetuximab and panitumumab.

Currently, in contrast to the numerous approved small-molecule drugs targeting EGFR, only four anti-EGFR monoclonal antibodies have been approved globally (see table below). Among them, cetuximab is a chimeric human-mouse IgG1 monoclonal antibody; panitumumab is the first fully human monoclonal antibody; necitumumab is a human recombinant IgG1 monoclonal antibody; and nimotuzumab is an IgG1 monoclonal antibody constructed by grafting the complementarity-determining regions of a murine monoclonal antibody onto a human antibody framework using genetic engineering technology. Nimotuzumab is also the only approved targeted drug in China indicated for the treatment of nasopharyngeal carcinoma. Clinically, it is primarily used in combination with radiotherapy or chemoradiotherapy for the treatment of stage III/IV nasopharyngeal carcinoma with positive epidermal growth factor receptor (EGFR) expression.

Cetuximab was approved in China in 2004 under the brand name Erbitux. Its indications included use as monotherapy or in combination with irinotecan for the treatment of EGFR-overexpressing metastatic colorectal cancer that is refractory to irinotecan-based chemotherapy regimens. In 2018, it was officially included in the National Reimbursement Drug List (2017 Edition) for Basic Medical Insurance, Work-Related Injury Insurance, and Maternity Insurance, for the treatment of patients with RAS wild-type metastatic colorectal cancer. In September 2019, the National Medical Products Administration (NMPA) formally approved cetuximab for first-line treatment of RAS wild-type metastatic colorectal cancer, an indication that had already been approved in the United States in July 2012.

In China, in addition to colorectal cancer, Merck KGaA conducted a Phase III trial, CHANGE-II (registration number CTR20150241), evaluating cetuximab in combination with platinum-based chemotherapy for the treatment of recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC), as indicated on the official website of the Center for Drug Evaluation (CDE). The trial enrolled a total of 243 patients with recurrent/metastatic HNSCC. Two-thirds of the patients were randomized to receive cetuximab in combination with cisplatin (75 mg/m²) and 5-fluorouracil (5-FU), while one-third received chemotherapy alone. At the 2019 Chinese Society of Clinical Oncology (CSCO) Annual Meeting, Professor Guo Ye from Shanghai East Hospital affiliated with Tongji University presented the study results orally. The addition of cetuximab significantly improved the objective response rate (ORR) (50.0% vs. 26.6%), progression-free survival (PFS) (5.5 months vs. 4.2 months), and overall survival (OS) (11.1 months vs. 8.9 months). Regarding safety, cetuximab did not significantly increase chemotherapy-related toxicities; the incidence of grade 3/4 adverse events was similar between the two groups, both being less than 5%.

Head and neck cancer is the sixth most common malignant tumor worldwide, with over 550,000 new cases and more than 300,000 deaths annually. In China, there are a total of 176,000 patients with head and neck cancer, approximately 75,000 new cases each year, and around 36,000 deaths from this disease. More than 95% of head and neck cancers are squamous cell carcinomas, which are mostly incurable and often lead to local recurrence and metastasis.

For patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) outside China, platinum-based combination chemotherapy was the standard of care prior to the advent of targeted therapy. The introduction of cetuximab broke the 30-year plateau in efficacy associated with platinum-based chemotherapy. In China, however, cetuximab has not yet been approved for this indication. If approved successfully this time, it is expected to fill the gap in targeted therapy for HNSCC, thereby benefiting a larger patient population.

References:

[1] Official websites of the CDE and NMPA