by Dr.C.H. Weaver M.D. updated 11/2018
Erbitux is approved for use in combination with radiation and chemotherapy for the treatment of locally or regionally advanced squamous cell carcinoma of the head and neck, or as a single agent in recurrent or metastatic squamous cell carcinoma of the head and neck.
The epidermal growth factor receptor (EGFR) pathway
The epidermal growth factor receptor (EGFR) pathway is a biologic pathway that plays a role in cellular replication and is often over expressed in cancer. Medications that target the EGFR pathway can delay cancer growth and prolong survival.
Erbitux® (cetuximab) a monoclonal antibody (or protein) that was designed to bind to the EGFR and inhibit the receptor’s effects on cellular replication.
The EGFR pathway is involved in the growth and replication of cells, and is often over-expressed in cancer cells. Erbitux® has been designed through laboratory processes to bind to the EGFR on the outer surface of cancer cells. This binding action is believed to prevent or reduce the replication of the cancer cells, resulting in anti-cancer responses. Erbitux® was initially approved in the treatment of advanced colorectal cancer, and is in several clinical trials evaluating its efficacy in the treatment of various cancers.
About Head & Neck Cancer Treatment
Approximately 40,000 people in the U.S. are diagnosed with head and neck cancer every year. Cancers of the head and neck comprise several types of cancer affecting the nasal cavity and sinuses, oral cavity, nasopharynx, oropharynx, and other sites throughout the head and neck. According to the American Cancer Society, it is estimated that 11,000 people will die from head and neck cancer annually.
Standard treatment for head and neck cancer is largely determined by the stage (extent to which the cancer has spread) as well as the specific locations within the head or neck area where the cancer has spread. The patient’s overall medical condition is also a consideration. Treatment may consist of radiation therapy, chemotherapy, immunotherapy and depending on the stage and location of the cancer.
Once head and neck cancer has spread from its site of origin, long-term outcomes are generally sub-optimal. In addition, treatment for head and neck cancer often results in a compromised quality of life. However, there is continuing research into and development of new therapeutic approaches to improve long-term outcomes and quality of life for patients with this disease.
What Do the Studies Demonstrate?
Erbitux + Radiation for Locally Recurrent Head & Neck Cancer
A large phase III clinical trial (the MCL-9815 trial) was conducted to evaluate the effectiveness of Erbitux in head and neck cancers. This trial included over 420 patients with head and neck cancer that had spread from the site of origin within the head and neck area, but not to distant sites in the body. Approximately half of the patients were treated with Erbitux plus radiation, while the other half were treated with radiation alone.
The addition of Erbitux resulted in marked improvements in outcomes:
- The median overall survival was improved by nearly 20 months in the group treated with Erbitux/radiation compared to radiation therapy alone (49 months versus 29.3 months, respectively).
- The addition of Erbitux resulted in a 32% reduction in the risk of a cancer recurrence within the head and neck area.
- Survival at 3 years was 56.1% for patients treated with Erbitux/radiation, compared with 45% for those treated with radiation only.
- Rash and reactions during infusion of Erbitux were the only notable side effects associated with Erbitux.
The researchers concluded that the addition of Erbitux to radiation therapy significantly improves survival and reduces the risk of a cancer recurrence compared to radiation therapy alone in patients with head and neck cancer.
Erbitux + Chemotherapy for Recurrent Head & Neck Cancer
A study known as EXTREME (ErbituX in first-line Treatment of REcurrent or MEtastatic head and neck cancer) contributed to the approval of Erbitux. The study enrolled patients with metastatic or locally recurrent head and neck cancer who were not candidates for potentially curative treatment with surgery or radiation. Patients were treated with chemotherapy alone or in combination with Erbitux.
The combination of chemotherapy and Erbitux improved overall survival: Overall survival was 7.4 months among patients treated with chemotherapy alone and 10.1 months among patients treated with chemotherapy plus Erbitux. Erbitux also delayed cancer progression. The most common side effects in the Erbitux group included nausea, anemia, vomiting, low white-blood cell counts, rash, weakness, diarrhea, and loss of appetite.
In addition to its other uses, Erbitux is now approved in combination with platinum-based chemotherapy for the initial treatment of patients with recurrent and/or metastatic squamous cell cancer of the head and neck.
Erbitux® + Radiation Improves Survival in Locally Advanced Head and Neck Cancer
Erbitux® combined with high-dose radiation therapy improves the average duration of survival compared to high-dose radiation therapy alone in the treatment of locally advanced head and neck cancer.
The Erbitux Head and Neck Study Group evaluated 417 patients with locally advanced head and neck cancer. Approximately half of the patients were treated with Erbitux® plus high-dose radiation therapy, and the other half were treated with high-dose radiation therapy only and were directly compared. After over 3 years of follow-up (38 months), the average duration of survival was 58 months in the group of patients treated with Erbitux®/radiation, compared with only 28 months for those treated with radiation only. Three-year overall survival was 57% for patients treated with Erbitux®/radiation, compared with only 44% for those treated with radiation only. The only notable side effect associated with Erbitux® was skin rash.
The researchers concluded that the addition of Erbitux® to high-dose radiation therapy significantly improves survival compared to high-dose radiation therapy alone in the treatment of locally advanced head and neck cancer. The presenter stated that Erbitux® appears to provide comparable survival benefits to chemotherapy in the treatment of these patients, without the side effects associated with chemotherapy.
Erbitux® + Chemotherapy & Radiation Therapy Promising in Head and Neck Cancer
According to results published in the Journal of Clinical Oncology, the combination of Erbitux® plus chemotherapy and radiation therapy provides promising outcomes in the treatment of advanced head and neck cancer.
Researchers from the Memorial-Sloan Kettering Cancer Center (MSKCC) conducted a clinical trial to evaluate the treatment regimen consisting of Erbitux, radiation therapy, and the chemotherapy agent Platinol® (cisplatin). This trial included 22 patients with head and neck cancer whose cancer had spread from the site of origin, but not to distant sites in the body.
At a median follow-up of 52 months, the following results were observed:
- Overall survival at 3 years was 76%.
- Progression-free survival at 3 years was 56%.
- Locoregional control (cancer at and near the site of origin does not grow or spread) at 3 years was 71%.
- The most common serious side effect was acne-like rash, which occurred in 10% of patients.
The researchers concluded that the treatment combination consisting of Erbitux/radiation/cisplatin appears promising in the treatment of advanced head and neck cancer. However, the researchers caution that this treatment strategy should not be administered outside the setting of a clinical trial as safety issues need to be further addressed.
Patients diagnosed with advanced head and neck cancer may wish to speak with their physician regarding their individual risks and benefits of participating in a clinical trial further evaluating this or other treatment combinations.
Erbitux Effective in K-Ras Variant of Head & Neck Cancer
Researchers from UCLA have reported that a short course Erbitux® in combination with standard chemotherapy and radiation improves survival in individuals diagnosed with advanced head and neck squamous cell carcinoma and the KRAS genetic mutation.
In 2006, researchers discovered the KRAS-variant, an inherited genetic mutation found in up to 25 percent of people with cancer. The mutation has been shown to predict response to cancer therapy for many cancers, including head and neck cancer. It was not previously understood exactly how this bio-marker worked.
In the current analyses doctors from UCLA analyzed available samples from a previous phase 3 clinical trial of Erbitux in combination with chemotherapy and radiation therapy. The researchers accessed 413 biological samples from participants in the trial. They found a significant benefit of Erbitux treatment for all people with the KRAS-variant. Furthermore, the team found that Erbitux may in fact be working by helping the immune system of people with the KRAS-variant better fight their cancer.
The result of the study indicate the KRAS-variant’s potential to identify people with head and neck cancers who will respond differently to therapies that depend on the immune response. Doctors now uses the KRAS-variant and bio-markers like it to personalize radiation therapy as well as developing immune therapies for all cancer is very promising.
Single Agent Erbitux Improves Responses in Refractory Head and Neck Cancer
According to two articles published in the Journal of Clinical Oncology, the addition of the targeted agent Erbitux to chemotherapy improved anti-cancer responses in patients with advanced head and neck cancer that has stopped responding to standard therapies.
Researchers from Europe recently conducted a clinical trial to further evaluate the effectiveness of Erbitux in combination with platinum-based (Paraplatin®, Platinol®) chemotherapy. This study included 96 patients with advanced head and neck cancer that had stopped responding to previous treatment with platinum-based chemotherapy. Overall, the addition of Erbitux to platinum-based chemotherapy provided significant anticancer activity in these patients. Over half (53%) of patients achieved either a partial or complete disappearance of detectable cancer or disease stabilization following Erbitux/chemotherapy. Cancer did not progress for an average of approximately 85 days, and the average overall survival was approximately 183 days. Treatment was well tolerated. Skin reactions were the most common side effect attributed to Erbitux.
A second trial, including multiple institutions in the United States, was also conducted to evaluate the addition of Erbitux to cisplatin (Platinol)-based chemotherapy in patients with advanced refractory head and neck cancer. The trial included 76 patients who had previously received cisplatin-based chemotherapy alone. Of the participants, 25 patients’ cancer had progressed during this treatment, and 51 patients’ cancer had stabilized. None of these patients achieved an anticancer response while receiving cisplatin-based chemotherapy alone. For the trial, these patients were given Erbitux in addition to cisplatin-based chemotherapy. Twenty-six percent of patients whose cancer had progressed while being treated with cisplatin-based therapy alone achieved anti-cancer responses with the addition of Erbitux to cisplatin-based chemotherapy. Of the patients who achieved disease stabilization on cisplatin-based chemotherapy alone, 18% achieved anticancer responses with the addition of Erbitux. Again, skin-like reactions appeared to be the most common side effects of treatment with Erbitux.
The researchers concluded that the addition of Erbitux to platinum-based chemotherapy regimens appears to provide anticancer responses and possibly improves long-term outcomes in patients with head and neck cancer that had stopped responding to platinum-based chemotherapy alone.
Patients with refractory head and neck cancer may wish to speak with their physician regarding their individual risks and benefits of participating in a clinical trial further evaluating Erbitux or other novel therapeutic approaches.
- Pfister D, Su Y, Kraus D, et al. Concurrent Cetuximab, Cisplatin, and Concomitant Boost Radiotherapy for Locoregionally Advanced, Squamous Cell Head and Neck Cancer: A Pilot Phase II Study of a New Combined-Modality Paradigm. Journal of Clinical Oncology. 2006; 24: 72-1078.
- Baselga J, Trigo J, Bourhis J, et al. Phase II Multicenter Study of the Antiepidermal Growth Factor Receptor Monoclonal Antibody Cetuximab in Combination With Platinum-Based Chemotherapy in Patients With Platinum-Refractory Metastatic and/or Recurrent Squamous Cell Carcinoma of the Head and Neck. Journal of Clinical Oncology. 2005; 23: 5568–5577.
- Herbst R, Arquette M, Shin D, et al**.** Phase II Multicenter Study of the Epidermal Growth Factor Receptor Antibody Cetuximab and Cisplatin for Recurrent and Refractory Squamous Cell Carcinoma of the Head and Neck. Journal of Clinical Oncology. 2005;23: 5578–5587.
- Bonner J, et al. Phase III study of high dose radiation with or without cetuximab in the treatment of locoregionally advanced squamous cell cancer of the head and neck. Proceedings from the 40th annual meeting of the American Society of Clinical Oncology. New Orleans, LA. 2004. Abstract #5507.
- Weidhass J, Harris J, Schaue D, et al. The KRAS-Variant and Cetuximab Response in Head and Neck Squamous Cell Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. Published online December 22, 2016. doi:10.1001/jamaoncol.2016.5478
- ImClone Systems. Independent Clinical Review of Phase III Trial Shows Erbitux and Radiation Control Spread of Advanced Squamous Cell Cancer of the Head and Neck Better Than Radiation Alone; Primary and Secondary Study Endpoints Met with Statistical Significance. Available at: . Accessed June 2005.
- Imclone. ERBITUX(R) Data on Locoregional Control and Overall Survival in Phase III Head and Neck Cancer Study Presented at AACR-NCI-EORTC Meeting. Available phoenix.corporate-ir.net/phoenix.zhtml?c=97689&p=irol-newsArticle&ID=783696&highlight=. Accessed November 2005.