Head and Neck Cancer Patients get New Treatment Option
Patients with advanced head and neck cancer have a new, “targeted” treatment option. Until now, recurrent disease was usually treated with combinations of chemotherapies that are broadly acting against tumor cells. But just last month the FDA approved the first ever targeted therapy - cetuximab (Erbitux®) - for recurrent squamous cell carcinoma of the head and neck (SCCHN). In studies, patients who received cetuximab plus chemo lived longer, overall, than those on the traditional regimen. Cetuximab inhibits a protein called EGFR (Epidermal Growth Factor Receptor). Although no link has been seen between high tumor levels of EGFR and response to the drug, it does appear that certain SCCHN patients are more likely to respond to this treatment than others. Cetuximab is a valuable new option for these patients and we’ll be paying careful attention to the follow-up studies as they occur.
To learn more details about this important development in the treatment of SCCHN, please read the analysis provided by our expert advisors, below.
“Combination therapy including the anti-epidermal growth factor receptor (EGFR)-antibody cetuximab was FDA-approved for recurrent/metastatic squamous cell carcinoma of the head and neck”
Ann Marie Egloff, PhD, MPH and Jennifer R. Grandis, MD
In 1992 two published randomized clinical trials (Jacobs et al. and Forastiere et al.) laid the groundwork to define the standard of care for systemic first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) to be platinum-based chemotherapy, either cisplatin or carboplatin, in combination with 5-flurouracil (5-FU)(1-2). Though median patient overall survival with the platinum-based doublet chemotherapy in the 2 trials, 5.5 months and 6.6 months, respectively, did not represent a significant improvement over single-agent therapy, the platinum-based doublet therapy produced higher response rates. Since 1992, other doublet chemotherapies have been tested in clinical trials for recurrent/metastatic SCCHN. However, no tested doublet chemotherapy proved to be more effective than cisplatin plus 5-FU or carboplatin plus 5-FU, and this treatment regimen remained standard of care for over a decade and a half. On November 7, 2011, the U.S. Food and Drug Administration (FDA) approved the use of cetuximab (Erbitux; ImClone LLC), an epidermal growth factor receptor (EGFR)-targeted antibody, in combination with platinum-based chemotherapy and 5-FU for treatment of recurrent locoregional and/or metastatic SCCHN, thereby redefining the standard of care for the first-line treatment of patients with recurrent or metastatic SCCHN(3).
The FDA approval of cetuximab/platinum/5-FU was primarily based on a 2008 multi-institutional randomized trial by Vorkmorken et al. involving 442 recurrent/metastatic SCCHN patients that reported improved survival for the 222 patients who were treated with cetuximab/platinum/5-FU compared to 220 patients who were treated with platinum/5-FU without cetuximab (4). Patients who received cetuximab in addition to chemotherapy had significantly increased median overall survival compared to patients who received chemotherapy without cetuximab (10.1 months versus 7.4 months, respectively). Response rates for the cetuximab plus chemotherapy treated patients were also significantly improved. Grade 3 or 4 adverse events were generally comparable between the two treatment arms except for higher rates in the cetuximab arm of sepsis (4% versus 0.4%) and skin toxicity (9% versus 0.4%). Quality of life was not compromised by the addition of cetuximab to platinum/5-FU (5). Therefore, this trial, which was mainly based in Europe and used a European Union (EU)-approved cetuximab, demonstrated improved survival for patients with recurrent and/or metastatic SCCHN with the addition of cetuximab without unacceptable toxicities or diminished quality of life.
Identifying patient and/or tumor characteristics that define who will respond to a specific therapy is the basis for personalized medicine. The characteristics defining patients who would most likely to benefit from combined cetuximab/platinum/5-FU are still largely undefined. Neither high levels of tumor EGFR protein, which included 83% of tumors in the Vorkmorken study, nor tumor EGFR gene copy number were predictive biomarkers for response to cetuximab/platinum/5-FU in the Vorkmoken et al. study (6). These results are in contrast to metastatic colorectal cancer for which response to cetuximab has been more pronounced in tumors with EGFR gene amplification (7-9). No other molecular characteristic has yet been evaluated for correlation with treatment response for this study cohort. Based on planned subset analysis, the benefit of adding cetuximab to platinum/5-FU was most evident in patients less than 65 years of age and those with better performance scores (4). Patients whose tumors were well or moderately differentiated or arose in the oral cavity were also more likely to benefit from cetuximab plus chemotherapy. Therefore, some general characteristics of patients more likely to respond to the cetuximab/platinum/5-FU treatment have been identified, but these characteristics are more likely prognostic in nature rather than predictive of which patients would respond to this specific combination therapy, as younger patients with better performance status and lower grade tumors generally respond better to treatment.
In March of 2006 cetuximab was FDA-approved as a single agent for second-line treatment of patients with recurrent or metastatic SCCHN who had failed platinum-based therapy (3). The November 2011 FDA approval of cetuximab as a part of first line combination therapy for recurrent/metastatic SCCHN disease provides these patients with a much needed treatment option.
Ann Marie Egloff, PhD MPH
Assistant Professor, Department of Otolaryngology
University of Pittsburgh
Jennifer R. Grandis, MD
Professor of Otolaryngology & Pharmacology
University of Pittsburgh School of Medicine
Program Leader, Head & Neck Cancer Program
University of Pittsburgh Cancer Institute
References
1. Jacobs C, Lyman G, Velez-Garcia E, Sridhar KS, Knight W, Hochster H, et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol. 1992;10:257-63.
2. Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. Journal of Clinical Oncology. 1992;10:1245-51.
3. Institute NC. FDA Approval for Cetuximab. In: Richard Pazdur MD, editor. Cancer Drug Information; 2011.
4. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. The New England journal of medicine. 2008;359:1116-27.
5. Mesia R, Rivera F, Kawecki A, Rottey S, Hitt R, Kienzer H, et al. Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol. 2010;21:1967-73.
6. Licitra L, Mesia R, Rivera F, Remenar E, Hitt R, Erfan J, et al. Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study. Annals of Oncology. 2011;22:1078-87.
7. Personeni N, Fieuws S, Piessevaux H, De Hertogh G, De Schutter J, Biesmans B, et al. Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res. 2008;14:5869-76.
8. Campanella C, Mottolese M, Cianciulli A, Torsello A, Merola R, Sperduti I, et al. Epidermal growth factor receptor gene copy number in 101 advanced colorectal cancer patients treated with chemotherapy plus cetuximab. J Transl Med. 2010;8:36.
9. Scartozzi M, Giampieri R, Maccaroni E, Mandolesi A, Giustini L, Silva R, et al. Analysis of HER-3, insulin growth factor-1, nuclear factor-kB and epidermal growth factor receptor gene copy number in the prediction of clinical outcome for K-RAS wild-type colorectal cancer patients receiving irinotecan-cetuximab. Ann Oncol. 2011.
To learn more details about this important development in the treatment of SCCHN, please read the analysis provided by our expert advisors, below.
“Combination therapy including the anti-epidermal growth factor receptor (EGFR)-antibody cetuximab was FDA-approved for recurrent/metastatic squamous cell carcinoma of the head and neck”
Ann Marie Egloff, PhD, MPH and Jennifer R. Grandis, MD
In 1992 two published randomized clinical trials (Jacobs et al. and Forastiere et al.) laid the groundwork to define the standard of care for systemic first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) to be platinum-based chemotherapy, either cisplatin or carboplatin, in combination with 5-flurouracil (5-FU)(1-2). Though median patient overall survival with the platinum-based doublet chemotherapy in the 2 trials, 5.5 months and 6.6 months, respectively, did not represent a significant improvement over single-agent therapy, the platinum-based doublet therapy produced higher response rates. Since 1992, other doublet chemotherapies have been tested in clinical trials for recurrent/metastatic SCCHN. However, no tested doublet chemotherapy proved to be more effective than cisplatin plus 5-FU or carboplatin plus 5-FU, and this treatment regimen remained standard of care for over a decade and a half. On November 7, 2011, the U.S. Food and Drug Administration (FDA) approved the use of cetuximab (Erbitux; ImClone LLC), an epidermal growth factor receptor (EGFR)-targeted antibody, in combination with platinum-based chemotherapy and 5-FU for treatment of recurrent locoregional and/or metastatic SCCHN, thereby redefining the standard of care for the first-line treatment of patients with recurrent or metastatic SCCHN(3).
The FDA approval of cetuximab/platinum/5-FU was primarily based on a 2008 multi-institutional randomized trial by Vorkmorken et al. involving 442 recurrent/metastatic SCCHN patients that reported improved survival for the 222 patients who were treated with cetuximab/platinum/5-FU compared to 220 patients who were treated with platinum/5-FU without cetuximab (4). Patients who received cetuximab in addition to chemotherapy had significantly increased median overall survival compared to patients who received chemotherapy without cetuximab (10.1 months versus 7.4 months, respectively). Response rates for the cetuximab plus chemotherapy treated patients were also significantly improved. Grade 3 or 4 adverse events were generally comparable between the two treatment arms except for higher rates in the cetuximab arm of sepsis (4% versus 0.4%) and skin toxicity (9% versus 0.4%). Quality of life was not compromised by the addition of cetuximab to platinum/5-FU (5). Therefore, this trial, which was mainly based in Europe and used a European Union (EU)-approved cetuximab, demonstrated improved survival for patients with recurrent and/or metastatic SCCHN with the addition of cetuximab without unacceptable toxicities or diminished quality of life.
Identifying patient and/or tumor characteristics that define who will respond to a specific therapy is the basis for personalized medicine. The characteristics defining patients who would most likely to benefit from combined cetuximab/platinum/5-FU are still largely undefined. Neither high levels of tumor EGFR protein, which included 83% of tumors in the Vorkmorken study, nor tumor EGFR gene copy number were predictive biomarkers for response to cetuximab/platinum/5-FU in the Vorkmoken et al. study (6). These results are in contrast to metastatic colorectal cancer for which response to cetuximab has been more pronounced in tumors with EGFR gene amplification (7-9). No other molecular characteristic has yet been evaluated for correlation with treatment response for this study cohort. Based on planned subset analysis, the benefit of adding cetuximab to platinum/5-FU was most evident in patients less than 65 years of age and those with better performance scores (4). Patients whose tumors were well or moderately differentiated or arose in the oral cavity were also more likely to benefit from cetuximab plus chemotherapy. Therefore, some general characteristics of patients more likely to respond to the cetuximab/platinum/5-FU treatment have been identified, but these characteristics are more likely prognostic in nature rather than predictive of which patients would respond to this specific combination therapy, as younger patients with better performance status and lower grade tumors generally respond better to treatment.
In March of 2006 cetuximab was FDA-approved as a single agent for second-line treatment of patients with recurrent or metastatic SCCHN who had failed platinum-based therapy (3). The November 2011 FDA approval of cetuximab as a part of first line combination therapy for recurrent/metastatic SCCHN disease provides these patients with a much needed treatment option.
Ann Marie Egloff, PhD MPH
Assistant Professor, Department of Otolaryngology
University of Pittsburgh
Jennifer R. Grandis, MD
Professor of Otolaryngology & Pharmacology
University of Pittsburgh School of Medicine
Program Leader, Head & Neck Cancer Program
University of Pittsburgh Cancer Institute
References
1. Jacobs C, Lyman G, Velez-Garcia E, Sridhar KS, Knight W, Hochster H, et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol. 1992;10:257-63.
2. Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. Journal of Clinical Oncology. 1992;10:1245-51.
3. Institute NC. FDA Approval for Cetuximab. In: Richard Pazdur MD, editor. Cancer Drug Information; 2011.
4. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. The New England journal of medicine. 2008;359:1116-27.
5. Mesia R, Rivera F, Kawecki A, Rottey S, Hitt R, Kienzer H, et al. Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol. 2010;21:1967-73.
6. Licitra L, Mesia R, Rivera F, Remenar E, Hitt R, Erfan J, et al. Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study. Annals of Oncology. 2011;22:1078-87.
7. Personeni N, Fieuws S, Piessevaux H, De Hertogh G, De Schutter J, Biesmans B, et al. Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res. 2008;14:5869-76.
8. Campanella C, Mottolese M, Cianciulli A, Torsello A, Merola R, Sperduti I, et al. Epidermal growth factor receptor gene copy number in 101 advanced colorectal cancer patients treated with chemotherapy plus cetuximab. J Transl Med. 2010;8:36.
9. Scartozzi M, Giampieri R, Maccaroni E, Mandolesi A, Giustini L, Silva R, et al. Analysis of HER-3, insulin growth factor-1, nuclear factor-kB and epidermal growth factor receptor gene copy number in the prediction of clinical outcome for K-RAS wild-type colorectal cancer patients receiving irinotecan-cetuximab. Ann Oncol. 2011.
DISCLAIMER:
The opinions expressed in the above article are of the author and the author alone and are provided here for informational purposes only. They do not reflect the opinions of N-of-One Therapeutics, Inc. ("N-of-One") and they have not been reviewed by an N-of-One scientist, physician or any member of the N-of-One editorial staff for accuracy, balance or objectivity. The contents of the www.N-of-One.com website and this article are not a substitute for professional medical advice, diagnosis, or treatment. Never delay or disregard seeking professional medical advice from your physician or other qualified health provider because of something you have read herein or on any other website. N-of-One does not endorse any specific product, service or treatment.
<< Home