Drug Insight: Cetuximab in the Treatment of Recurrent and Metastatic Squamous Cell Carcinoma of the Head and Neck

Jacques Bernier

Nat Clin Pract Oncol. 2008;5(12):705-713.

Summary and Introduction

Summary

Patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) have a poor prognosis, particularly those whose disease has progressed on previous platinum-containing therapy. The epidermal growth factor receptor (EGFR) is expressed at very high levels in SCCHN and is associated with a poor prognosis. Several phase II–III studies have shown that the EGFR-targeting monoclonal antibody, cetuximab, offers clinical benefit for patients with SCCHN. Cetuximab monotherapy is active in patients whose cancer progresses on platinum-containing therapy. Tumor response and patient survival are in excess of what is achieved with commonly used therapies in this setting. Addition of a platinum regimen to cetuximab in patients with disease that progresses on platinum seems to confer no further benefit over cetuximab alone, either in terms of response rate or survival. In the first-line setting, cetuximab plus platinum and 5-fluorouracil significantly prolongs overall survival compared with platinum and 5-fluorouracil alone. The superior survival observed with cetuximab compared with platinum-based treatment demonstrates that cetuximab is the most active treatment for recurrent and/or metastatic SCCHN, and is of particular clinical significance.

Introduction

The epidermal growth factor receptor (EGFR)-targeting IgG₁ monoclonal antibody cetuximab is an example of the advantages offered by targeted therapy in the clinical setting. Cetuximab is the first targeted therapy to show a significant benefit in head and neck cancer, and received FDA regulatory approval for use in this setting. Approval of this agent for locally advanced squamous cell carcinoma of the head and neck (SCCHN) was based on the results of a landmark trial, in which the combination of cetuximab and radiotherapy led to significant improvements in median overall survival (49 months versus 29.3 months; hazard ratio for death 0.74, P = 0.03) and locoregional control (24.4 months versus 14.9 months; hazard ratio for locoregional progression or death 0.68, P = 0.005) compared with radiotherapy alone.^[1] In addition to demonstrating the efficacy of cetuximab in this setting, the trial confirmed that the administration of cetuximab does not compromise the delivery of scheduled doses of radiotherapy: patient compliance with radiotherapy was balanced between the treatment arms. Cetuximab is now widely approved in European and non-European countries for use in combination with radiotherapy in locally advanced SCCHN, and in combination with irinotecan for the treatment of patients with EGFR-expressing, KRAS wild-type metastatic colorectal cancer (mCRC). In the US and countries in central and south America and Asia, single-agent cetuximab is approved for use in patients with recurrent and/or metastatic SCCHN progressing despite chemotherapy, in patients with mCRC with disease progression, and in those who are intolerant to irinotecan.

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Cite this: Drug Insight: Cetuximab in the Treatment of Recurrent and Metastatic Squamous Cell Carcinoma of the Head and Neck - Medscape - Dec 01, 2008.

Table 1. Overall Relative Staining Intensity of EGFR Expression in Head and Neck Tumorigenesis ^[12]
Histological type	Number of samples	Mean relative staining intensity (±SE)^a	P value
Control epithelium (1)	4	0.38 ± 0.07	–
Normal epithelium adjacent to tumor (2)	28	0.78 ± 0.06	0.021^b
Hyperplasia (3)	15	0.64 ± 0.17	0.81^c
Dysplasia (4)	24	0.71 ± 0.11	0.92^d
Squamous-cell carcinoma (5)	36	1.16 ± 0.08	0.01^e

^aRelative staining intensity: staining of tissue relative to that of cells from a head and neck cancer cell line that expresses EGFR (886 cell line).
^b1 versus 2,
^c2 versus 3,
^d3 versus 4,
^e4 versus 5.
Abbreviation: SE = standard error. Permission obtained from American Association for Cancer Research © Shin DM et al. (1994) Dysregulation of epidermal growth factor receptor expression in premalignant lesions during head and neck tumorigenesis. Cancer Res 54: 3153–3159.

Table 2. Phase II Studies of Cetuximab With or Without Chemotherapy in Recurrent and/or Metastatic SCCHN Progressing on Platinum-based Therapy
Treatment regimen	Number of patients	RR (%)	DCR (%)	Median PFS (months)	Median OS (months)	Reference
Cetuximab monotherapy	103	13 (7–21)	46 (36–56)	2.29^a	5.84	Vermorken et al. (2007)^[38]
Cetuximab + cisplatin or carboplatin	96	10 (5–18)	53 (43–63)	2.79^a	6.01	Baselga et al. (2005)^[36]
Cetuximab + cisplatin	79	10^b	56^b	NA	NA	Herbst et al. (2005)^[37]
PD/1^c	25	20 (7–41)	64 (43–82)	3.0 (1.9–4.1)	6.1 (2.6–7.6)	Herbst et al. (2005)^[37]
PD/2^d	54	6 (1–15)	52 (38–66)	2.0 (1.6–2.9)	4.3 (3.0–5.8)	Herbst et al. (2005)^[37]

^aTime to progression.
^bCombined data for patients with disease progressing on platinum (PD/1 and PD/2)—see text for details. Figures in parentheses represent 95% CI values, where available.
^cPD/1—patients progressing on protocol-specified platinum-based therapy (cisplatin and either paclitaxel or 5-FU).
^dPD/2—patients with disease progressing on any platinum-based therapy. Refer to the text for doses.
Abbreviations: DCR = disease control rate; NA = not applicable; OS = overall survival; PFS = progression-free survival; RR = response rate.

Table 3. Randomized Phase III Trials of Cetuximab in the First-line Treatment of Recurrent and/or Metastatic SCCHN
Treatment regimen	Number of patients	RR (%)	P value	Median PFS, months (95% CI)	P value	Median OS, months (95% CI)	Hazard ratio (P value)	Reference
Cisplatin plus cetuximab versus cisplatin plus placebo (n = 117^a)
Cisplatin (100 mg/m² once every 4 weeks) plus cetuximab	57	26	0.03	4.2 (3.71–5.55)	0.09	9.2 (7.1–12.1)	NP (0.21)	Burtness et al. (2005)^[39]
Cisplatin (as above) plus placebo	60	10	NA	2.7 (1.9–3.8)	NA	8.0 (6.1–10.6)	NA	NA
Cisplatin/carboplatin plus 5-FU plus cetuximab versus cisplatin/carboplatin plus 5-FU (n = 442)
Cisplatin or carboplatin plus 5-FU plus cetuximab	222	NA	NA	NA	NA	10.1 (8.6–11.2)	0.797 (0.036)	Vermorken et al. (2007)^[41]
Cisplatin or carboplatin plus 5-FU	220	NA	NA	NA	NA	7.4 (6.4–8.3)	NA	NA

^a112 patients evaluable for response.
Abbreviations: 5-FU = 5-fluorouracil; NA = not applicable; NP = not provided; OS = overall survival; PFS = progression-free survival; RR = response rate.

Table 3. Randomized Phase III Trials of Cetuximab in the First-line Treatment of Recurrent and/or Metastatic SCCHN
Treatment regimen	Number of patients	RR (%)	P value	Median PFS, months (95% CI)	P value	Median OS, months (95% CI)	Hazard ratio (P value)	Reference
Cisplatin plus cetuximab versus cisplatin plus placebo (n = 117^a)
Cisplatin (100 mg/m² once every 4 weeks) plus cetuximab	57	26	0.03	4.2 (3.71–5.55)	0.09	9.2 (7.1–12.1)	NP (0.21)	Burtness et al. (2005)^[39]
Cisplatin (as above) plus placebo	60	10	NA	2.7 (1.9–3.8)	NA	8.0 (6.1–10.6)	NA	NA
Cisplatin/carboplatin plus 5-FU plus cetuximab versus cisplatin/carboplatin plus 5-FU (n = 442)
Cisplatin or carboplatin plus 5-FU plus cetuximab	222	NA	NA	NA	NA	10.1 (8.6–11.2)	0.797 (0.036)	Vermorken et al. (2007)^[41]
Cisplatin or carboplatin plus 5-FU	220	NA	NA	NA	NA	7.4 (6.4–8.3)	NA	NA

^a112 patients evaluable for response.
Abbreviations: 5-FU = 5-fluorouracil; NA = not applicable; NP = not provided; OS = overall survival; PFS = progression-free survival; RR = response rate.

Table 4. The Most Common and Relevant Cetuximab-related Adverse Events. ^[38]
Special adverse event category	Grade	Single-agent therapy phase^a (%; n = 103)	Combination therapy phase^a (%; n = 53)
Rash	All 3/4	49 1	19 2
Acne	All 3/4	26 0	6 0
Asthenia	All 3/4	24 4	11 6
Nail disorder	All 3/4	16 0	4 2
Dry skin	All 3/4	14 0	6 0
Fever	All 3/4	14 1	2 2
Nausea	All 3/4	13 1	19 0
Vomiting	All 3/4	11 2	8 0
Dyspnea	All 3/4	5 4	0 0
Infusion-related reactions	All 3/4	6 1	0 0

^aSingle-agent phase is cetuximab monotherapy; combination therapy phase is cetuximab plus platinum. If a patient experienced more than one adverse event, the patient was counted once according to the highest toxicity grade in that category. Reproduced with permission from the American Society of Clinical Oncology © Vermorken JB et al. (2007) Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 25: 2171–2177.

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