A suggestion of the anti-tumor activity of cetuximab in patients with advanced head and neck cancer was apparent early on in phase I investigations, including an unconfirmed partial response (PR) as well as 2 PRs in patients with HNSCC who received cetuximab doses of 200mg/m2
with cisplatin. 43
A single institution phase I study also reported activity of cetuximab in HNSCC patients, with 2 CR’s and 4 PR’s among 9 evaluable patients (RR 67%). 45
Based on these encouraging findings, randomized and non-randomized studies were conducted in HNSCC patients with advanced, incurable disease.
A number of studies have shown that cetuximab may be combined safely with platinum regimens (). 43, 45, 54
Burtness and colleagues in ECOG randomized 117 patients with recurrent/metastatic HNSCC who had not received chemotherapy for recurrent/metastatic disease to either cisplatin 100 mg/m2
every 4 weeks with placebo, or to cisplatin at the same dose and schedule together with cetuximab (E5397). 4
There was a statistically significant improvement in response rate from 10% to 26% (p=0.03). The study was underpowered for its survival endpoints, and the overall survival was confounded by crossover to cetuximab for patients in the latter half of the study who had disease progression on the control arm. The overall survival improved from 8 to 9.2 months with the addition of cetuximab, although this difference was not statistically significant. In addition, there was an improvement in progression free survival (2.7 months versus 4.2 months) with a HR of 0.78. As with other studies incorporating EGFR inhibitors, the incidence of skin toxicity was associated with improved survival. One of the correlative endpoints for this study was an analysis of EGFR expression levels, expressed as an EGFR immunoreactivity score composed of EGFR staining density and intensity. Tumors were classified as very high EGFR immunoreactive if 3+ staining was present on ≥ 80% of cells, and low-moderate if there were lesser degrees of staining. The arms were well-balanced with regard to the distribution of EGFR immunoreactivity scores, and about a third of the patients in each group with EGFR stains available had very high immunoreactivity. The addition of cetuximab led to a significant increase in response rate in the moderate staining group only, with no benefit from the addition of cetuximab for the very immunoreactive group. The results of E5397 provided proof of principle for the addition of cetuximab to cisplatin, and set up the design of a larger phase III study, conducted in Europe and known as the EXTREME trial. 55
Cetuximab in recurrent/metastatic disease
In this multicenter, phase III European trial, 442 patients with recurrent/metastatic HNSCC not amenable to curative therapy were randomized between a platin-containing chemotherapy doublet or such a doublet given with cetuximab. Cross-over of patients after disease progression was not allowed. Prior treatment for recurrent/metastatic disease excluded patients from participation. The chemotherapy regimen was either cisplatin 100 mg/m2 day 1 or carboplatin AUC 5 day 1, in combination with 5-FU 1000 mg/m2 days 1–4, for a maximum of 6 cycles. Cetuximab was administered weekly at the standard loading and maintenance doses and continued beyond chemotherapy discontinuation. With the addition of cetuximab to standard chemotherapy, there was a statistically significant improvement in overall survival from 7.4 to 10.1 months (HR.80). Patients treated with cetuximab had a greater incidence of diarrhea and vomiting. In a subset analysis, there was a greater benefit for the following subgroups: those under 65 years of age, those with better performance status, and those who received cisplatin (as three quarters of study participants did). The data remain preliminary: data on response, time to progression and quality of life are not yet public. The relative worth of cetuximab in first or later lines of therapy in metastatic/recurrent disease cannot be assessed from this study because there was no cross-over. This study will likely establish cetuximab, cisplatin and 5-fluorouracil as a standard first-line approach for fit younger patients, while leaving open the question of whether cetuximab would have an equal benefit with lesser cost or toxicity if used later in the course of the disease, as appears to be the case, for example, in the treatment of colorectal cancer.
Other smaller studies support the activity of cetuximab in advanced, incurable HNSCC. Hitt et al. recently presented their results of a phase II study in which 46 patients received cetuximab and weekly paclitaxel. Among the 35 evaluable patients, the combined complete and partial response rate was 71%. 56
These patients had not received prior chemotherapy in the advanced disease/metastatic setting. EGFR gene copy number by FISH did not predict for a response to treatment in their study. While this is a small study, it does indicate that cetuximab may add value to cytotoxic agents besides cisplatin.
Patients with platinum-refractory disease may also achieve a treatment benefit with the addition of cetuximab as shown in a trial conducted by Baselga et al. in which 96 patients with platinum-refractory disease were treated by adding cetuximab at the standard doses to the platinum dose and schedule that the patients had received previously and were failing. 57
The response rate was 10%, with a disease control rate of 53%, and the overall survival was 183 days. While these numbers were modest, they do provide evidence of cetuximab activity in a platinum refractory population, which historically has a very low response rate to subsequent chemotherapy. The same result was reported in a phase II study of similar design conducted in the USA in patients who had progressive HNSCC on prior platinum-based therapy. 58
In this trial the addition of cetuximab yielded a response rate of 18% among patients who had stable disease on prior platinum therapy on protocol, 20% among patients who had progressed on prior platinum therapy on protocol, and 6% among those who had progressive disease with prior platinum therapy off study (these patients were subsequently enrolled after a protocol amendment). Cetuximab also has activity as monotherapy in patients with recurrent and/or metastatic SCCHN who had failed platinum-based chemotherapy,. 59
with a 12.6% response rate, disease control rate of 46%, and median response duration of ~ 6 months. This latter study provided the main support for the regulatory approval of single agent cetuximab for this population. The response rates to cetuximab in patients in these 3 studies are highly concordant and support the conclusion that cetuximab monotherapy rather than the combination of cetuximab and cisplatin, is the preferred approach for patients who have not received cetuximab in first line. The striking differences in objective response rates and survival among the 3 distinct cohorts in the Herbst et al. study 58
provide a reminder that cetuximab is likely to have differential efficacy among varying populations of patients. Little information is available from any of these studies about EGFR content, activation of downstream effectors that could be markers of response or resistance, or other features that would permit an assessment of how comparable the populations are. The Vermorken et al. study of cetuximab monotherapy permitted the reintroduction of cisplatin for patients with initial progression on cetuximab alone; 53 such patients received cisplatin plus cetuximab, and objective responses were not reported. This does not prove that cisplatin/cetuximab may not be superior for some patients as the decision to treat with the doublet at cross over may have involved a selection bias.