Cetuximab has become part of the standard of care in the treatment of mCRC and locally advanced and metastatic head and neck cancer [9
]. Monoclonal antibodies against EGFR have a different spectrum of activity compared with small molecule tyrosine kinase inhibitors (TKIs) [25
]. For example, monoclonal antibodies against EGFR are active in colon cancer while small molecule TKIs are not. We and others have shown that gefitinib and erlotinib were inactive in recurrent ovarian carcinoma [26
]. The low response rate correlated with a low activation mutation rate of EGFR [26
]. More recently, EMD72000 (matuzumab) has been reported as inactive but well tolerated in patients with recurrent ovarian cancer [28
]. Only 5% of the patients had PFS greater than 6 months.
There is a known correlation between clinical outcome and the intensity of skin rash in patients with mCRC treated with cetuximab [14
]. Similar results were reported in patients with ovarian cancer treated with erlotinib and gefitinib [26
]. In light of these findings, the current trial was designed to evaluate if cetuximab, dose escalated to induce grade 2 acneiform rash, to ensure delivery of a biologically active dose, would increase the response rate in patients with recurrent ovarian carcinoma. The low level of clinical efficacy and small number of patients in this trial precludes identifying a relationship between dose and response. In a similar but larger trial involving 166 evaluable patients with mCRC, dose escalation of single agent cetuximab to grade 2 rash improved its response rate [14
Cetuximab has been combined with carboplatin and paclitaxel as front-line treatment in a feasibility trial [29
]. The data from the first 17 accrued patients showed that combination was well tolerated. Median PFS of 14.4 months though was not better than that observed in large frontline trials such as GOG 182 (approximately 16 months) [3
] although clearly, comparisons with historical controls are not conclusive. EGFR targeted therapy seems to have minimal activity as a single agent treatment and offers little improvement when combined with chemotherapy in the treatment of epithelial ovarian carcinoma.
While the development of cetuximab has explored clinical utility by evaluating its use in nearly all subjects, efforts are needed to better identify patients more likely to benefit from this therapy. A targeted approach to patient selection could potentially improve survival, spare patients' needless toxicity and reduce expenses associated with futile therapy. It may also be possible to accelerate the development of cetuximab in front-line indications by enrichment of clinical trial populations with those patients that are more likely to respond. For example, we and others have shown that mCRC patients with a mutation in K-RAS
are less likely to respond to cetuximab [30
].Other studies have since discovered that the K-RAS
mutation also predicts response to a related drug, panitumumab [34
]. Although K-RAS
mutations have been reported in ovarian cancers, especially the mucinous subtype [36
], it is unlikely that lack of activity observed in our trial can be attributed to RAS mutations. In addition, we have reported previously that expression and/or mutation of the EGFR was associated with response to another EGFR inhibitor, gefitinib [27
]; however we have no evidence that either were a factor in the clinical responses observed in this trial. Therefore, additional progress is needed to identify biomarkers that may prove useful for selecting ovarian cancer patients with an improved chance of responding to therapy [37
In this aspect, a goal of this study was to assess the utility of screening the serum of patients for proteins potentially associated with drug activity and/or clinical outcome. Many clinical trials incorporate correlative components including serum proteomic analysis to identify predictors of response to therapy [38
]. However, most of these studies are limited in the scope of markers evaluated. Tumors have systemic effects that are best evaluated by monitoring the numerous proteins that represent a variety of pathways. The predictive capabilities of multi-marker combinations tend to be superior to any single marker [19
]. The current study incorporated multiplexed immunoassays to measure nearly 100 serum proteins as part of this multi-center Phase II clinical trial. Unfortunately, our study was limited due to the number of patients showing clinical response, thus precluding enrollment of patients in this two-stage study design. Nevertheless, we identify 12 markers whose baseline levels were significantly elevated in patients who had PD relative to PR/SD ( and Table S2
). These proteins remained elevated following two cycles of cetuximab treatment ( and Table S3
) suggesting these may be important prognostic markers rather than predictors of response to therapy.
The markers identified include several cytokines (IL-6, IL-8, TNF-α) that have immunomodulatory properties, serum levels of which have all been well documented to be associated with ovarian cancer [49
]. Proteases (MMP7 and KLK10) that may facilitate metastasis have also been reported to be associated with ovarian cancer [21
]. HE4 is a relatively novel serum marker that has been recently reported as well [66
]. Most of the remaining markers have also been reported in serologic evaluations related to ovarian cancer [69
]. These reports and the current data warrant further validation of these markers as being predictive of disease progression. The promise of personalized medicine is gaining ground; however, a quick and easy test to direct an entire course of treatment is not yet reality. The ability to scan a patient's tumor tissue and/or blood for proteins, genes, or other traces of molecular information that will delineate the specific nature of that individual's disease is technically possible. The type of exploratory studies we report are necessary and timely to advance personalized care for ovarian cancer patients, but will clearly benefit greatly from larger trials with more favorable responses. Nevertheless, personalized care, once the appropriate markers are discovered, will have profound implications for patients, their physicians, and the entire pharmaceutical industry.