Clinical Trials Targeting EGFR in HNSCC
Many of the single-agent clinical trials have involved TKIs. A recent phase II trial of erlotinib enrolled 114 patients with advanced HNSCC refractory to chemotherapy. Of the 78 patients evaluated for tumor response, 10 (23%) had a partial response, 23 (29%) had stable disease, and 45 (58%) had progressive disease. Observed toxicity included acne-like skin rushes (28% grade 1, 34% grade 2, 8% grade 3, and drug discontinuation in two patients), nausea, vomiting, headache, diarrhea, and fatigue.
A phase II trial of gefitinib(Drug information on gefitinib) monotherapy, focusing on recurrent or metastatic HNSCC, reported on 40 evaluable patients, 8 (20%) of whom experienced a complete or partial response. An additional 14 (35%) showed stable disease, and 18 (45%) experienced disease progression at 8 weeks. Toxicity included grade 3 drug-related neurotoxicity (myelopathy), which resolved after termination of treatment. One patient discontinued therapy due to grade 2 acne-like rash, and three patients required dose reduction after experiencing mild-to-moderate diarrhea. Common side effects were grade 1/2 diarrhea (45%), acne-like rashes (45%), nausea (14%), and anorexia (20%). Of note, acne-like rash appeared to predict for response to gefitinib and was associated with improved survival. This association has not been clearly demonstrated in gefitinib monotherapy trials in other disease sites such as lung cancer.
CI-1033, an orally active, irreversible pan-erbB TKI, has undergone phase I testing to determine the doselimiting toxicities, minimal toxic dose, and pharmacokinetic profile. Initial reports detailed the treatment of 34 advanced-stage cancer patients including 3 with head and neck cancer. Doselimiting hypersensitivity reactions occurred in two patients at 560 mg.
EMD 72000, a humanized monoclonal antibody against EGFR, has also been evaluated in patients with advanced malignancies, including patients with HNSCC. In this phase I study, 5 of 22 patients achieved a partial response, including 2 patients with heavily pretreated advanced HNSCC, resulting in an overall response rate of 23% (95% confidence interval: 8%-45%). As in studies of cetuximab(Drug information on cetuximab) or gefitinib, no correlation between the degree of EGFR expression and tumor response to EMD 72000 was observed. Sufficient inhibition of the EGFR signaling pathway was achieved at EMD 72000 doses well below the minimal toxic dose.
Finally, ABX-EGF is a high-affinity, completely human IgG2 monoclonal antibody with strong activity against human EGFR. ABX-EGF prevents receptor binding of EGF/TGFalpha through competitive linking to the EGFR, inhibiting intracellular tyrosine phosphorylation and tumor cell activation. In A431 tumor models in nude mice, ABX-EGF prevented tumor formation and cured large, established tumors. Treatment with this agent alone, sans chemotherapy or radiotherapy, resulted in marked tumor growth inhibition at modest doses.
EGFR Inhibition and Chemotherapy
In parallel with trials combining EGFR inhibitors and radiation for HNSCC, it is worth mentioning several studies that have combined EGFR inhibitors with platinum-based chemotherapy in advanced or recurrent HNSCC. Initial phase I trials established the loading dose of cetuximab at 400 mg/m2 with a maintenance dose at 250 mg/m2 as achieving a high percentage of EGFR saturation in tumor tissue. Six (67%) of nine evaluable patients also achieved major responses, including two complete remissions.
The Eastern Cooperative Oncology Group (ECOG) performed a randomized phase III trial comparing cisplatin(Drug information on cisplatin) vs cisplatin and cetuximab.[ 33] A total of 121 patients with metastatic or recurrent HNSCC who had not received prior therapy for metastatic disease or induction or adjuvant therapy within 3 months were enrolled. Grade 3/4 hypersensitivity, neutropenia, and rash/desquamation occurred in 6%, 17%, and 11% of patients, respectively. Most patients had stable disease, with 15% of patients experiencing complete or partial response. At the last reported follow-up, the difference between the two arms with regard to survival was not statistically significant.
The use of cetuximab has also recently been investigated in combination with carboplatin(Drug information on carboplatin) in cisplatinrefractory patients with recurrent or metastatic nasopharyngeal cancer. Ninety-three percent of tumors were EGFR-positive (56/60 patients). A partial response rate of 17% was reported, with an additional 42% of patients experiencing stable disease. A majority of the responses occurred within the first two cycles. A recent phase I trial in patients with recurrent or metastatic HNSCC combining cetuximab and cisplatin or carboplatin concurrently at fixed dose levels with escalating doses of fluorouracil(Drug information on fluorouracil) (600, 800, and 1,000 mg/m2) reported 10 partial responses and 8 cases of stable disease.
EGFR Antagonists and Radiotherapy
Table 1 depicts some of the clinical trials that are ongoing or have been completed with EGFR inhibitors and radiation or chemoradiation in HNSCC. An early phase I study from the University of Alabama at Birmingham demonstrated that cetuximab could be given safely at a loading dose of 400 mg/m2 and a maintenance weekly dose of 250 mg/m2 with either conventional daily radiation (1.8 Gy per fraction) or 1.2 Gy per fraction, twice a day, to 76.8 Gy. The majority of side effects were attributable to radiotherapy, and all patients in this study experienced an objective response.
A subsequent phase III study investigated the use of cetuximab combined with radiation vs radiation alone in locally advanced HNSCC. The toxicity and response results of this study were reported at the annual meeting of the American Society for Clinical Oncology (ASCO) in 2004. A statistically significant advantage was observed in favor of cetuximab plus radiation in terms of locoregional control at 2 years (P = .01), progressionfree survival, and overall survival. Of major importance was the fact that, overall, mucosal toxicity was not significantly higher than that seen in the radiotherapy-alone arm. These impressive initial findings without the use of conventional chemotherapeutics are provocative and perhaps suggest that the use of targeted agents and radiation should be tested against chemoradiation regimens in the future.
At ASCO 2003, investigators from Memorial Sloan-Kettering Cancer Center reported on the toxicity and results of combined weekly cetuximab with concomitant boost radiation and cisplatin (100 mg/m2 IV, weeks 1 and 4) for patients with stage III/IV HNSCC. Several reported grade 4 toxicities including anaphylaxis, myocardial infarction, and mucositis as well as two patient deaths were of concern. However, the results in the surviving patients were encouraging. Although this trial closed early due to toxicity, the 2-year actuarial and overall survival rates were both 76%, and 16 of 21 patients are disease-free at 26 months of median follow-up.
Trials combining TKIs with radiation and cisplatin are currently under way, using both erlotinib and gefitinib in patients with advanced HNSCC. At the University of Colorado Comprehensive Cancer Center, in collaboration with the National Cancer Institute and several other participating institutions, an ongoing phase I trial is testing combinations of gefitinib concurrent with radiation in intermediate-stage disease, and gefitinib with radiation plus cisplatin (30 mg/m2/wk) in patients with stage IVA/ IVB disease.
Alternative or Complementary EGFR Targeting Strategies
Many different approaches to disrupting upstream or downstream EGFR-associated activity are being studied (Figure 3). Along with the above mentioned strategies for EGFR inhibition, examples of additional attempts at EGFR signal perturbation warrant a brief discussion.
Anti-EGFR Antibody-Linked Toxins
Preclinical studies targeting EGFRoverexpressing cells using conjugates of toxins linked to anti-EGFR antibodies have shown some promise. The idea is that these "smart bombs" will selectively deliver the toxins to the receptor, either limiting cell proliferation by disrupting its signaling or killing the cell outright. A potential advantage of this approach is the possible "bystander effect" (in surrounding tumor cells) created with toxin delivery. Anti-HER2/neu Pseudomonas exotoxin has shown antitumoral efficacy when injected into HNSCC tumors in vivo.
Alternatively, radioactive isotopes or chemotherapeutic agents can be used instead of toxins. Delivery of these anti-EGFR conjugates should be selective, as systemic therapy may result in EGFR-rich organs such as the liver becoming injured in the process. The opportunity to combine these molecules with radiation is intriguing.
STATs are transcription factors involved in the regulation of gene expression and associated with EGFR signaling. Seven STAT proteins have been identified, and STATs 1, 3, and 5 are constitutively activated in HNSCC overexpressing EGFR. In HNSCC, constitutive activation of STAT3 and STAT5 has been linked to TGF-alpha/EGFR signaling in vitro and in vivo. Reduction of STAT3 has been shown to inhibit the growth of HNSCC. Although frequently associated with EGFR activation, STAT3 may also act independently of EGFR signaling in head and neck cancer and is amplified in some HNSCC lines that have low EGFR expression. This appears to be related to its interaction with interleukin-6 cytokines in a separate autocrine/paracrine loop. Perhaps downstream inhibition of STAT3 might complement upstream blockade of EGFR activation and improve response to EGFR targeting.
Targeting downstream proteins associated with EGFR activation may improve response to EGFR inhibitors. In this regard, the mammalian target of rapamycin (mTOR) belongs to a recently identified family of protein kinases termed phosphoinositide 3- kinase related kinases (PIKKs) downstream of the EGFR, which are involved in cell-cycle progression and checkpoints that govern cellular responses to DNA damage, repair, and recombination.
Compounds designed to interfere with this molecule include CCI-779, a clinically relevant analog of rapamycin. Both agents block cell-cycle progression from G1 to S phase through interference with mRNA translation of cell-cycle proteins. Inactivating cyclin/cyclin-dependent kinase/cyclin- dependent kinase inhibitors by blocking cancer cells in the early phases of the cell cycle enables mTOR inhibitors to stop the growth of cancer cells.