The epidermal growth factor receptor (EGFR) regulates multiple cellular processes, including proliferation, differentiation, survival, motility, and blood vessel formation. Genetic alterations in the sequence of the EGFR gene or aberrations in the levels of protein expression may result in deregulation of EGFR function. Abnormally active EGFR may become an important contributor to oncogenic processes. The rationale for anti-EGFR therapies in cancer treatment relies on the role that EGFR may play in tumorigenesis and the frequent overexpression or hyperactivation of EGFR noted in many tumor types, including colorectal cancer (CRC), squamous cell carcinoma of the head and neck (SCCHN), and non-small-cell lung cancer (NSCLC). Overexpression of EGFR correlates with poor outcome and affects all aspects of carcinogenesis, including cell growth and invasion, angiogenesis, and metastasis.[1-4] In addition, the presence of activating mutations of EGFR may be common in malignant cells and correlates with neoplastic progression.
Although tyrosine kinase inhibitors (TKIs) and monoclonal antibodies both inhibit EGFR signaling, their mechanisms of action fundamentally differ. Monoclonal antibodies bind specifically and with high affinity to the extracellular domain of the EGFR, competitively inhibiting binding of other growth factor ligands, including the epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α). Another important mechanism of action is antibody-receptor internalization; the EGFR disappears from the cell surface. This prevents ligand-induced autophosphorylation of the EGFR, interrupting the signaling cascade and leading to inhibition of cell growth, migration and metastases, and angiogenesis and induction of apoptosis.[6,7] Monoclonal antibodies may also activate immunologically mediated mechanisms, including antitumor-dependent cellular cytotoxicity and complement-mediated cytotoxicity, although the contribution of this activity to efficacy has not been conclusively demonstrated. By contrast, TKIs bind to the catalytic domain of the EGFR within the cell to block the activation of downstream effectors. Inhibition by TKIs may be either reversible or irreversible, depending on the type of molecule.
Several phase II/III clinical trials have evaluated anti-EGFR therapy in various treatment settings. This article reviews the clinical activity of the TKIs and monoclonal antibodies in CRC, NSCLC, and SCCHN.
Clinical Experience in Metastatic Colorectal Cancer
The majority of the clinical experience with anti-EGFR therapy in metastatic colorectal cancer has been conducted with the monoclonal antibody cetuximab (Erbitux); see Table 1. Phase II trials have shown activity of cetuximab as a single agent and in combination with both irinotecan (Camptosar)- and oxaliplatin (Eloxatin)-based chemotherapy in previously treated patients with metastatic colorectal cancer.[8,9,11,12] Results of a recent phase II trial also show the feasibility and activity of cetuximab plus bevacizumab (Avastin), with or without irinotecan, in patients with metastatic colorectal cancer who failed irinotecan, oxaliplatin, and fluoropyrimidines.
A large, phase II randomized trial conducted by Cunningham et al showed impressive activity alone or in combination with irinotecan in patients with irinotecan-refractory disease. Enrolled patients had documented progression during or within 3 months following irinotecan-based therapy and immunohistochemical evidence of EGFR expression. Patients randomized to cetuximab plus irinotecan achieved an overall response rate of 23%; those treated with cetuximab alone achieved an overall response rate of 11%. The degree of EGFR expression, the number of prior therapies, and previous treatment with oxaliplatin did not affect the activity of study therapy. Treatment was generally well tolerated; the most commonly reported adverse event was skin toxicity. The incidences of diarrhea and neutropenia with irinotecan plus cetuximab were in the range that would be expected with irinotecan alone.
Importantly, the addition of cetuximab to chemotherapy showed modest response in patients who previously progressed on the same chemotherapy regimen, suggesting that addition of cetuximab may overcome treatment resistance in some patients. Correlation of EGFR expression, as determined by immunohistochemistry, with clinical activity of cetuximab is inconsistent. In clinical trials, the degree of EGFR expression as either percentage of cells staining positive or maximal staining intensity per cell did not correlate with response to cetuximab.[8,11] A retrospective analysis has also demonstrated that the activity of cetuximab is similar in both EGFR-negative and EGFR-positive patients, further highlighting the shortcomings of EGFR expression as a selection criterion. A separate retrospective analysis, however, indicated a correlation between increased EGFR copy number as measured by fluorescence in situ hybridization (FISH) and response to anti-EGFR monoclonal antibodies. Response to cetuximab is not dependent on the presence of EGFR mutations.
Several clinical studies have examined whether cetuximab improves the efficacy of the first-line standard chemotherapy regimens FOLFOX (fluorouracil [5-FU]/leucovorin/oxaliplatin) or FOLFIRI (5-FU/leucovorin/irinotecan) in patients with untreated metastatic colorectal cancer. An international phase II study (ACROBAT) has shown that cetuximab improves treatment outcomes when combined with FOLFOX-4 in colorectal cancer patients with untreated, EGFR-overexpressing stage IV disease. Patients administered this combination achieved an overall response rate of 81%, which compares favorably to the 45% observed for FOLFOX-4 alone in the Intergroup 9741 trial. An additional seven patients experienced stable disease, leading to an overall disease control rate of 98%the highest reported to date in any clinical trial for advanced, metastatic colorectal cancer. The safety profile was tolerable, as the addition of cetuximab to FOLFOX-4 did not produce increases in diarrhea or neutropenia.
Clinical data also show the addition of cetuximab to FOLFIRI to be a safe and potentially efficacious first-line regimen for metastatic colorectal cancer. The feasibility of this combination was first demonstrated in two early-phase clinical studies that showed that cetuximab plus FOLFIRI is active and tolerable as first-line therapy in patients with EGFR-positive metastatic colorectal cancer.[21,22] In addition to these initial promising results, a second phase II study has also shown efficacy for cetuximab with FOLFIRI in this setting. Patients with untreated, EGFR-positive disease achieved response and disease control rates of 43% and 88%, respectively. The addition of cetuximab did not exacerbate the safety profile of FOLFIRI.
Based on these promising results, clinical studies are ongoing to evaluate cetuximab in combination with FOLFOX or FOLFIRI in previously untreated patients with metastatic colorectal cancer. A phase II trial is ongoing to determine the efficacy of cetuximab in combination with FOLFOX-6 as first-line therapy in this setting. The Cancer and Leukemia Group B (CALGB) is conducting a phase III study to compare the FOLFOX-4 and FOLFIRI regimens with or without cetuximab. A second ongoing phase III study, CRYSTAL, is evaluating the efficacy of cetuximab in combination with FOLFIRI in previously untreated patients with EGFR-overexpressing disease.
Tyrosine Kinase Inhibitors
Results of three phase II trials of TKIs in colorectal cancer are available (Table 1). Fisher and colleagues evaluated FOLFOX-4 plus gefitinib (Iressa) in previously treated or untreated patients with advanced colorectal cancer. Previously untreated patients achieved an overall response rate of 77%; previously treated patients achieved an overall response rate of 29%. Treatment resulted in considerable grade 3/4 toxicities, including diarrhea (54%), neutropenia (52%), and vomiting (22%), which were all reported at higher incidences than typically associated with FOLFOX-4 alone. A smaller phase II trial of 5-FU/leucovorin/irinotecan plus gefitinib in previously treated patients with advanced colorectal cancer showed minimal activity, with dose-limiting neutropenia and dehydration/metabolic abnormalities. A trial of single-agent erlotinib (Tarceva) in advanced colorectal cancer patients previously treated with irinotecan or 5-FU reported no objective responses.