Targeting HER1/EGFR to Improve Outcomes for Patients With Non-Small Cell Lung Cancer
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by Ulrich Gatzemeier, MD
Use of Biologic Agents for Non-Small Cell Lung Cancer
My topic is the molecular targeted therapy for non-small cell lung cancer, especially concerning epidermal growth factor receptor (EGFR) inhibition.
Chemotherapy for advanced non-small cell lung cancer has only slightly been improved over the past 10 years, reaching a plateau of 35% to 40% 1-year survival. There is no major difference between third generation platinum combinations, as shown in the 4-arm randomized trial published in the New England Journal of Medicine in 2002.
To reach further improvement, novel strategies are needed. An increasing number of patients expect improved survival in the future, as well as improved quality of life. In addition, a lot of patients with poor performance status and morbidity are not candidates for combination chemotherapy. Nevertheless, they ask for therapeutic options. Even in the palliative setting, there is a need for prolongation of the time to progression without symptoms.
To reach this goal, there are different possibilities. Better prevention and screening programs with early detection can probably decrease mortality. The current chemotherapy can be optimized with less toxicity and a better quality of life. We tried to define subgroups of patients who may benefit from different treatment options. Finally, novel targeted therapies can be given or incorporated into present concepts. Pemetrexed, for example, is one of the new compounds that has shown activity in second-line treatment of advanced non-small cell lung cancer. Erlotinib and bevacizumab are molecular-targeted compounds with activity in solid tumors.
There are different biologic targets for this new strategy. The inhibition of the EGFRs is one principle that leads to tumor regression in terms of increased apoptosis. There are others, like inhibition of signal transduction pathways, tumor-associated antigens, proteasomes, cell survival pathways, or angiogenic pathways.
The EGFR can be inactivated by the inhibition of the intracellular domain -- by the tyrosine kinase (TK) inhibitors, erlotinib and gefitinib (Iressa) -- or by the blocking of the extracellular domain by these monoclonal antibodies, like cetuximab. Other compounds are angiogenesis inhibitors like bevacizumab (Avastin). Concerning the signal transduction inhibitors, there are some negative phase III results so far. Cyclooxygenase-2 (COX-2) inhibitors seem promising. Epidermal Growth Factor Receptor Inhibitors in Non-Small Cell Lung Cancer
The use of the EGFR inhibitors can be first or second line (with or without chemotherapy) in advanced disease, despite negative INTACT data; second- or third-line monotherapy after chemotherapeutic failure; or first line in patients with poor performance status or contraindications for standard chemotherapy. We have to prove the activity in neoadjuvant or adjuvant settings in earlier stages. Subgroups of patients who may benefit from these targeted therapies have to be defined, probably by defining clinical features. Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL) trials with gefitinib have shown encouraging efficacy in a subset of patients.
The rationale for EGFR-targeted therapy in non-small cell lung cancer is the frequency of the receptor overexpression, up to 80% in this tumor type. Different tumor models have shown EGFR activation, which initiates a signal transduction cascade that promotes tumor cell proliferation and survival. EGFR overexpression is correlated with poor prognosis of non-small cell lung cancer patients; but there are probably interactions with other signaling pathways and receptors.
The question is: Is EGFR a good target for non-small cell lung cancer? Concerning experimental and clinical data, the answer is yes. Non-small cell lung cancer has a high level of overexpression, compared with healthy tissue. There is no critical function in healthy tissue. EGFR activation plays a major role in the tumor cell growth and function. There is no severe toxicity in clinical trials; and finally, the receptor inhibition can block the downstream activity in vitro. Pivotal Trial Data With Erlotinib
Erlotinib (Tarceva) is one of the compounds that inhibits the TK phosphorylation and is highly selective and potent. In tumor models, the effect is additive when combined with cytotoxic agents, producing stasis and regression in non-small cell lung cancer and other human xenografts. There is no increase in toxicity in combination with chemotherapy. The drug is orally available and well tolerated.
There are different trials with erlotinib under way. The most important trials are listed here. There are 2 phase III first-line trials -- with carboplatin and paclitaxel, and with cisplatin and gemcitabine (with or without erlotinib) -- both trials are closed, and the results will be available at the end of this year. The BR.21 trial is a phase III trial in second-line or third-line monotherapy with erlotinib vs placebo. We will have the results in the first quarter of 2004.
There are some other phase II trials -- one is completed, others are in progress -- of monotherapy with erlotinib in pretreated patients or in bronchioloalveolar carcinoma (BAC). Interesting is the combination phase II trial with bevacizumab.
Bevacizumab is the recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), which has a key role in tumor angiogenesis and maintenance of established blood vessels. In colorectal cancer, this compound improves survival in first-line therapy by 30%. The combination of the inhibition of these 2 different pathways seems attractive.
Here are selected studies of other EGFR-targeted agents. Gefitinib has been investigated in phase II and III, with negative results in the INTACT trials but with positive results in IDEAL 1 and 2. Concerning cetuximab, there are encouraging phase II results, especially our randomized phase II trial that led to a markedly higher response rate, in comparison with cisplatin-vinorelbine alone Non-Small Cell Lung Cancer: The Future
The use of EGFR agents in non-small cell lung cancer is described in this graph. Gefitinib was launched in mid 2002 in Japan and in mid 2003 in the United States. The negative results of INTACT trials were published at the ECHO conference in November 2002 in Nice, France. At the American Society of Clinical Oncology (ASCO) in 2003, gefitinib showed activity in second-line therapy for advanced non-small cell lung cancer. Tirapazamine failed to show efficacy in 2 large randomized trials. The data from erlotinib phase III trials will be available soon.
There are a lot of challenges for the future. First, we have to select the patient group that will benefit from the targeted therapy, by utilizing predictive markers for response. We have to optimize dose and sequence of the EGFR-targeted therapy, probably chemotherapy first and then maintenance therapy. We need surrogate markers of activity. We have to examine the use at different stages, for example, the adjuvant setting.
For the future, hopefully, we can optimize our treatment options for patients with non-small cell lung cancer. Besides the 3 classic options (surgery, radiotherapy, and chemotherapy), there might be other modalities, like EGFR inhibition or angiogenesis inhibition. *** POSTED JULY 27, 2004 *** |
