Advances in EGFR Inhibitors
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Guidelines for the Practicing Clinician: EGFR-Based Therapies In 2008
The epidermal growth factor receptor (EGFR) has emerged in the past decade as the most validated target in the therapeutic arsenal against lung cancer. We have witnessed the development of effective small-molecule inhibitors of the receptor tyro sine kinase, as well as monoclonal antibody-based therapy that appears effective when combined with standard chemotherapy. These agents have activity when used in three separate "lines" of therapy and may even play a role when given with radiation therapy. Since much has been learned about the biology of EGFR-dependent lung cancer, we are beginning to gain insight into which molecular features of lung cancer might predict for benefit from these agents. From the standpoint of the treating clinician, this is an appropriate time to assess where we are with these drugs and how they can optimally be used to improve patient care. Several key questions are raised by the data on EGFR-based therapy, many of which should find answers in trials that are due to mature soon.
1. Is there a role for first-line use of single-agent tyrosine kinase inhibitors (TKIs) in stage IV non-small cell lung cancer (NSCLC)?
Since the identification of EGFR mutations in 2004, a number of prospective studies have shown benefit from first-line EGFR-TKI therapy in mutation-positive patients. The study by Sequist and colleagues showed a >50% response rate, with a median survival of >20 months.33 However, reasonable concern was raised that EGFR mutation status might only serve as a prognostic factor for better outcome. The IPASS study results have provided clear evidence that first-line TKI therapy should be standard of care. This trial showed that progression-free survival and quality of life were significantly prolonged in patients that harbor EGFR mutations when treated with first-line gefitinib.10 Perhaps more importantly, this trial demonstrated that clinical criteria alone were not sufficient, since outcomes were worse for patients with EGFR wild-type tumors. Currently, standard of care for EGFR-mutated lung cancer patients should be first-line TKI, using either gefitinib or erlotinib. The FDA-approved dose for erlotinib is 150 mg qd. For patients with EGFR wild-type tumors, platinum-based chemotherapy in combination with either bevacizumab or cetuximab is a reasonable standard.
2. How should TKI toxicity be managed?
It is important to be aware of possible toxicities and to manage them expectantly. Toxicity with TKIs, including rash, diarrhea, rare pneumonitis, and rare liver necrosis, is generally manage able. EGFR-TKIs should be taken without food to allow for more reliable absorption. Many dermatologists also recommend the routine use of moisturizers to help ameliorate EGFR-TKI-related rash.
3. How is TKI resistance clinically relevant, and does it influence choice of agents?
We have learned that there are at least three potential mechanisms of acquired resistance to EGFR-TKIs: T790M mutation, c-MET amplification, and IGF-mediated PI3K activation.34,181 There are undoubtedly additional mechanisms that we currently do not understand. Furthermore, the potential exists for some patients to become resistant to an EGFR-TKI through more than one mechanism. The clinical implication is that we will need to work toward developing multidrug combinations, which ideally would start early in the treatment of EGFR- mutated lung cancer.
4. What are the most promising second-generation TKIs, and will they find a niche in NSCLC?
A number of second-generation agents appear promising, including compounds that are irreversible dual kinase inhibitors of both EGFR and HER2. At this point, it is unclear which of these agents will prove to be the most active or useful in lung cancer. It is unlikely that these compounds will see the greatest use as second-line agents but rather as potentially superior first-line drugs for mutation-positive patients. It is not at all clear if these TKIs will have any role in the treatment of EGFR wild-type patients.
Table 4
5. How should cetuximab be incorporated into first-line therapy?
Cetuximab has shown consistent but modest activity in lung cancer when combined with chemotherapy. Data from the FLEX trial support the use of cetuximab when given with cisplatin and vinorelbine as first-line treatment,40 and cetuximab is a reasonable option for chemonaive patients with stage IV NSCLC. Supportive data (in terms of response rate) have been obtained in trials of cetux imab combined with taxanes and gemcitabine,133,135 but these results have not clarified whether cetuximab can prolong survival. (The gemcitabine- based regimen was a randomized phase II, and survival data have not yet reported for the trial using taxanes.) Given that the one trial with a survival advantage used EGFR IHC testing, many feel that use of cetuximab should be restricted to patients with IHC-positive tumors. The hope is that cetuximab, like bevacizumab, eventually will find wide application for multiple chemotherapy platforms in NSCLC.
6. Are there biomarkers that clinicians should be using to choose patients for cetuximab treatment?
In colorectal cancer, we have emerging evidence that KRAS status is crucial in predicting benefit from cetuximab-based therapy.42 There is great hope in examining the role of KRAS, EGFR gene copy number, EGFR mutation status, and EGFR expression in lung cancer. However, it is possible that KRAS mutations in lung cancer patients with tobacco-induced tumors might have very different biology and activity than tumors of the colon. Currently, there is no guidance on the use of biomarkers for cetuximab-based treatment in lung cancer, but the strong hope is that such data will be developed over the next 3 years.
7. How do we approach the use of EGFR-based treatments in second-line lung cancer?
EGFR-TKI therapy with erlotinib has been shown to prolong survival in second- and third-line NSCLC,182 and gefitinib has been found to be equivalent to docetaxel for second-line therapy.144,145,183 At this point, it is very reasonable to consider erlotinib or gefitinib therapy as a standard choice for second- and third-line therapy.
8. What is the optimal way to incorporate EGFR-based therapies in the treatment of locally advanced disease?
It is highly unlikely that erlotinib or gefitinib will prove to have a major role in locally advanced lung cancer. In contrast, cetuximab is emerging as a promising combination with radiation treatment. Trials using cetuximab plus a platinum-taxane135 or platinum-pemetrexed181 combination have demonstrated prom ising preliminary results for patients with stage III NSCLC. These combinations are not yet standard of care, but their ultimate role will be defined in large randomized studies that are currently accruing patients.
9. What should I recommend if a patient initially responds to TKI therapy but then starts to progress?
Patients who show resistance to TKI treatment should be referred to an academic center to consider enrollment in a clinical trial. Selected US trials that are now enrolling patients are listed in Table 4 above.