Small Molecule Tyrosine Kinase Inhibitors with the EGF or HER2 Receptors as a Target
As we briefly touched on in the introduction to targeted therapies, the epidermal growth factor receptor (EGFR) family comprises EGFR itself (also known as human epidermal receptor type 1 [HER1] or ErbB1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). This pathway is present in all normal human cells but is activated in many types of cancer. A thorough discussion of the detailed function of all the members of the EGFR family is beyond the scope of this review and as such, we will be focusing on EGFR itself ([HER1] or ErbB1) and HER2.
HER2 (ErbB2) HER2 is a member of the EGFR family with a well-established role in invasive breast cancers where increased expression has been associated with decreased survival and resistance to commonly employed chemo- and endocrine therapies. Approximately 15-25% of breast cancers overexpress HER2, and tend to grow faster and more aggressively than tumors not overexpressing HER2. Trastuzumab is an antibody used in the treatment of breast cancers that will be more completely explored in Part Two, which discusses antibody targeted therapies.
A significant proportion of data concerning TKIs involves the use of these therapies in lung cancer and that will serve as our starting point. About 170,000 new cases of lung cancer are diagnosed each year in the U.S., and lung cancer is the leading cause of cancer death worldwide in both men and women. There are two main categories of lung cancer: non-small cell lung cancer (NSCLC), which represents about 80% of cases and includes both adenocarcinoma and squamous cell carcinoma. The other category is small cell lung cancer (SCLC), which represents the remaining 20%. This distinction of NSCLC versus SCLC is made based on the appearance of the lung cancer cells under the microscope, as well as their clinical behavior and influences treatment recommendations. Historically, chemotherapy has had a measurable but small impact on survival and despite treatment with surgery, radiation, and chemotherapy, the 5-year overall survival (OS) rate is very low with only 15-20% of patients alive at five years after diagnosis.
Gefitinib (Iressa, ZD1839) and erlotinib (Tarceva, OSI-774) are small molecules that target the EGFR TK and are the two most extensively studied TKIs in lung cancer. It should be mentioned that other targeted therapies are also used in lung cancer, specifically the monoclonal antibodies cetuximab (EGFR) and bevacizumab (VEGF), will be more completely explored in Part Two on antibody targeted therapies.
Non-Small Cell Lung Cancer
More than half of non-small cell lung cancers (NSCLC) express too much EGFR: approximately 50% of adenocarcinomas and nearly 80% of squamous cell carcinomas. Early phase I and II clinical trials with TKIs produced dramatic responses in some patients, several of whom had been resistant to available chemotherapies. IDEAL-2 was a seminal study that led to the FDA's accelerated approval of gefitinib. The full study was published in October 2003 in the Journal of the American Medical Association and was a double blind, randomized, phase II study conducted at 30 U.S. medical centers. As with all phase 2 studies, this one was designed to evaluate 1) objective tumor response (based on decreased tumor size on CT scan); 2) disease-related symptom response; and 3) safety of gefitinib monotherapy. In both this study and IDEAL-1, single agent therapy with gefitinib produced radiographic response in 12%-18% and improved symptoms in 40%-43% of patients with advanced NSCLC who had failed chemotherapy.
Results with TKIs in previously treated lung cancer patients was furthered with the publication of the BR.21 phase III trial in the New England Journal of Medicine in July 2005, in which advanced or metastatic NSCLC patients who had been treated with one or two prior chemotherapeutic regimens were assigned to erlotinib or placebo. This study was the first to demonstrate a significant survival advantage for treatment with an EGFR TKI in NSCLC patients that had previously been treated with chemotherapy. Side effects were typically mild; In BR.21, only 5% of patients had to discontinue erlotinib because of toxic effects.
Tyrosine kinase inhibitors targeting EGFR demonstrate activity in unselected patient populations but consideration of the molecular characteristics of tumors will certainly help us guide costly therapies for those patients most likely to benefit. There have been multiple studies examining features of NSCLC thought to increase the likelihood of a response to TKI-based therapy. These include: adenocarcinoma histology, female sex, non-smoking history and Asian ethnicity. Many of these findings are believed to be due to differences in the frequency of EGFR and K-ras mutations, the former of which are more common in non-smokers and Asian populations. The importance of K-ras mutations will also be explored in the context of cetuximab therapy in patients with colorectal cancer in the following section.
More recently, the single agent therapeutic approach with gefitinib was published in the September 2009 issue of the New England Journal of Medicine as the phase III IPASS trial, which randomized patients with adenocarcinoma of the lung to gefitinib or carboplatin plus paclitaxel. Carboplatin and paclitaxel are a common combination chemotherapy treatment for advanced lung cancer. Patients were included in this study based on perceived therapeutic response to gefitinib, as all patients had the adenocarcinoma subtype of NSCLC and all were either former or light smokers. In this study, at one year, 24.9% of patients on gefitinib were free from progression of disease compared to 6.7% in the carboplatin-paclitaxel group. However, when the investigators looked at EGFR status in these patients, the benefit was restricted to patients with mutations in EGFR. In contrast, those without an EGFR mutation had a significantly shorter progression-free survival with gefitinib (median 1.5 versus 6.5 months), although there was crossover between the two treatment groups. Data from this trial is still maturing but this was a landmark study validating the notion that the presence of EGFR mutations is a strong predictor of response to oral EGFR TKIs. Data regarding clinical benefit were corroborated by two additional phase III trials reported on at ASCO 2009 and in the Journal of Clinical Oncology in February of 2010. These trials, the Sequential Tarceva in Unresectable NSCLC (SATURN) trial and Iressa NSCLC Trial Evaluating Response and Survival versus Taxotere (INTEREST) trial, respectively, demonstrated a benefit in patients with mutations in the EGFR. Future studies will help to clarify the roles that KRAS and EGFR mutation status play in responses and outcomes in patients with NSCLC treated with TKIs, particularly with respect to an overall survival benefit.
In the treatment of lung malignancies, both gefitinib and erlotinib have been evaluated in combination with standard chemotherapies and have failed to demonstrate a survival benefit. INTACT 1 and 2, both phase III trials, were not able to demonstrate a benefit in survival when gefitinib was combined with either carboplatin plus paclitaxel or gemcitabine plus cisplatin. Likewise, the Tarceva Lung Cancer Investigation Trial and TRIBUTE studies failed to demonstrate an improvement using combinations containing erlotinib.
Erlotinib is also approved for the treatment of pancreatic cancers when used in combination with a chemotherapy drug gemcitabine for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer. As is the case with lung cancer, the outcomes for pancreatic cancer are poor, and the disease is the fourth leading cause of cancer deaths. The CONKO-001 trial was a phase III trial published at the ASCO 2008 annual meeting and demonstrated that the addition of gemcitabine following resection of pancreatic cancer significantly increased disease-free and overall survival compared to observation alone. Subsequently, this chemotherapy became the standard of care for these patients, and was combined with erlotinib in an NCI-Canada study published in the Journal of Clinical Oncology in 2007. The combined treatment group demonstrated a statistically significant improvement in survival with the addition of erlotinib, although the absolute improvement could be measured in weeks.
Gefitinib and Erlotinib and Toxicities
One of the more common side effects resulting from agents targeting the EGFR pathway (whether small molecule TKIs or antibodies against EGFR) is an acne-like rash, which is approximately 60% more common than with patients taking placebo. The rash infrequently requires the discontinuation of therapy (only 5% in BR.21), but interestingly, the presence and severity of the rash appear to correlate with treatment efficacy. With gefitinib, other common adverse effects (?1% of patients) include: diarrhea, nausea, vomiting, anorexia, inflammation of the linings of the mouth, dehydration, skin reactions, elevations of liver enzymes, and conjunctivitis or eyelid swelling. Similar toxicities are observed in erlotinib therapy. However, in the spring of 2009, the FDA issued a warning on erlotinib reporting serious gastrointestinal tract, skin, and ocular disorders in some patients taking the drug.
In summary, here is the current FDA approved indication for gefitinib:
- Adults with locally advanced or metastatic NSCLC who have failed platinum-based and docetaxel chemotherapies.
Dosing recommendation for gefitinib: dosing is 250 mg per day.
Here are the following current FDA approved indications for erlotinib:
- Patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.
- In combination with gemcitabine for the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.
Dosing recommendations for erlotinib:
- NSCLC: 150 mg/day.
- Pancreatic cancer: 100 mg/day in combination with gemcitabine.
Note: Active cigarette smoking affects the absorption of erlotinib. For example, Hamilton et al., have published data suggesting there is increased metabolic clearance of the drug in patients who are actively smoking, which may decrease the efficacy of the therapy. Patients should not smoke while receiving erlotinib therapy and may require smoking cessation assistance prior to initiating therapy.
Lapatinib ditosylate monohydrate (Tykerb, GW572016) is an oral dual erbB1/2 TK inhibitor that reversibly inhibits both EGFR and HER2/neu. It became FDA approved in March 2007 for use in combination with an oral chemotherapy agent known as capecitabine (Xeloda), for the treatment of patients with advanced or metastatic HER2+ breast cancer who have already received previous therapy with anthracyclines, taxanes and trastuzumab. Unlike trastuzumab (Herceptin), which is an antibody-based therapy against HER2/neu only, lapatinib possesses activity at both EGFR and HER2/neu, the latter of which is overexpressed in approximately 15%-25% of breast cancers. HER2 overexpression is associated with adverse tumor characteristics and inferior clinical outcomes in breast cancer patients. It is therefore an attractive target for therapeutic intervention, a strategy that had been clinically validated with trastuzumab and which we will explore more fully in the next section on antibody therapies. Lapatinib is currently the only TKI approved for breast cancer, but many others, such as neratinib, are at various stages of development. As such, it will be the focus of this section.
Phase I trials have shown that lapatinib is well tolerated, with mild diarrhea and skin rash as common adverse effects. However, unlike the "pure" anti-EGFR TKIs, there appears to be no correlation between the presence of skin rash and treatment efficacy. Following some early clinicaltrials, a phase III trial was published in the New England Journal of Medicine in December of 2006 with HER2/neu positive metastatic breast cancer (MBC) patients who had receivedmultiple previous treatments, demonstrated that the additionof lapatinib to capecitabine significantly prolonged time to disease progression but there was no difference in overall survival. It should be noted, however, that there was a great deal of crossover between the groups. Ultimately, the studies published to date reveal that the therapeutic effect of lapatinib is predominately limited to patients with HER2/neupositive breast cancer.
Unlike some of the indications for anti-EGFR TKIs, the role of lapatinib for first-line therapy is currently undefined, although some interesting preliminary results have been reported. A phase II study (EGF103009) of lapatinib monotherapy presented at the 2006 ASCO meeting looked at patients with relapsed or refractory inflammatory breast cancer. This study demonstrated that with HER2/neu positive patients, 62% responded with an additional21% of the patients experiencing stable disease (no evidence of progression).
Lapatinib and Side Effects
As we will discuss in further detail in the following section on antibody therapies, the HER2/neu therapy with the longest track record, trastuzumab, confers a risk of cardiac toxicity, particularly when combined with anthracycline-based chemotherapy. Interestingly, a 2006 study presented at the annual ASCO meeting looking at 2812 subjects who had received lapatinib in 18 separate clinical trials, reported a very low incidence of cardiac toxicity (1.3%). This was further explored in a study presented at ASCO 2007, which demonstrated that lapatinib does not appear to increasethe risk of cardiomyopathy, even when used in combination with trastuzumab. However, until more data are available, the use of lapatinib should be restricted to trastuzumab-refractory and chemorefractory HER2-positive metastatic breast cancer, which is the current FDA approved indication for the drug.
Like many small molecule tyrosine kinase inhibitors, lapatinib is generally well tolerated. The most common side effects reported are diarrhea, fatigue, nausea and rash. Some studies have reported a minor incidence of drug-induced hepatitis (liver inflammation), although this is typically reversible when the treatment is stopped.
Here is the current FDA approved indication for lapatinib:
1. In combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab.
Dosing recommendations for lapatinib: 1,250 mg/day on days 1-21 continuously in combination with capecitabine 2,000 mg/m2/day (administered orally in two doses approximately 12 hours apart) on days 1-14 in a repeating 21-day cycle.