CHAPTER 15: IRESSA AND EPIDERMAL GROWTH FACTOR INHIBITORS

 (excerpted from  Lung Cancer and Mesothelioma, available November 1, 2004, to order contact the author, or exlibris.com). 

15.0  THE EPIDERMAL GROWTH FACTOR PATHWAY 

    15.01  Normal Cell Signaling 

Duplication of genes is a normal process in the human body.   Proteins called growth factors provide signals for cell replication, but malfunctions in these growth factors are a critical part of cancer.  A basic model of cancer suggests it is is a product of a growth factor prompting unnecesary duplication of cells and the failure of a tumor suppresor gene to regulate them. 

A more sophisticated model suggests cancer presents a complex system with many growth factors, multiple tumor suppresor genes, and damage to other cellular regulators.   As we enter the 21st century we are learning that both models may be correct for different types of cancers- there are simple ones with only a few components of growth and more complex ones with numerous contributing factors.  In the 60's and 70's, we learned that cancers acted differently depending upon their site; today we are seeing that lung cancer represents a heterogenous group of cancers, some of which respond very differently to treatment than others.   We now look to one important growth factor, (EGF) and its treatment. 

     15.02  Epidermal Growth Factor                             

The Epidermal growth factor EGF and its associated receptor (EGFR) play a role in normal human development with function which include repair of damaged tissue and development of new tissue in fetuses.   Klein (49).  EGF is also a  critical factor in various cancers.        

“The epidermal growth factor receptor (EGFR) autocrine pathway contributes to a number of processes important to cancer development and progression, including cell proliferation, apoptosis, angiogenesis, and metastatic spread. The critical role the EGFR plays in cancer has led to an extensive search for selective inhibitors of the EGFR signaling pathway. The results of a large body of preclinical studies and the early clinical trials thus far conducted suggest that targeting the EGFR could represent a significant contribution to cancer therapy. A variety of different approaches are currently being used to target the EGFR. The most promising strategies in clinical development include monoclonal antibodies to prevent ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity to inhibit autophosphorylation and downstream intracellular signaling."  Tartora, (2), See also FDA (1) .  See also (Baselga 24).   

    15.03 EGFR's Inhibition of Normal Apoptotic Processes (elimination of damaged cells)            

The body has mechanisms to deal with chromosome damage, one of which is apoptosis, the elimination of damaged cells.    When activated EGF appears to frustrate that process, and has an anti-apoptotic effect protecting mutated cells from orderly elimination.    EGFR activation seems to promote tumor growth by sending signals for growth downstream, to other cellular regulators and growth factors. 

    15.04 EGF and EGFR  

To initiate cell reproduction, a growth factor links with an associated receptor,
like a lock and key.  EGF links with EGFR, the epidermal growth factor receptor. 

"growth factor receptors are found on the surface of cells and normally play a role in the regulation of cellular growth and differentiation processes. The discovery that these receptors are present in unusually high  numbers in many tumours then suggested that they play a role in carcinogenesis. Various attempts were therefore made to selectively inhibit [EGFR} signalling pathways. In one approach, antibodies that block the extracellular part of these receptors were developed, while another approach resulted in the development of low-molecular-weight substances known as cell signalling inhibitors that block the intracellular part of the receptors." 

In recent years, the receptor rather than the growth factor itself has become the target of new drugs.  

15.1 THE STRUCTURE OF EGFR  

      15.11 Receptor Structure  

The receptor has two basic parts.  The first part is called the extracellular ligand-binding domain.  There the receptor receives a signal from a growth factor and a process called ligand binding occurs.   
Once binding occurs, a signal is sent to the second part of the receptor called the tyrosine kinase domain.  and a process called autophosphorylation occurs.    A chemical change occurs and signals are sent to other cells:   "In each receptor a molecule of adenosine triphosphate (ATP) becomes attached and an energy-rich phosphate group is transferred to the  amino acid tyrosine.  Activation of tyrosine kinase and phosphorylation of tyrosine residues (see Fig. 2) leads to activation of intracellular signalling pathways."
Roche (61).  

    15.12 The tyrosine kinase portion of the receptor 

What does the tyrosine kinase do, 

"Tyrosine kinases are proteins that can attach a phosphate group to the amino acid tyrosine. This action  serves at least two basic roles: It allows two proteins to bind to one another, and it can serve as a switch that turns a function on or off.  Thus, tyrosine kinases act like small keys that can regulate a cascade of events, including cellular division. Tyrosine kinase can be a freestanding enzyme within a process or it can be associated with a receptor that is a trigger for a cascade of processes -- aptly named a tyrosine kinase receptor. A receptor is simply a docking point for an outside chemical, much like a docking port for the space shuttle on the space station."  Tyrosine Kinase (66). 

In cancer, the signals generated by this chemical process are abnormal, and other cells are told to duplicate or perform other aberrant functions.  Tyrosine kinases are becoming a primary target for cancer research:   

"Cancer is characterized by successive changes in cell behavior caused by accumulated genetic alterations.  Two kinds of cellular changes are particularly important in cancer pathology. First, the cell division cycle becomes deregulated, causing overproliferation and tumor growth.  Second, these transformed cells may gain mobility: they lose contacts with their neighbors and the extracellular matrix (ECM), become motile, crawl into the circulatory system, and crawl out at a new location distant from the original tumor. This mechanism accounts for metastasis, the systemic spread of cancer.

Both of these pathological behaviors are controlled by cell signaling pathways that employ tyrosine phosphorylation as a molecular on/off switch (Hunter, 1998). Numerous oncogenes encode overactive mutant forms of protein tyrosine kinases (PTKs), whose normal counterparts regulate cell division and differentiation in response to extracellular signals. PTKs also contribute to regulation of the cytoskeleton and cell adhesion systems that determine whether a cell will remain in place or migrate."
Cancer pathology & tyrosine phosphorylation (65). 

Cancer drugs can work in two basic ways, they can try to prevent binding, or autophosphorylation.   The fact that there are two separate functions means that drugs may later be combined, and anti-EGFR drugs are likely to have different degrees of effectiveness depending upon the specific area of cell damage in the epidermal growth factor receptor.   

   15.12 The EGF Family of Receptors

EGFR is part of the Erb family of receptors, and is also called Erb1.   There are four receptors in the Erb receptor family, Erb1, 2, 3, and 4. 

It would be simple if there were a single growth factor and single receptor.  Unfortunately the human body is far more complex.  Multiple growth factors can contact EGFR to initiate signalling.  The primary one we address here is the epidermal growth factor.  In a simple model, EGF contacts EGFR.  In a more complex but accurate model, other growth factors may contact EGFR, and when binding occurs, EGFR will send signals to other members of the Erb family, "cross-talk." 

15.2 CLINICAL TRIAL RESULTS 

    15.21 Initial results and grouping 

Initial studies with Iressa found that about 12% of patients achieved a partial response, that is, reduction of 50% of the tumor.   More patients found their diseases stabilized.  FDA Trial 16 found about 35% of patients  experienced disease stabilization .  FDA 1).   In addition to extending life, the drug improved quality of life, with one third of patients reported relief of at least one pulmonary related symptom. FDA Advisory Committee (1).   Funokuora, reported symptom improvement rates of 40.3%  and 37.0% in his study. "  (45).   Nonetheless, Iressa did not significantly extend life for most patients, though disease stabilization and symptom relief were clearly important. 

Based upon these studies, the FDA approved Iressa for third line treatment of non-small lung cancer.  That is Iressa would be recommended after two types of chemotherapy were no longer effective.    Chemotherapy has response rates of about 20%.   Because these response rates were higher than Iressa's 12%, the new drug could not be recommended for routine treatment.  Nonetheless Iressa was reported to improve symptoms and stabilize disease in some patients along with providing responses in some.    Therefore, Iressa was approved as third line therapy, to be used after platinum based chemotherapy (Cisplatin or Carboplatin) and Taxol.    While the FDA's recommendation is important, physician can prescribe the drug off label, in other ways.    Further studies reported in 2003 and 2004 have provided important information about who is likely to benefit from Iressa. 

  15.22 Who Responds to Iressa  

The category non-small lung cancer includes adenocarcinoma, squamous cell carcinoma, large cell cancer, and a host of subgroups within these categories.    In the past 40 years, many similarities among these types were found, particularly their responsiveness to radiation, chemotherapy, and surgery.    Non-small cell lung tumors share the common characteristic of behaving differently than small cell cancers.   Within the non-small category, treatment has been essentially the same for all three types for the last half century.   This may change with Iressa. 

Recent studies found that patients with bronchioloalveolar lung cancer (BAC), a subtype of adenocarcinoma, particularly seemed to respond to Iressa.  Additionally, non-smokers with lung cancer also benefited: 

1) The first study was published in the prestigious New England Journal of Medicine (56, full-text available online at no charge).    Nine patients were found to respond to Iressa.  Four had BAC, a subtype of adenocarcinoma while five had adenocarcinoma itself.   None of those who responded had squamous cell or large cell lung cancer.   None of the responders were smokers, six had never smoked, while 3 were former smokers.   Lynch (55).  For the 9 who responded, mutations were observed in eight clustered within the tyrosine kinase domain of EGFR.    Iressa inhibits autophosphylation from the tyrrosine kinase which helps explain why the drug would be effective with patients having tyrosine kinase cellular malfunctions.  

2.  A second study also found that response to Iressa could be predicted by the existence of abnormalities in the tyrosine kinase region of the EGFR:  "While sequencing of the kinase domain (exons 18 through 24) revealed no mutations in tumors from the four patients who progressed on gefitinib, all five tumors from gefitinib (Iressa)-responsive patients harbored EGFR kinase domain mutations."  Paez (56)

The authors then tested tissue from lung cancer patients and found the type of damage to the tyrosine kinase to be relatively rare.    Only one of sixty one randomly selected patients had it.   However, almost all who responded to Iressa had it.    Cell analysis confirmed the efficiency of Iressa.  When cells from patients with the defect were tested, Iressa was effective at 100 milligrams.   However, 100 times the dosage was required to duplicate that response with other cell lines.   Paez (56).   Genetic testing of patients to determine whether they are likely to respond to Iressa makes sense.  The how, why, and cost of such testing remains to be determined. 

Other studies have shown similar results.   In one study, non-smokers had a response rate of 29.4% (10/34) compared with 4.6% (5/108) for smokers. FDA (1) (43).  In Wong's study, "6/7 responders were non-smokers."  FDA Center (48, at 7),   In Shah's study, "bronchioalveolar carcinoma and having never smoked were the only predictors of response."   FDA Center (48, at 7).   

 Study Name                          Responses to Iressa           Cellular Characteristics       Characteristics of                 Importance                                                                                                                                                            Non-responders                   the  Study 

Lynch, Specific Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non-Small-Cell Lung Cancer to Gefitinib. The New England Journal of Medicine (online April 29, 2004).  9 patients benefit, 4 with BAC, 5 with adenocarcinoma  responders had detectible mutations in the kinase region of EGFR 0 patients with squamous or large cell had responses.  Initial study finds that BAC and adenocarcinom patients benefit from Iressa and have specific defects in tyrosine kinase domain. 
Sloan Kettering Study 
Pao, EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib, PNAS | September 7, 2004 vol. 101  no. 36  13306-13311
"Nine of 12 (75%) mutation-positive tumors in this study had adenocarcinoma histology and were derived from never smokers." 
" mutations in the TK domain of EGFR are common in surgically resected NSCLCs derived from never smokers but infrequent in former or current smokers.  We  sequenced exons 2-28 of EGFR from  81 primary NSCLCs derived from former or current smokers, and 24 tumors had squamous cell histology.   Four of 81 (5%) had mutations in the EGFR TK domain; . Interestingly, among the four tumors with the L858R mutation, three (specimens 65, 98, and 134) arose in patients with a limited exposure to cigarette smoking: all three had smoked ≤1 pack per day for 9 years (9 "pack years") and had quit at least 30 years before surgery

 

None of eight Iressa-resistant  tumors contained mutations within exons 18-24 of EGFR."   Found non-smokers 
and very light former smokers had tyrosine kinase mutation, few  found in smokers.  Identified  specific genetic area where response is likely to occur. 
         
Asco Annual Meeting Presentation Summary  Summarizes the studies listed above.    -   - Study were presented by the Society of Clinical Oncologists, underscoring their importance and significance. 
         

15.24 Implications for BAC and Adenocarcinoma Patients

A clear pattern is arising.   Iressa is very effective with patients with tyrosine kinase defects.  Nonsmokers, patients with BAC, and some adenocarcinoma patients appear to have that genetic damage, it plays a prominent role in their cancers, and Iressa is effective for a substantial percentage.   The response rates for BAC patients and nonsmokers far exceed those with chemotherapy or radiation.  
Nonsmokers are unlikely to have the extensive genetic abnormalities affecting growth factors, receptors, and tumor suppressor genes that smokers have.   Instead their tumors appear to be largely egfr driven, and for some, Iressa the silver bullet that attacks the specific abnormality.  For non-smokers and brief former smokers, a single or small number of gene abnormalities is causing or prompting their cancers.   Thus, if that area of damage can be identified and addressed, the prognosis may be good.   

    15.241 Should Iressa be First-Line Treatment for BAC Nonsmokers and Adenocarcinoma patients

Physicians will need to investigate whether Iressa should be first-line treatment for patients in this group.  Currently Iressa is recommended as third-line treatment after two forms of chemotherapy.   See FDA (1).   However, Iressa's 35-40% response rates with certain groups drawfs the 20% response rates found in chemotherapy.   Additionally, since Iressa targets only a specific kinase, it generates far fewer side effects that chemotherapies which impact a large number of dividing cells. 

Whether oncologists will accept these results and prescribe Iressa first-line for BAC and adenocarcinoma patents, particularly nonsmokers, remains to be seen.   Some will follow the current FDA recommendations which recommend Iressa as third-line treatment, and wait for a pronouncement from a major organization before adopting a different approach.   Major research institutions may be more agressive and innovative in treatment strategies.  Patients will have some tough decisions and may switch oncologists to obtain what they see as the most beneficial treatment. 

    15.242  Insurance Questions

Insurance issues will arise.   The studies indicate cell testing can predict who is likely to respond to Iressa.   Will insurance pay for such testing.  Since that test is not publicly available, the cost is uncertain. 

15.25 Iressa and  Squamous cell and Large Cell patients. 

Results are discouraging for squamous cell and large-cell patients.  Few responses came in these two groups and the pattern of genetic damage in the tyrosine kinase region does not appear to be generally present in squamous cell or large cell patients.   

The FDA recommendation and findings would seem accurate for these groups.  That is, Iressa is third line treatment to be used after two forms of chemotherapy are no longer effective.  The overall response rate for Iressa was about 11%, we now know that the rates are appreciably higher for certain forms of cancer, and correspondingly lower for squamous cell and large cell.  For the squamous cell and large cell groups, Iressa may stabilize disease  and relieve symptoms.  This is presumably because EGF plays some role in cancer spread, but not a critical or dispositive one for these patients. 

An Asco presentation (American Society of Clinical Oncology) suggested there are three groups involved with Iressa response.  First are adenocarcinoma and BAC patients, none and former light smokers with tyrosine kinase damage, who will substantially benefit from Iressa, secondly, squamous cell and other patients may secure a modest benefit from Iressa, and thirdly those with properly functioning egfr but other abnormalities who will receive no benefit from Iressa. 

    15.251 Other Forms of Treatment

Some of these patients may look to other forms of treatments.  If the patients do not have the defect in the tyrosine kinase region, a tyrosine kinase treatment seems misdirected.  For EGFR treatment, they might consider Tarceva which attacks the binding process or other drugs.  Perhaps their cancers are not primarily EGFR driven in which case other types of treatment like cox-2 inhibitors and anti-angiogenic drugs are preferable.  More research is needed.  In the upcoming months, cell tests may be developed, and drugs could be tested in a laboratory rather than on the patient. 

15.26 Duration of Response     

For patients of all types, when can a response be expected?  Trial 39 reported, "the majority of patients (72%, 16/22) who achieved a response did so by the third (4 patients) or fourth week (12 patients); 3 patients a response by week 7, 1 by week 12, and 2 by week 16. FDA (46).  The final FDA report likewise concluded that those who benefit do so relatively quickly: 

"Many patients had a prospectively defined improvement in disease-related symptoms: the symptom improvement rates were 40% in IDEAL 1 and 43% in IDEAL 2. Symptom relief was rapid: the median time to improvement was 8 days in IDEAL 1 and 10 days in IDEAL 2 (the times of the first post-baseline assessment for each study).   

There was a significant improvement in disease-related symptoms in most patients with a partial/complete response or stable disease in the FDA Ideal studies.  Natale (8).

 15.27 Dosage

Optimal dosage remains unclear.  Some studies reported no significant increase in efficacy from 250mg to 500mg.   The FDA evaluated both 250 mg (milligrams) per day and 500 mg dosages, but reached no clear conclusion.   In their studies, the efficacy was similar between two dosages with some fewer side effects at the lower dose.    FDA (46), at 51.  The FDA also noted a higher response rate for women than men.  More women experienced tumor responses at either the 250-mg/day and 500/mg day doses."  (FDA 47).  In trial 39, the response rate (diminution of 50% tumor volume) for women was 17.5% but 5% for men." FDA statistical review, 48 at 4.  Janne found all those who had responses were women.   FDA statistical review.  FDA Approval Package at 62.   

15.3 IRESSA AND CHEMOTHERAPY AND RADIATION

15.31 Complimentary impact seen in cell and animal studies

The use of different drugs in combination has become standard in treating lung cancer. Logically one could believe that Iressa would compliment chemotherapy and there are cell studies supporting that hypothesis:

“ The cooperative growth inhibitory effect of cytotoxic drugs and ZD 1839 was shown to involve the induction of apoptosis (cell death). In fact, treatment with ZD 1839 potentiated cytotoxic drug induced apoptosis by approximately 2 to 3.5 fold... Studies have also used ZD 1839 and cytotoxic drugs (paclitaxel, topotecan or raltitexed) in vivo in murine models of human tumors. A cooperative antitumor effect was observed with each combination; there was a significant suppression of tumor growth and prolonged survival. This effect was most pronounced with the ZD 1839 plus paclitaxel cogitation.“ Ciardiello (13).  Studies showed Iressa reduced or eliminated at a considerable percentage of solid tumors on laboratory mice, and also reduced other factors associated with cancer. Fortunate (12). While commentators suggested that Iressa would improve chemotherapy’s effect, a positive result was not demonstrated in a recent clinical trial. 

15.32 Human Clinical Trials Using Iressa and Chemotherapy Failed to Demonstate a Benefit from the Combination

Two large scale clinical trials found Iressa did not improve the effects of chemotherapy.  (50).  The well-publicized clinical trial compared patients who took chemotherapy and Iressa with those who took chemotherapy alone.  The group taking the combination did no better than the group using chemotherapy alone.  Rates of survival, partial response, and complete response were similar between the two experimental groups using 250mg and 500 mg Iressa + chemotherapy, versus the control group taking chemotherapy alone with placebo. 

15.33 Explanations and Conclusions

The lack of benefit may be a product of a plateau effect known in other areas where the addition of new drugs does not significantly improve results. For example, adding a third chemotherapy drug to patient’s treatment does not significantly improve response rates or survival. The patients were in a group with very advanced cancer, so either chemotherapy alone or with Iressa could provide only limited help.   The study was limited to patients with advanced lung cancer.  It remains to be seen whether earlier intervention with a combination of chemotherapy and Iressa would be beneficial to patients with less advanced disease. 

15.4 SIDE EFFECTS

    15.41 Rash


The most prevalent side effect is a localized rash. Patients have reported it but it appears to be localized and not unusually serious.  Additionally, some studies have found the existence of a rash indicates Iressa is working with patients with rashes having  longer survival rates, though other studies found no impact.  (53) 

        15.411 Treatment of the Rash. 

Some suggest a moisturizing product is helpful in addressing the rash.  At a non-small cell lung cancer newsgroup, patients and care-givers discuss dealing with drug side effects and offer suggestions.
See www.acor.org

    15.42 Diarrhea

Diarrhea though not particularly severe has also been reported.   

    15.43 Pneumonitis

One serious side effect has been an unusual form of pneumonia. Pneumonia is associated with lung cancer and chemotherapy generally. However, there have been a series of pneumonitis deaths linked to Iressa initially reported in Japan:
“We assessed four patients who had non-small cell lung cancer causing severe acute interstitial pneumonia in association with gefitinib. Although two patients recovered after treatment with steroids, the other two died from progressive respiratory dysfunction. On the basis of autopsies and bilateral distribution of diffuse ground-glass opacities in chest CTs, we diagnosed diffuse alveolar damage, which was consistent with acute interstitial pneumonia. Patients with interstitial pneumonia also had other pulmonary disorders such as previous thoracic irradiation and poor performance status. Physicians should be aware of the alveolar damage induced by gefitinib, especially for patients with these characteristic features.” Inoue (22)

    15.431 Presentation of Pneumonitis 


FDA describes the onset this way, “patients often present with the acute onset of dypnea (difficulty breathing), sometimes associated with cough or low-grade fever, often becoming severe within a short time and requiring hospitalization.” FDA (1).

    15.432 Monitoring

Careful monitoring for this side effect has been recommended. Patients on Iressa should monitor temperature rises, fevers, and immediately report problems to their oncologist. FDA suggests that “persons with concurrent pulmonary fibrosis have a higher mortality rate. This would presumably includes people with silicosis, asbestosis and similar fibrotic disease.

15.5 OTHER EPIDERMAL GROWTH FACTOR THERAPIES

15.51 Tarceva 

Tarceva ( also called OSI-774 or Orlotinib) is a less publicized epidermal growth factor inhibitor.  Like Iressa, it is directed to the tyrosine kinase portion of the epidermal growth factor receptor.   A phase 1 clinical trial reported, “OSI-774 was well tolerated, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease.” (17).   One study found a 12% response rate with symptom improvement, findings similar to Iressa.   Perez-Soler (59).   Like Iressa, the occurence of a rash correlated with response to the drug.    

An important study compared Tarceva with a placebo and found it improved survival. Asco  (63). 

 15.511 Who is Likely to Benefit  

Initial results are similar to Iressa, with a response rate of  9%, a small bit lower than Iressa but within the range of chance.  As with Iressa, non-smokers seem to benefit most with Iressa.   25% of non-smokers responded compared with 4% of smokers.   Asco (63).   For smokers, the survival rate was almost the same with or without the drug.  See Asco (63) citing Tribute trial.   

    15.512 Asco report of Tribute trial. 

The percentage of adenocarcinoma responders was 14% compared with 4% for other.   Women had a 14% response rate compared with 6% for men.   Interestingly, performance status, a measure of how sick the patient is as indicated by mobility and like factors was not a significant factor.   As with Iressa, there appears to be a narrow group of non-smokers with adenocarcinoma who benefit greatly from Tarceva.   As the other end, smokers with squamous cell cancer and normal functioning EGFR seem to benefit little if at all.  In the middle, there seems to be a group who have a modest benefit in disease stabilization, and a mild increase in survival, with that group perhaps having small abnormalities in EGFR, or multiple growth factors.  

    15.513 Side Effects

An important blind trial assessed side effects, with patients not knowing whether they were being given placebo or Tarceva.  Many side effects were reported including anemia, vomiting and fatigue.  However, the results for most side effects were essentially the same for placebo and drug.  

Two were significant.  Again, patients reported a rash at substantially higher rates.  Diarhrea was higher with the drug.   Patients participating in the Acor online newsgroup reported though that it could be controlled.   

    15.514 Chemotherapy + Tarceva 

One study showed no substantial benefit from adding Tarceva to chemotherapy, mirroring results with Iressa.  Asco (63).  

 However, favorable results were reported with a combination of Bevacizubak and Tarceva.  (Asco (63).  The 51% one year survival rate was higher than the 34% one year rate reported in the Tarceva trial alone.  

    15.515 FDA Status 

An application has been submitted to the FDA, with a presentation similar to Iressa focusing on disease stablizationa and symptom relief.  Since its mode of action is similar to Iressa, it is unclear what Tarceva does that Iressa does not.     

15.52 Erbitux 

Erbitux (IMC-C225 or Cetuximab) is  a monoclonal antibody (Maps) directed against ligand binding in the extracellular domain of EGFR.   While it is an epidermal growth factor inhibitor like Iressa, it has a different mode of action, since it prevents ligand binding rather than autophosphylation.   Erbituz has been used with colon cancer.  (58)   

    15.521 Erbitux and chemotherapy

Adding Iressa to chemotherapy provided no additional efficacy.  However, the combination of Erbitux and chemotherapy did create higher response rates in a clinical trial.   

Cetuximab, inhibits tumor growth and is synergistic with chemotherapy and radiation. Cetuximab has been studied in combination with chemotherapy in previously untreated metastatic NSCLC. The response rates in preliminary reports range from 29% to 53%. In patients with refractory/recurrent NSCLC, the combination of docetaxel and cetuximab resulted in a promising response rate of 28%, higher than the typical response rates seen with docetaxel monotherapy in this setting. Addition of cetuximab to chemotherapy is generally well tolerated. Molecular mechanisms predicting response to cetuximab therapy are currently not well understood. Studies are ongoing to assess the single-agent activity of cetuximab in metastatic NSCLC.   Mattar (56). 

    15.552 Erbitux and Chemotherapy for Squamous and large cell patients 

As we saw above, squamous cell and large cell patients generally had few responses from Iressa.  These patients generally did not have the tyrosine kinase damage that is the hallmark of the non-smoker BAC lung cancers that responded to Iressa.   For squamous cell and large cell patient, Erbitux  should be considered since its mode of action may conceivably be more effective against these cancers.  More research is needed and how much weight a single clinical trial should be given is difficult to say.  

15.53 Herceptin

Herceptin (Trastuzumab) has been FDA approved for metastatic breast cancer. The drug targets Erb2 which is a “molecular marker of ductal breast cancer although it is overexpressed in other adenocarcinomas as well (e.g. endometrial, colorectal and lung cancers).” While drug effectiveness is organ specific, lung, colon, and breast are categorized as solid tumors and have some common characteristics. For example, the chemotherapy drug Taxol is used for both breast and lung cancer.

    15.531 Basis for FDA Approval of Breast Cancer


“The safety and effectiveness of Herceptin were studied in two trials with women whose metastatic breast cancers produced excess amounts of HER––2. In one clinical trial, women received either Herceptin and chemotherapy or chemotherapy alone. The women who received Herceptin and chemotherapy had slower tumor growth, greater reduction in tumor size, and longer survival than the women who received chemotherapy alone. In another trial, women received Herceptin by itself. In 14 percent of these women, the tumor got smaller or disappeared. Scientists continue to study the safety and effectiveness of Herceptin in clinical trials.”
The FDA has not approved Herceptin for lung cancer. Since it is an FDA approved drug, a few physicians might consider it for lung cancer. The role of Erb2 in lung cancer is unclear. A 2002 report found that patients who overexpressed erb2 had poorer survival. Predictive Role of Her-2 (30).

    15.533 Side Effects of Herceptin

The National Cancer Institute provides this list of side effects for breast cancer patients taking Herceptin, Side effects that most commonly occur during the first treatment with Herceptin include fever and/or chills. Other possible side effects include pain, weakness, nausea, vomiting, diarrhea, headaches, difficulty breathing, and rashes. These side effects generally become less severe after the first treatment with Herceptin. (NCI) (31).  There were also a small number of reports of heart problems.

15.54 CI-1033

Iressa is designed to inhibit one specific epidermal growth factor receptor at erb1. A new drug developed by Pfizer, CI-1033 was created to inhibit the entire family of receptors at erb-1, and erb-2-4.

"The erbB receptor family is part of the receptor tyrosine kinase superfamily and consists of four members, erbB-1, erbB-2, erbB-3, and erbB-4. A majority of solid tumors express one or more members of this receptor family, and coexpression of multiple erbB receptors leads to an enhanced transforming potential and worsened prognosis. The erbB receptor family has been shown to play an important role in both the development of the normal breast and in the pathogenesis and progression of breast cancer. Receptor overexpression has also been shown to be a negative prognostic indicator and to correlate with both tumor invasiveness and a lack of responsiveness to standard treatment. Clinically, blockade of the erbB-2 receptor has recently been shown to provide benefit in a subset of chemotherapy-resistant breast cancer patients. CI-1033 is an orally available pan-erbB receptor tyrosine kinase inhibitor that, unlike the majority of receptor inhibitors, effectively blocks signal transduction through all four members of the erbB family. In addition, it blocks the highly tumorigenic, constitutively activated variant of erbB-1, EGFRvIII, and inhibits downstream signaling through both the Ras/MAP kinase, and PI-3 kinase/AKT pathways. CI-1033 is also unique in that it is an irreversible inhibitor, thereby providing prolonged suppression of erbB receptor-mediated signaling."

    15.541 Side effects

If targeting one receptor has caused only limited side effects, targeting the family of receptors seems to have increased adverse effects.  A study reported about a one forth of patients experiencing nausea, vomiting or diarrhea.   (Asco 33)

    15.542 Irreversibility

It appears the impact upon epidermal growth factors is irreversible.  (34).  That fact may indicate it is more powerful, but should be used only on patients with advanced cancer. 

15.55 Relationship between EGFR and Erb2

Some preliminary studies have found that two or more of the epdimeral growth inhibitor drugs can be used together with increased effectiveness. Normanno (26). EGFR or Erb1, the target for Iressa, and Erb2, the target for Herceptin, are part of the Erb family. Some suggest that activation of Erb-1 may prompt or coincide with activation of Erb2. “ Co-expression of EGFR and its ligands has also been found in primary breast carcinomas, suggesting that an autocrine loop may be operating in these tumors.” Given that the two receptors are related, using two drugs to target the combination makes logical sense.

15.6 COMBINING DRUG THERAPIES 

15.61 Iressa and Chemotherapy 

Surprising and disappointing many, Iressa and related therapies have not improved the efficacy of chemotherapy according to two clinical trials.  

15.62 Combining two types of Epidermal Growth Factor Treatments

Combining two types of drugs makes sense particulary among those patients without a clearly identifiable tyrosine kinase defect.  Some have found success with dual treatment in cell studies.  

The combined treatment with gefitinib and cetuximab resulted in a synergistic effect on cell proliferation and in superior inhibition of EGFR-dependent signaling and induction of apoptosis. In a series of in vivo experiments, single-agent gefitinib or cetuximab resulted in transient complete tumor remission only at the highest doses. In contrast, suboptimal doses of gefitinib and cetuximab given together resulted in a complete and permanent regression of large tumors. In the combination-treated tumors, there was a superior inhibition of EGFR, mitogen-activated protein kinase, and Akt phosphorylation, as well as greater inhibition of cell proliferation and vascularization and enhanced apoptosis. Using cDNA arrays, we found 59 genes that were coregulated and 45 genes differentially regulated, including genes related to cell proliferation and differentiation, transcription, DNA synthesis and repair, angiogenesis, signaling molecules, cytoskeleton organization, and tumor invasion and metastasis.Conclusions: Our findings suggest both shared and complementary mechanisms of action with gefitinib and cetuximab and support combined EGFR targeting as a clinically exploitable strategy. Mattar (57)  

Given the limited limited response to Iressa among squamous cell and large cell patients and tolerability of EGFR drugs, a combination makes sense for these groups.  For these groups, Iressa is unlikely to provide significant relief, while a drug combination holds forth that possibility. 

15.63 Iressa and Cox-2 Inhibitors 

Celebrex is a Cox-2 inhibitor.   Since Cox-2 plays an important role in lung cancer, scientists have looked at combining the two treatments. 

"In this study, we have evaluated the possibility of obtaining a control of tumor growth without using cytotoxic drugs, by the combined blockade of EGFR, PKAI, and Cox-2 three molecules that interact in nodal points of distinct yet related signaling pathways. To translate this hypothesis in an experimental setting, we have used three novel agents with specific properties, including oral activity: the selective EGFR tyrosine kinase inhibitor  ZD1839; a hybrid DNA/RNA MBO AS-PKAI; and thee Cox-2 inhibitor   SC-236. All these agents have demonstrated antiproliferative and antiangiogenic properties in different tumor models, alone and in combination with cytotoxic drugs.

We have demonstrated, in human colon and breast cancer cell types, that these agents in combination have a cooperative growth inhibitory effect, achieving maximal activity when the three agents are used together, even at very low doses. The antitumor effect is accompanied by down-regulation of the expression of Cox-2 as well as of VEGF and bFGF angiogenic proteins. Moreover, secretion of VEGF (a growth factor connected with metastasis) in the CM was inhibited by combined treatments."

15.7 CELL TESTING 

15.71 The Harvard EGFR Test 

The Harvard Gene laboratory is now offering a test to detect EGFR mutations.  Their press release states: 

The Harvard Medical School - Partners HealthCare Center for Genetics and Genomics (HPCGG) has begun to offer a test that gives doctors a valuable new tool to guide the treatment of certain lung cancers. The test – known as EGFR Kinase Domain Sequencing – was developed in cooperation with the pathology laboratories of Brigham and Women’s Hospital and Massachusetts General Hospital, and detects mutations in a critical part of the gene called epidermal growth factor receptor (EGFR). The gene mutation is present in a subset of non-small cell lung cancers, most commonly adenocarcinomas and bronchoalveolar carcinomas arising in nonsmokers. When the mutation is present, it is associated with a response to the anti-cancer drug Iressa (gefitinib). Iressa works by blocking the function of the mutant EGFR protein that these cancer cells need to survive and proliferate.

Last April, two teams of investigators – one led by Thomas Lynch, MD, and Daniel Haber, MD, PhD, at Massachusetts General Hospital, and one by Bruce Johnson, MD, William Sellers, MD, and Matthew Meyerson, MD, PhD, at the Dana-Farber Cancer Institute – discovered the molecular marker that identifies lung cancer patients whose tumors will respond to Iressa. Until then, doctors had been unable to understand why Iressa caused tumors to shrink significantly in only 13.6 percent of patients, even though some of those responses were rapid and dramatic. The discovery of the EGFR mutation provided the answer.

Now, less than six months after the gene mutation discovery, the HPCGG Laboratory has prepared a molecular test to screen lung cancer tumors for the mutation. The test, which takes approximately two weeks to complete, involves extracting DNA from a tumor tissue sample. The test is significant because it gives doctors the information they need to decide which patients may benefit from Iressa at the earliest possible time, within weeks of diagnosis.

The MGH and DFCI investigators have applied for a patent for the test and are in the process of licensing the EGFR test to a commercial diagnostic partner so that it can be performed throughout the country and eventually the world. In the meantime, HPCGG will continue to offer the test through its Cambridge lab

It appears the test will cost  $895.00.  What type of sample is needed is unclear, though samples from a standard bronchosopy may be sufficient.   One can presume cost will decrease, health care insurers will arrange for volume discounts, and other laboratories will develop similar tests.    At this time, doctors and patients will want to consider tests to identify the treatment most likely to benefit them.  Basically, adenocarcinoma and BAC patients, particularly non-smokers  and light former smokers will want to consider Iressa and have the test to confirm tyrosine kinase mutations.   Smokers with squamous cell cancer may want to use the test to exclude Iressa, or use it in conjunction with other drugs. 

ame of Drug        Mechanism of Action     Area of Success          Area of Failure            Questions 

Iressa  Inhibits tyrosine kinase portion of EGFR  Adenocarcinoma, BAC, nonsmokers, patients with defined damage to tyrosine kinase binding area of EGFR.  For others,t the drug  appears to stabilize disease and relieve symptoms for a moderate period of time, generally less than 18 months. .    Smokers, swquamous cell cancers, patients without damage to tyrosine kinase.    1. Will patients without tyrosine kinase damage benefit from the drug. 
Tarceva  Similar to Iressa, Inhibits tyrosine kinase portion of EGFR  Less data than Iresa but appears to have similar findings, helping adenocarcinoma, BAC nonsmokers with tyrosine kinase damage.  Similar to Iressa.  1. Are there any significant differences from Iressa. 
Erbitux (IMC-C225 or Cetuximab) Prevents ligand-binding of the EGFR   A study found that Erbitux combined with chemotherapy had better survival than chemotherapy alone.  This is contrasted with studies finding Iressa added to chemotherapy did not improve survival.  The reasons for the difference remains unclear.   Erbitux has been FDA approved for colon cancer, and can be prescribed off-label for lung.   Limited data with lung cancer.   1. Should this drug be used in areas where Iressa is not successful.  

2. Will a drug combination make sense. 

         

 

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Comments are welcomed and may be included in revisions of our book.  howian@aol.com This article is not intended to provide medical advice and for treatment, please see your doctor.

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