IRESSA (ZD1839) REVIEW and EPIDERMAL GROWTH FACTOR INHIBITORS

1.0 SUMMARY 

While the nature of cancer is complex, scientists believe cancer begins and spreads through growth factors which prompt improper cell duplication.   The epidermal growth factor (EGF) is one of the stimuli to this cell duplication.  The process begins when EGF connects to a receptor (EGFR).   By preventing this connection,  Iressa aims to show the cancer process and has shown   promising results in some clinical trials for non-small cell lung cancer . 

In one trial, 4 of 16 nsclc patients had a partial reduction in tumor size, with another 2 having their disease stabilized.  See the FDA preliminary report on Iressa at the FDA.gov website. http://www.fda.gov/ohrms/dockets/ac/02/briefing/3894B1_01_AstraZeneca.pdf.

On November 1, 2001, a press release reported, "Phase II trial results showed Iressa succeeded in shrinking lung tumors by at least half in 18.7 percent of seriously ill patients who failed to respond to conventional chemotherapy.  In 52.9 percent of patients the disease stabilized." (though the time period for stabilization was not identified).   A recent study did quantify the period of disease stabilization which was modest, "One patient experienced a partial response, but antitumor activity manifested mainly as prolonged stable disease (45% of patients >/= 3 months, 22% >/= 6 months, and 7.2% >/= 1 year)."  Selective Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 Is Generally Well-Tolerated and Has Activity in Non-Small-Cell Lung Cancer and Other Solid Tumors: Results of a Phase I Trial, J Clin Oncol 2002 Sep 15;20(18):3815-25.

Many believed that combining Iressa with chemotherapy would become the standard treatment.  Since Iressa's side effects are generally limited, it was hoped the drug could be added to standard chemotherapy to create a powerful drug combination to fight lung cancer  for non-small cell lung cancer, and perhaps other diseases.

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1.02 Disappointing Results with the Iressa/ Chemotherapy Combination 

A recent clinical trial was disappointing, causing Astra-Zeneca's stock to decline by 20% in one day, with scientists and investors believing the results cast doubt on the drug's viability and use in fighting lung cancer.    The study reported, "adding Iressa (ZD1839) to standard platinum-based chemotherapy does not add any  survival benefit for patients with non-small cell lung cancer, the drug's manufacturer AstraZeneca reported on Monday."

"AstraZeneca will focus on testing Iressa as a monotherapy, after two phase III trials presented at the European Society for Medical Oncology conference showed the drug added no survival benefit to chemotherapy in non-small cell lung cancer. The INTACT1 and INTACT2 trials investigated the use of Iressa in combination with two chemotherapy regimens most commonly used in non-small cell lung cancer--gemcitabine plus cisplatin, and paclitaxel plus carboplatin. Iressa inhibits the tyrosine kinase of epidermal growth factor receptor, which is implicated in cancer cell division, angiogenesis, metastasis and prevention of apoptosis."   Wan,  Iressa to be investigated as monotherapy for lung cancer after phase III failures" http://www.druginfozone.org/news/Oct02/Oct02_news131.html, Giuseppe Giaccone,
Combination of a new agent (ZD1839) with chemotherapy:  Emerging data
October 18, 2002 Presentation to the European Society for Medical Oncology.   See also, Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth Annals of Oncology 13:65-72, 2002

While the results were disappointing,  they should not have been completely surprising.   The incremental value of most drug combinations has been limited.  While drug A may have a 20% partial response rate and drug B the same, combining the two has never led to a 40% response rate.  The absence of any benefit though is disappointing, and the full results remain to be disclosed.

Disclaimer

The writer is not an oncologist and this analysis is intended to provide general information.  For specific advice regarding diagnosis or treatment, please consult your physician.

1.03 A Disturbing Side Effect Interstitial Pneumonia

In recent months, a disturbing side effect was seen in some patients, interstitial pneumonia.  First identified in Japan, an unusual type of pneumonia developed in some Iressa patients which could cause death if not adequately treated. 

1.04 FDA Preliminary Recommendation for Approval for Patients Who No Longer Respond to Conventional Chemotherapy

Today Iressa stands as a plausible alternative to conventional chemotherapy for patients with advanced lung cancer, especially those concerned about side effects.  In studies of lung cancer patients who no longer respond to platinum-based chemotherapy, Iressa is preferable to no treatment.   For patients with advanced lung cancer who no longer respond to chemotherapy  Iressa is an important alternative and the FDA's committee has recommended the drug be approved for that group.   Ascertaining Iressa's utility outside that group is debatable.  We do not have a clinical trial showing that Iressa  and chemotherapy are better that chemotherapy.    

1.04 Scientists have not Determined that Iressa is Better than Standard Chemotherapy

Likewise, we do not know whether Iressa is better than chemotherapy with each used alone.   Whether Iressa is more effective than standard chemotherapy drugs like Taxol or Carboplatin has not been determined.   We do not have any clinical trials testing Iressa against Carboplatin or Taxol.

1.05 Manufacturer's Restrictions on the use of Iressa.

The manufacturer has chosen to prohibit patients in expanded use programs from using Iressa with radiation or chemotherapy, placing patients in the position of relying upon a drug whose ultimate efficacy remains uncertain.   It appears Astra-Zeneca will allow the user to go off Iressa to undergo radiation prohibiting the use of Iressa during only the period of radiation, but  prohibits use of Iressa with any other type of chemotherapy or gene therapy treatment.

1.06 A Possible Subgroup who Benefit from Iressa, Non-smokers with lung cancer.

Anecdotally, some report that non-smokers with lung cancer, a small subgroup, seem to be doing better with Iressa, though the reasons for that remain speculative and that finding is not reflected in published literature.

1.07 Disease Stabilization as the Primary Benefit 

It appears Iressa's primary impact will be to stabilize disease for a period of time, rather than provide an overall cure.   Those patients who benefited had the disease stabilized and that is becoming an important endpoint for the assessment  of this class of drugs.  Only a limited number of patient had substantial tumor reductions.  

      1.081 Iressa Support Group and Online Sources of Information

www.acor.org has an excellent online support group devoted to Iressa.  Group members discuss side effects, when Iressa becomes effective, dealing with physicians and many other important issues facing patients and their families.   EGFR-info.com is a technical online journal devoted to Iressa and other epidermal growth factor inhibitors.  Alcase.org is a lung cancer support and advocacy group.   The National Library of Medicine through Medline compiles medical abstracts throughout the world on Iressa and other subjects.  Go to  http://www.ncbi.nlm.nih.gov/

We can provide some basic conclusions here which are explored below in some further detail:

1) Iressa is a viable alternative for stage 4 non-small cell patients with prior unsuccessful chemotherapy.  The drug has limited side effects and good results in stabilizing disease though it is not a cure.   Iressa is an important option for older patients who do not wish chemotherapy, and patients with poor pulmonary capacity.   In some cases Iressa will not work, so patients should be carefully monitored.   The main adverse side effect may not come from the drug itself, but the possibility that some patients you will be using an ineffective drug on a serious disease.  This problem is highlighted by the fact that in the US patients are prohibited from using Iressa with chemotherapy  or radiation. 

2) In the future, we may be able to identify  by chemical tests which patients will do best with Iressa, perhaps by measuring levels of epidermal growth factor.  No such test is widely used today (though it may be available in specialized pathology laboratories), and there is no clear evidence that such measurements indicate how effective the drug will be.  

3) Patients should carefully monitor new clinical trials.  A discussion group dealing with lung cancer and Iressa is available at www.acor.org and is a good source of information

1.1 EPIDERMAL GROWTH FACTOR

1.11 Gene Duplication as a Normal Process

Duplication of genes is a normal process.  When we lose hair or skin cells, our body replenishes them, utilizing growth factors like the epidermal growth factor (EGF).  However, the delicate process of cell replication or multiplication can malfunction, with genes directed to continually replicate.   Cancer is unrestrained growth of cells.  Growth factor research aims to identify how and why genes replicate and cancers develop, and how the process can be frustrated. While epidermal (roughly skin) growth factor plays a role in normal bodily functions, scientists have identified its disturbing role in tumor production and spread.   A key driver for growth is the epidermal growth factor (EGF) and the receptor for EGF (the EGFR) has been implicated in the development and progression of a number of human solid tumors including those of the lung, breast, prostate, colon, ovary, head and neck."  EGFR-Info.com              

1.12 Epidermal Growth Factor and Lung Cancer

" The high level of expression of the EGFR on non small cell lung cancer (NSCLC) and the important role of EGFR in signal transduction make it potentially an excellent target for antibody directed therapy."  Zhonghua, The Growth Inhibition of Anti-EGF receptor monoclonal antibody to Human Lung Adenocarcinoma cells,  Jie He He Hu Xi Za Zhi 1998 Apr; 21(4):233-5.   One study found EGFR expression was found in 94 of 169(56%) non small cell lung cancer cases.  Cox, Matrix Metalloproteinase 9 and the epidermal growth factor signal pathway in operable non-small cell lung cancer, Clin Cancer Res 2000 Jun; 6(6):2349-55

1.2 MECHANISMS OF ACTIONS FOR EGF INHIBITORS

1.20 General Theory of EGF Inhibitors

One writer explains the mechanism of Iressa:  

Iressa works by blocking (inhibiting) signals within the cancer cells preventing a series of chemical reactions that cause the cell to grow and divide.  It is known as a signal transduction inhibitor.... 

On the surface of many types of cancer cells are structures known as epidermal growth factor receptors (EGFR's).  The receptors allow epidermal growth factor ( a particular protein present in the body) to attach to them.  When the epidermal growth factor (EGF) attached to the receptor the receptor is triggered to produce a particular chemical called tyosine kinase.  Tyosine kinase is an enzyme which triggers chemical processes inside the cell which cause the cell to grow and divide.

Iressa works by attaching itself to the EGF receptor inside the cell.  It then blocks the activation of tyrosine kinase, thereby switching off the signals from the EGFR.    


1.201 Iressa and the Tyrosine Kinase

Scientists and others have been discussing Iressa and the tyrosine kinase:

"Another set of oncogenes ripe for exploitation as anticancer targets are those that encode enzymes termed protein kinases.... In normal cells, protein kinases help to regulate many important processes. Some of these activities include sending signals between the cell membrane and the nucleus, initiating a cell's progress through the cell cycle, and controlling various metabolic functions of the cell.   Protein kinases control these processes by activating other proteins in response to particular stimuli.

" Oliff,  New Molecular Targets for Cancer Therapy, www.sciant.com

1.21 Erbrreceptor

Iressa attempts to specifically target the ErbB1 receptor tyosine kinase.

Klein, Inhibition of Tyrosine Kinase activity decreases Expression of surfactant protein A in a Human Lung Adenocarcinoma cell line independent of Epidermal Growth Factor Receptor,  Biochim Biophys Acta 1997 Mar 1;1355(3): 218-30

1.22 Clinical Studies and Research within the Medical Community

A report presented to the American Society of Clinical Oncology stated:

ZD1839 (Iressa) is an orally active, selective EGFR-TKI, which blocks signal transduction pathways implicated in cancer growth. This Phase I dose-escalation trial aimed to evaluate the tolerability and activity of ZD1839 in patients (pts) with solid malignant tumors known to express or overexpress EGFR.... Antitumor response was most evident among the 16 NSCLC pts: 2 pts had a partial response (300 mg, 9+ mo; 525 mg, 6+ mo); an additional 2 pts had confirmed significant regression of disease (400 mg, 2 mo; 700 mg, 6+ mo); 2 pts had stable disease (225 mg, 5 mo; 525 mg, 5+ mo). Currently, 7 pts are receiving treatment. Final results will be presented. In conclusion, daily oral ZD1839 was well tolerated, demonstrated predictable pharmacokinetics and showed encouraging antitumor activity, particularly in NSCLC. Ferry, Intermittent Oral ZD1839 (Iressa), a Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI), Shows Evidence of Good Tolerability and Activity: Final Results from a Phase I Study C. www. asco.org.

The study appears to report a 25% response rate (4 of 16), and a 38% success rate, defined as either disease stabilization or regression.  Indeed, the success rate is arguably higher because it appears the trial was continuing. The population would appear to be a group of patients with advanced lung cancer, perhaps who had unsuccessful chemotherapy. This success rate exceeds that of virtually all other non-chemotherapy drugs. Not surprisingly, some are discussing FDA approval in a year, at least for advanced non-small cell patients with prior unsuccessful chemotherapy.

Another group of studies showed even more impressive results:

                    Dr. M. Kris presented data from 99 NSCLC patients in four phase 1 dose
                    escalation studies....Overall, 8 confirmed  objective partial responses
                    and significant tumor  regressions, lasting 1-16 months, were reported.  In addition,
                    approximately one third of patients had stabile disease lasting at least 3 months. 

Conference Report, Targeting the Epidermal Growth Factor Receptor in Lung Cancer,  Signal, Volume 2, Issue 1, 17-20.

The large group of patients with stabile disease highlights a likely finding.  That is, Iressa primary role may well be to stabilize rather than eliminate disease.

A Japanese study also showed positive but more modest results :

"ZD1839 (Iressa™™) is an orally active, selective EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor) which blocks signal transduction pathways implicated in cancer growth and survival. The objective of this trial is to investigate the tolerability, pharmacokinetics and efficacy of intermittent daily oral dosing of ZD1839 in Japanese patients (pts) with solid tumors known to commonly express or overexpress EGFR. To date, 25 pts with NSCLC (20), CRC (4) and H & N (1) tumors have been recruited... 3 pts with NSCLC have shown partial responses (at 225mg, 400 mg and 525 mg, confirmed). In conclusion, interim results indicate that once-daily oral ZD1839 is well tolerated and shows evidence of clinical activity in Japanese pts. Updated results will be presented at the Conference. " Uejima, A Phase I intermittent dose-Escalation Trial of ZD1839 (Iressa) in Japanese patients with solid tumors. Annals of Oncology, Vol 11, Suppl. 4 October 2000, page 110

Understanding cancer terminology and the cancer process can be difficult.    The process begins when EGF connects with a EGFR, epidermal growth factor receptor.  "The EGFR is a member of a family of four receptors [EGFR (HER1 or ErbB1), ErbB2  (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4)]. www.egfr-info.com.  These receptors are proteins in a cell; when the receptor and growth factor meet, that initiates cellular reactions which ultimately result in cell division.  

 Rusch and colleagues reported overexpression of EGF-R (epidermal growth factor-receptor) in 45% and 61% of NSCLC tumors." Pass, Editor, Lung Cancer, 186 Lippincott, 2000) citing Rusch, Differential Expression of the Epidermal Growth Factor Receptor and its Ligands in Primary Non-Small Cell Lung Cancers and Adjacent benign lung, Cancer Res 1993; 53:2379.  It is unclear whether Iressa is intended to only affect Erb1, or related parts of this family of tyrosine kinases. 

1.23  Can the Patient Who Will Benefit from Iressa be Identified by Measuring Levels of Epidermal Growth Factor

The study are showing 40-50% of patients have either partial responses are disease stabilization, though some patients seem unaffected by Iressa.  Which ones will experience positive results and can they be identified.  Are patients with high levels of EGF likely to benefit most from Iressa, with little gain to others. 

One study of cells in a laboratory found that Iressa inhibited growth of cells overexpressing EGF and a related substance Erb2.  Anderson, ZD1839 (Iressa), a Novel epidermal growth factor receptor (EGFR) tyrosine kinaseinhibitor, Potently inhibits the growth of EGFR-positive cancer cell lines with or without ErbB2 Overexpression, . Int J Cancer 2001 Dec 15;94(6):774-82   At present, physicians are not limiting Iressa to persons with certain levels of EGF, or  other characteristics.  Iressa has been limited to non small cell patients with advanced cancers.

1.24 Will Iressa Be More Successful with Squamous Cell Cancer than  Adenocarcinoma

One report suggests that Iressa is more effective with squamous cell cancer than other forms of non-small cell cancer:   "EGFR was highlighted as a particularly relevant target for non-small cell lung cancer (NSCLC) as it is overexpressed in around 80% of squamous and 50% of
adeno- and large-cell carcinomas."  Nakagawa, author, Conference Report, Targeting the Epidermal Growth Factor Receptor in Lung Cancer, Signal, vol. 2, issue 1, 17-20.    

Others have not found this distinction.      A Japanese study found, "Overexpression of the receptor was observed in 6 (24.0%) of 25 squamous cell carcinomas, 16 (23.2%) of 69 adenocarcinomas and 23 (23.7%) of a total of 97 tumors." Sekine, Role of epidermal growth factor receptor overexpression, K-ras point mutation and c-myc amplification in the carcinogenesis of non-small cell lung cancer, Oncol Rep 1998 Mar-Apr;5(2): 351-4.   A British study concluded, "No significantly elevated or decreased serum values for p53 protein, EGF-R, or anti-p53 antibodies as a function of histological tumour type, age, or degree and type of exposure (asbestos, smoking, ionizing radiation) could be found. "  Schneider, Pp53 protein, EGF receptor, and anti-p53 antibodies in serum from patients with occupationally derived lung cancer, Br J Cancer 1999 Aug;80(12):1987-94.

This type of data would support the hypothesis that epidermal growth factor inhibitors would be equally effective among different types of non-small cell cancer.   We look at some data regarding epidermal growth factors and specific types of lung cancer.

           1.244 EGR and Prognosis

While it is clear that EGR plays a role in the developement of lung cancer, its influence on survival and spread is not settled.   A Russian journal concluded,  EGF is found in tumors more frequently than in unaltered tissue, and higher levels of EGF have been associated with a poorer prognosis.  Kostyleva, EFR-like peptides and their receptors as prognostic factors for the survival of patients with non-small cell lung cancer, Vopr Onkol 1999;45(6):617-22.  Others have suggested that Epidermal Growth Factor works at early stages, and its presence may indicate little about prognosis. 

1.25 Dosage Issues

Dosage questions have not been resolved. The study presented to the Society of Clinical Oncology involved varying and escalating doses- Escalating doses of ZD1839 (50-700 mg once daily, 4-8 pts per dose level) were given orally for 14 days followed by 14 days' observation."  Ferry, Intermittent Oral ZD1839 (Iressa), a Novel Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI), Shows Evidence of Good Tolerability and Activity: Final Results from a Phase I Study C. www. asco.org.   The maximum dose was 700 mg daily in the American study, but 525 mg in the Japanese study which showed lesser results. Neither study had significant side effects.

With chemotherapy, it is generally true that higher doses bring better results, but greater side effects.  Thus, determining the optimum dose is a question of balancing response rates with side effects.  That may not be true with Iressa and the group of tyrosine kinase inhibitors.  Some suggest that the maximum tolerated dose may be greater than the maximum effective dose.   That is, the body could tolerate greater doses without significant side effects but the greater dose would not be more effective.   The lack of significant side effects may enable Iressa to be combined with other drugs.

1.26 Animal Studies with Iressa 

One study showed Iressa reduced or eliminated at a considerable percentage of solid tumors on laboratory mice, and also reduced other factors associated with cancer: 

"In this study, we evaluated the antiangiogenic and antitumor activity of ZD1839 in human colon (GEO, SW480, and CaCo2), breast (ZR_75_1 and MCF-7 ADR), ovarian (OVCAR_3), and gastric (KATO III and N87) cancer cells that coexpress TGF_alpha and EGFR. ZD1839 treatment determined a dose_ and time_dependent growth inhibition accompanied by the decrease of VEGF, bFGF and TGF-alpha production in vitro. Treatment of immunodeficient mice bearing well-established, palpable GEO xenografts with ZD1839 determined a cytostatic dose-dependent tumor growth inhibition. Immunohistochemical analysis of GEO tumor xenografts after ZD1839 treatment revealed a significant dose dependent reduction of TGF_alpha, bFGF, and VEGF expression in cancer cells and of neoangiogenesis, as determined by microvessel count. Furthermore, the antitumor activity of ZD1839 was potentiated in combination with the cytologic drug paclitaxel in GEO tumor xenografts. Tumor regression was observed in all mice after treatment with ZD1839 plus paclitaxel, and it was accompanied by a significant potentiation in inhibition of TGF_alpha, VEGF, and bFGF expression with a few or no microvessels. Furthermore, 6 of 16 mice bearing well_established, palpable GEO xenografts had no histological evidence of GEO tumors at the end of treatment with ZD1839 plus paclitaxel. These results demonstrate that the antitumor effect of ZD1839 is accompanied by inhibition in the production of autocrine and paracrine growth factors that sustain autonomous local growth and facilitate angiogenesis, and that this effect can be potentiated by the combined treatment with certain cytotoxic drugs, such as paclitaxel." Fortunate, Inhibition of Growth Factor Production and Angiogenesis in Human Cancer Cells by ZD1839 (Iressa), a Selective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor,  Clin Cancer Res 2001 May;7(5):1459-1465    

1.27 The Difficulty of Delivering the Drug to the Entire Tumor

With gene therapy generally, one difficulty has been getting the drug or vaccine to the tumor. In experiments with mice, it is easy for the experimenter to administer sufficient doses of a drug to encompass the entire tumor. With humans, there has been difficulty with gene and other therapy in delivering the drug to the entire relevant area.  "In all of these studies, it has been difficult to deliver recombinant virus into solid tumors so as to transduce a significant fraction of the tumor cells, and the effect is limited to the injected nodule, which be of limited real clinical benefit." Lee, Gene Therapy, excerpted in Pass, Lung Cancer (Lippincott 2000). 

Researchers may be no more successful in delivering Iressa to the tumor.  The studies show modest rates of partial response averaging about 20%, less than conventional chemotherapy.  Nonetheless, Iressa's rate of disease stabilization is impressive, with one study showing half of the patients experienced stabilization.  By inhibiting transduction, Iressa may prevent growth of the tumor, and in a few, the lack of growth combined with apoptosis (cell death) ends up combining to be a reduction.  Iressa studies highlight the importance of determining appropriate measuring tools.  If you measure levels of complete response (elimination of the tumor on x-ray or Ct Scan) the drug's effectiveness is minimal, but when you calculate rates of stabilization, it is highly effective. 

1.28 Side Effects

Chemotherapy drugs target rapidly dividing cells,  Therefore they impact various types of dividing cells in addition to tumor cells.  For example, hair loss is a common side effect since hair derives from dividing cells.

Iressa and similar drugs target a specific type of cells, and their impact on other normal cells is, at least theoretically, going to be limited.  Indeed, only limited side effects have been seen in clinical trials.  "In phase I studies, toxicity was manageable. Most common side effects were skin rash, nausea, vomiting, and diarrhea."  Meric, Le ZD 1839: "Iressa", Bull Cancer 2000 Dec; 87(12): 873-6.  The skin rash makes sense because the epidimeral (skin) growth factor  has been disrupted. 

    1.281 Pneomonia

A Japanese study reported a series of deaths among patients using Iressa apparently from an unusual type of pneumonia, some call interstitial pneumonitis. .

    "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." Innoue. Severe acute interstitial pneumonia and gefitinib, Lancet 2003 Jan 11;361(9352):137-9

However, since some of these causes are associated with the disease itself, and there is a high mortality associated with advanced lung cancer, it is difficult to quantify the risk.   Patients should be aware of this side effect and immediately see a physician for rise in temperature or pthe appearance of pneumonia on x-ray.    

1.3 COMBINING CHEMOTHERAPY AND OTHER DRUGS WITH  IRESSA

1.31 Complimenting Chemotherapy

The side effects with Iressa have been limited.  Many suggest that Iressa will compliment chemotherapy with the combined therapy more effective than either.  In laboratory research this has been shown:

"We have demonstrated previously that ZD1839 treatment potentiates the antitumor activity of several conventional cytotoxic drugs including paclitaxel. Because there is evidence that paclitaxel has an antiangiogenic effect, in this study we also investigated whether the antitumor activity of combined treatment with paclitaxel and ZD1839 could be attributable to inhibition of neovascularization in vivo. Treatment with the two drugs produced a complete regression of established palpable GEO tumors in mice; no histological evidence of GEO tumors was found in 6 of 16 mice at the end of 3 weeks of treatment. Furthermore, in the remaining mice, combined treatment with ZD1839 and paclitaxel resulted in almost complete suppression of tumor growth."  Ciardello, Inhibition of Growth Factor Production and Angiogenesis in Human Cancer Cells by ZD1839 (Iressa),a Selective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Clinical Cancer Research Vol. 7, 1459-1465, May 2001.  Another researcher stated, "coadministration of ZD1839 ... will enhance the efficacy of cytotoxic agents against human vulvar (A43), lung (A549 and SK-LC-16 NSCL and LX-1), and prostate (PC-3 and TSU-PR1) tumors.".

He goes on to detail his findings on specific cell lines:

"Combination Treatment against Lung Tumors.

The growth inhibitory action of CDDP and CBDCA against the A549 tumor was increased 4-fold in combination with ZD1839 (P < 0.01; Table 4 ). In addition, coadministration of ZD1839 increased the activity of CBDCA 3-fold against the LX-1 tumor (P < 0.01). Both taxanes markedly inhibited the growth of the LX-1 tumor, although PTXL was more effective than DTXL (Table 5)When combined with ZD1839, the activity of DTXL against LX-1 was increased 4-fold (P < 0.01), whereas PTXL resulted in pronounced tumor regression with three of nine mice having no detectable tumor at the end of treatment.
Sironak, Efficacy of Cytotoxic Agents against Human Tumor Xenografts Is Markedly Enhanced By Coadministration of ZD1839 (Iressa), an Inhibitor of EGFR Tyrosine Kinase, Clinical Cancer Research Vol. 6, 4885-4892, December 2000

Below is the author's diagram demonstrating the efficacy of the Iressa Paclitaxel combination compared with either alone. 

Fig. 5. The effect of ZD1839 alone and in combination with PTXL against the LX-1 tumor. Average of three experiments at three to four mice/group with SE of <13%. Animals treated with ZD1839 (qd x 5) x 2 and PTXL (every 3–4 days x 4). Additional details are given in the text. 

1.321 Recent Clinical Results

However, a recent clinical trial showed no increase in survival when Iressa was combined with platinum chemotherapy, as compared with the chemotherapy alone.   See Astra-Zeneca press release.  More research is needed.

1.33 Combining Iressa with Similar Drugs.

In the future, Iressa could be combined with other tyrosine kinase inhibitors and other gene therapies though today in its expanded use protocol, Astra-Zeneca prohibits the use of Iressa with any other drug.  In one recent study on mice  a drug combination  limited tumor growth and some of the tumors themseleves:  

"PURPOSE: Protein kinase A type I (PKAI) and the epidermal growth factor receptor (EGFR) play a role in neoplastic transformation and interact with each other in transducing mitogenic signals. We developed different PKAI and EGFR inhibitors, demonstrating their cooperation with cytotoxic drugs and the therapeutic potential of the combined blockade of PKAI and EGFR. In this study, we investigated the effect of orally active PKAI and EGFR inhibitors in combination with a novel taxane. Experimental Design: We combined a hybrid PKAI antisense oligonucleotide sequence (AS-PKAI), the EGFR inhibitor ZD1839 (Iressa), and the taxane IDN5109, studying their effect on human cancer growth, apoptosis, and angiogenesis and measuring vascular endothelial growth factor (VEGF) expression and vessel formation in vitro and after oral administration in nude mice. RESULTS: We demonstrated cooperative growth inhibitory and proapoptotic effects and inhibition of VEGF expression with any combination of two drugs and a marked synergistic effect when all three agents were combined. Oral administration of AS-PKAI, ZD1839, and IDN5109 in combination to nude mice caused a remarkable antitumor effect with no histological evidence of tumors in 50% of mice 5 weeks after treatment withdrawal, accompanied by complete suppression of vessel formation and VEGF expression. CONCLUSION: This is the first demonstration of the cooperative antitumor and antiangiogenic activity of three novel agents that block multiple signaling pathways after oral administration. Because all agents are under clinical evaluation in cancer patients, our results provide a rationale to translate this feasible therapeutic strategy in a clinical setting."  Tortora, Oral administration of a novel taxane, an antisense oligonucleotide targeting protein kinase a, and the epidermal growth factor receptor inhibitor iressa causes cooperative antitumor and antiangiogenic activity [In Process Citation], Clin Cancer Res 2001 Dec;7(12):4156-63.  Unfortunately, the abstract does not specify that these were lung cancer cells.  Nonetheless confirmation of a cooperative effect of various cancer drugs is an important first steps in coordinating their use.     

Animal studies like those must be reconciled with the unsuccessful results of combined therapy in AZA's recent clinical trial.  Here too, we have more questions than answers.

1.4 PENDING CLINICAL TRIALS WITH IRESSA

1.41 Sources for Listing of Clinical Trials 

Determining what clinical trials are pending and how they will work is a difficult task.  There are at least three sites which list clinical trials, Centerwatch.com, the National Cancer Institute website, and cybermed.com.   However, it appears there are trials or uses of Iressa which are not listed.  For example, calling Astra Zeneca, I was given a list of five hospitals in New Jersey where Iressa could be made available, though none of these facilities were listed on any website
Initially, it appeared that these hospitals were providing the drug under a compassionate or expanded use program, where patients may obtain a drug not approved by the FDA outside a clinical trial.  However, further investigation indicates these drugs may be used in some type of clinical trial.  Thus, getting complete and accurate information is a difficult task, where some information is not readily made public, policies may be flexible.   

1.42 Sloan Kettering Clinical Trial in New York City.  

Cybermed.com has a description of the Sloan Kettering clinical trial of ZD 1839 which it titles. Study of ZD 1839, an Epidermal Growth Factor Receptor Inhibitor, and Carboplatin/ Taxol Chemotherapy in the Treatment of Advanced or Metastatic Non_Small Cell Lung Cancer. All patients receive carboplatin and taxol, with different groups receiving varying amounts of ZD 1839 in addition. The study is limited to those with advanced cancer who have not received prior chemotherapy or biological therapy. There may be circumstances where the drug can be made available to those ineligible for the trial. Compounds, Medscape.com Set forth below is clinical trial information from the National Cancer Institute. It appears M.D. Anderson in Houston, Texas, and Sloan-Kettering Hospital, in New York are participating in clinical trials for Iressa. The trials will compare Gemcitabine and Cisplatin, two chemotherapy drugs, with medium dose or Iressa, higher dose, and placebo.

1.5 HOW CAN PATIENTS OBTAIN IRESSA

There are two ways to obtain an experimental drug: 1) participation in a clinial trial using the drug, 2) a compassionate use program outside the clinical trial.   Participation in a clinical trial is somewhat clearer than compassionate use. Expanded or compassionate use is a program which permits certain patients to obtain access to an experimental drug before FDA approval and outside the context of a clinical trial

1.51 Manufacturer's Policies with Compassionate Use

It appears that today (September, 2001) Astra-Zeneca is providing access to Iressa through various hospitals and physicians under compassionate use.  Its policies may change as further information is developed about the drug, as results of clinical trials are revealed, and as the FDA evaluates approving the drug for particular uses.

1.511 Why Manufacturers Sometimes Limit Compassionate Use     

Manufacturers want participation in clinical trials.  Clinical trials have various limits and restrictions; for example, the patient does not select the manner in which the drug will be used, but is instead assigned to a group.   Manufacturers have been concerned that easy availability would reduce clinical trial participation, delaying the release of the drug which would benefit more people overall.  Secondly legal considerations might lurk in the background.  There have been few suits with clearly marked experimental drugs and compassionate use programs.  Nonetheless, manufacturers worry about how a new drug will be used, or misused.   If a patient dies from the disease, that is sad but not the manufacturer's responsibility;  if he dies from misuse of an experimental drug, manufacturers worry about their liability, though again, few claims have been brought in such a circumstance.

1.512 Manufacturer's Discretion

Manufacturers determine how a compassionate use program will be applied.  Sometimes, no clear policies will be promulgated, or those that are publicized will be unduly restrictive.  There are reports of patients or family members who talked with the right person, had political pull, a particularly sympathetic cause, or other reasons which enabled them to obtain the drug where others could not.  Sixty minutes recently ran an informative story about two patients seeking a new colon cancer drug, with one obtaining the drug, and one not.  

1.53 Astra-Zeneca's Current Policies

A September 7, 2001 letter indicated availability as follows: 

       1) Iressa will be available to stage 3 and 4 non-small cell lung cancer patients,

       2) Who have taken but not benefited from chemotherapy,

       3) Who are not a candidate for a clinical trial,

       4) Who will not taking any other chemotherapy. 

There are some other restrictions which will affect relatively few people.  Iressa is not available to those who have another cancer (not a metastasis), those with certain other serious health problem (not clearly identified in Astra Zeneca materials). 

1.531 No other Chemotherapy

AZN will not permit its Iressa to be used with chemotherapy.  That is dangerous particularly in light of the recent clinical trials questions Iressa's effectiveness.  It may well be that traditional forms of chemotherapy are more effective than Iressa.  

1.532 The Argument in Favor of Allowing the Oncologist to Determine the Optimal Use of the   

AZ's own journal articles suggest that Iressa is less likely to act as a cure than as a stabilizing agent- "the predominant beneficial effect noted with EGFR-targeted therapies in preclinical tumor models is a decreased rate of tumor growth."  Rowinsky, EGFR-targeted cancer therapies: Is there a Need to Reconsider Clinical Trial Design, Signal, Volume 2, Issue 1, 4-12.   Thus, there is good reason to attempt to combine a drug which is not an overall cure, but has limited side effects, with another drugs which can also attempt the tumor.  

However, as I understand it, AZ prohibits him from doing so, insisting that he use Iressa alone or not at all.  Whether my argument is  persuasive or not, it is clearly academic.  Astra-Zeneca has determined its policies and they are unlikely to alter them on an individualized basis.      

1.6 Obtaining Iressa

Take the following steps if you are interested in the drug:

1) Speak with your oncologist, physician and other professionals, and make a decision of whether you can benefit from the drug.  In some circumstances, you may want to check with a regional cancer or leading teaching hospital such as Sloan Kettering, MD Anderson, or the like.

2) Contact Astra-Zeneca, and find out where clinical trials are occurring, and the details of participation,

3) At the same time, contact Centerwatch.com and other groups to determine what clinical trials are listed.

4) If you are not eligible for a clinical trials.  Review your options.  Confirm that there are no other clinical trials for which you would be eligible.  Confirm that you have investigated all locations and physicians.  Astra-Zeneca has a detailed list.  Remember some physicians may not be participating.

5) Contact Astra-Zeneca and other groups about compassionate use if you are not eligible.

6) Review information at www.acor.org and join their nonsmall cell lung cancer and Iressa lists.  Check with others regarding information about Iressa.  Contact www.alcase.org, the national lung cancer advocacy and information group. 

 6) Consider similar drugs like ISI-774, and see if you are eligible for clinical trials involving such drugs.

7) If you cannot obtain the drug through normal channels, write the manufacturer, your congressperson, insurance commission, and other persons or entities who could potentially influence them to provide the drug.  Write an individually summary of how you believe the drug could help you.  On the 60 Minutes show, a young woman managed to call a company official at home, and convince him to provide a new drug (not Iressa) on a compassionate use basis).  The task may not be easy but is sometimes successful. 

Today the basic difficulty is that Astra-Zeneca will not allow its Iressa to be used with chemotherapy.   There is a considerable body of experimental data suggesting that some combinations may improve survival and that Iressa compliments existing chemotherapy.  However, worried about potential side effects and eager to secure FDA approval, Astra-Zeneca has refused to permit its Iressa to be used with other drugs (at least as of the time of this writing). 

1.61 Iressa and Other Countries

Today Iressa has been approved only in Japan.  See www.Iressa.com.  There may be limited availability in other countriess though that is unclear.  The process of getting information is about the same.  Contact a prominent teaching hospital, contact Astra-Zeneca, or consider Tarceva and OSI 774, and check availability.

1.62 Iressa and Japan

Astra-Zeneca has been appapplied for permission to have Iressa approved in Japan.


"AstraZeneca today announced the submission of a New Drug Application (NDA) to the Japanese Ministry of Health, Labour and Welfare (MHLW) supporting the use of IRESSA for the treatment of non-small cell lung cancer (NSCLC). IRESSA is the first epidermal growth factor (EGFR) inhibitor to be filed in Japan. This means that the drug is now currently under regulatory review in two major global markets including the US.

Martin Wright, Regional Vice President, AstraZeneca Japan, said: "We are very excited by the positive data we have seen with IRESSA as the prognosis and treatment of lung cancer is poor and the symptoms extremely debilitating. If approved, IRESSA will offer patients a convenient once-daily oral therapy that is generally well tolerated, and can deliver fast and significant improvements in disease-related symptoms and disease control."

Lung cancer is becoming more prevalent. The worldwide market for medicines to treat lung cancer is currently worth $1.6 billion, the majority of which is accounted for by NSCLC. In Japan, the MHLW is forecasting an 80 per cent increase in the incidence of lung cancer in the next 15 years.

The Japanese submission was based on data from two phase II trials involving over 400 patients worldwide, which demonstrated that IRESSA given as monotherapy, at a dose of 250 mg/day leads to objective response or disease stabilisation in many previously treated patients with advanced NSCLC.Release issued 28 Jan 2002  www.atlas.pharmalicensing.com."

 

1.7 OTHER EPIDERMAL GROWTH FACTOR INHIBITORS

1.71 OSI 774

OSI 774, also called Tarceva is a similar drug manufactured by OSI Pharmaceutical and Genentech.  

A presentation at the American Society of Clinical Oncology stated: 

"OSI-744, another oral selective EGFR-tyrosine kinase inhibitor, has shown significant activity      in combination with platinum in the treatment of patients with platinum-refractory NSCLC (response rate 12%), as reported by Perez-Soler and colleagues.[6] Phase 2 data also indicate responsiveness to rechallenge with platinum in patients with refractory head and neck cancers.[7] CI-1-33 is also currently in phase 2 testing, while several other tyrosine kinase inhibitors are in various stages of phase 1 analysis, including PKI-1656, ICR62, and ABX-EGF." Mendelsohn, Targeting EGF Receptors in Clinical Practice ,  37th Annual Meeting of the American Society of Clinical Oncology - May 17, 2001, www.medscape.com

1.72 Press Release and Company Reports

OSI Pharmaceuticals has reported impressive results from OSI-774, though these results have not been set forth in a scientific journal:

"OSI Pharmaceuticals, Inc. announced data from two ongoing clinical studies using the     Company's lead anti-cancer drug candidate, OSI-774, as a single agent showing 48 percent of 56 patients with advanced, refractory non-small cell lung cancer and 42 percent of 78 evaluable patients with advanced head and neck cancer had either a partial response or evidence of disease stabilization after three months of daily oral dosing with OSI-774. www.pslgroup.com/dg/1e9fc6.htm

The press release explains:

"Philip Bonomi, M.D., a lead investigator and Director of Medical Oncology at the Rush Cancer Institute in Chicago, reported data from the Phase II study of 56 patients with advanced, refractory, non-small cell lung cancer (NSCLC). Eligibility criteria for the open label, single agent study required patients to have failed a platinum-based chemotherapy regimen and to have tumors that are histopathologically confirmed to be EGFR positive. OSI-774 (150 mg) was given orally as a single agent on a once-a-day dosing schedule.

Patients were evaluated at eight and 12 weeks and classified as partial responders (>50 percent reduction in tumor size), patients with stable disease or patients with progressive disease. Results showed that 48 percent of the patients had either a partial response or stable disease at 12 weeks and continued on the drug. Seven patients showed objective partial responses, while 20 patients demonstrated stabilization of their malignancy." Id.

The study demonstrates that you must compare apples with apples when evaluating journal reports.  Many studies have not separately categorized stabile disease. 

The newest report from the ASCO conference in 2002 reported similar results:

"Philip Bonomi, M.D., a lead investigator at Rush College of Medicine, Chicago, IL, provided an update of the Tarveca(TM) single agent Phase II non-small cell lung cancer (NSCLC) trial initially presented at the ASCO meeting in 2001.  In this study Tarceva(TM) was given orally as a single agent at a daily dose of 150 mg. Fifty-seven patients with advanced NSCLC were enrolled. All these patients had failed prior chemotherapy and 22 of the 57 (39%) were extensively pre-treated with three or more chemotherapy regimens prior to study entry. A final analysis of the data for objective response rate confirms that one patient (2%) achieved a complete response and six patients (11%) achieved a partial response. Disease stabilization was documented in an additional 20 patients (35%) providing an overall response and disease stabilization rate of 48%. Of note, four responses were observed in patients previously treated with three or more regimens of chemotherapy. The median survival in this study was 36.4 weeks (257 days) with 40% of the patients alive at 12 months. Twelve patients (21%) in the study survived for longer than 18 months. As of April 2002, nine patients (16%) remain alive with a follow up ranging from 18 to 24 months after trial entry.
The most common side effect exhibited by all EGFR targeted therapies currently in development is a rash which was observed in 75% of the patients in this study. The second most common side effect noted in the study was diarrhea which was mild in the majority of the cases. In total only 2 patients (one each for rash and diarrhea) exhibited moderate to severe toxicities (grade 3) in these categories. "

Phase Ib Combination Trials Update

OSI initiated several Phase Ib combination trials in 2001 to evaluate the effects of Tarceva(TM) used in conjunction with various chemotherapy drugs. Chemotherapy agents currently evaluated in the Phase Ib combination studies include docetaxel, and combinations of paclitaxel/ carboplatin, and gemcitabine/cisplatin. Interim data were presented indicating that no unexpected toxicities have emerged as a result of combining Tarceva(TM) with these established chemotherapy agents. Pharmacokinetic (PK) data presented by Dr. Bahram Forouzesh of the Institute for Drug Development, San Antonio, TX, indicated that no PK interaction with docetaxel was evident in their Phase 1b study combining the two agents. However, it was apparent that for some advanced and/or heavily pre-treated cancer patients the dose of Tarceva(TM) (150mg/day) previously used in monotherapy trials may not be tolerated when given in combination with certain cytotoxic regimens. Anti-tumor activity in the form of complete responses, minor responses and disease stabilization was noted in these studies. "
 

CNET reported similar results:

"OSI Pharmaceuticals Inc.'s and Genentech Inc.'s experimental cancer drug OSI-774 performed well enough against a common type of lung tumor for final testing to start later this year, researchers said. OSI-774, also known as Tarceva, was given to 57 people with advanced non-small-cell lung cancer that wasn't responding to other treatments. Tumors disappeared or shrank by at least half in 16 percent of the patients."

At some point in the future, the drugs will be compared.  At present, both show significant promise and must seriously be considered by the Stage 4 patient, particularly those whose chemotherapy is not longer providing effective.  CNET.com, OSI, Genentech's OSI-774 Does Well Against Lung Tumor 5/12/01 (Bloomberg News).

The article suggests that Iressa may be approved first,  "For OSI-774, the most direct competition in the class is AstraZeneca's drug, Iressa, which Goddard said is one year ahead in development for lung cancer."   CNET.com, OSI, Genentech's OSI-774 Does Well Against Lung Tumor 5/12/01 (Bloomberg News).

1.73 Method of Action

OSI-774 works similarly to Iressa:

"Epidermal growth factor receptors (EGFR) are small proteins that are found on the surface of all cells. EGFR binds exclusively to small proteins circulating in the blood called growth factors. The binding action between EGFR and growth factors stimulates biological processes within the cell to promote growth of a cell in a strictly controlled manner. However, in many cancer cells, EGFR is either abundantly overexpressed or the EGFR biological processes that normally stimulate cell growth are constantly active, leading to the uncontrolled and excessive growth of the cancer cell.

OSI-774 is a novel therapeutic agent aimed at blocking the EGFR pathway. OSI-774 halts excessive cellular growth by inhibiting the EGFR process within a cell. Clinical trials are currently underway evaluating OSI-774 in a variety of cancers. Recently, a multi-institutional clinical trial was conducted evaluating OSI-774 in 30 patients with advanced ovarian cancer who had stopped responding to standard therapies. All patients in this study overexpressed EGFR. Eight weeks following treatment with OSI-774, 15 patients achieved a stabilization of their cancer and 3 patients achieved a 50% or greater reduction in their cancer." OSI-774 Shows Promise in Advanced Ovarian Cancer, www.cancerconsultants.com

1.74 OSI-774 and Head and Neck Cancers

OSI recently showed promised in a study of advanced head and neck cancers:

"Data from a study using OSI-774 at 150mg per day in advanced head and neck cancer (SCCHN) patients were presented by Dr Neil Senzer (Abstract #6). EGFR status was determined, although a positive EGFR status was not a mandatory recruitment requirement for patients to enter this open label study given the high incidence of EGFR overexpression seen in head and neck cancer. In this patient cohort (n=114) 12% had 2+ EGFR staining and 82% were 3+. Objective responses occurred in 7 (5.6%) of the study participants, while 49 patients (39%) showed disease stabilization for 3 or more months. Response did not appear to correlate with prior therapy, level of EGFR expression, stage of disease (locally advanced or metastatic). www.egfr-info.com
Lynch, 37th Annual Meeting of the American Society of Clinical Oncology (2001)  

1.8 ASSESSING GOALS CURE OR STABILIZATION

An increasing body of research is suggesting that the likely best case scenario for Iressa is not that it will be a complete cure, but that it will stabilize disease, for some period, with minimal side effects.    In the above study of OSI-774 with head and neck cancers, the benefit to most patients, 39%, was to stabilize disease. 

1.81 Implications

Assuming that Iressa's primary impact will be to stabilize disease in many patients, it would appear the drug can be combined with chemotherapy, to further attack disease, limit metastasis,  increase the possibility of cure, and overcome MDR, multi-drug resistance, the sad phenomenon where the body adjusts to chemotherapy making it less effective.
   
 

____________________________________________________________________________________

APPENDIX 1 United States Phase 3 Trials with Iressa

Phase III Randomized Study of ZD 1839 Combined With Gemcitabine and Cisplatin in Chemotherapy Naive Patients With Stage IIIB or IV Non-Small Cell Lung Cancer (Summary Last Modified 04/2001)

Protocol IDs:

ZENECA-1839IL/0014

Protocol Type:

treatment

Sponsorship:

pharmaceutical

Status:

Active

Age Range:

18 and over

Objectives

I. Compare the 1 year survival rate, time to worsening of disease related
symptoms, and progression free survival in chemotherapy naive patients with
stage IIIB or IV non-small cell lung cancer treated with one of two doses of
ZD 1839 or placebo combined with gemcitabine and cisplatin.

Protocol Entry Criteria

--Disease Characteristics--

Histologically proven non-small cell lung cancer
 Stage III disease that is not curable with surgery or radiotherapy OR
 Stage IV disease
Chemotherapy naive--Prior/Concurrent Therapy--
Endocrine therapy:
 No concurrent systemic endocrine therapy that is known to have an effect on
  non-small cell lung cancer
Radiotherapy: See Disease Characteristics
Prior localized irradiation allowed
Surgery: See Disease Characteristics
Prior surgery allowed
Other:
 No concurrent drugs with known significant cytochrome P450 3A4 inhibitory
  effects (e.g., ketoconazole, itraconazole, troleandomycin, erythromycin,
  diltiazem, verapamil)
--Patient Characteristics--

Age: 18 and over

Performance status: 0-2

Life expectancy: Not specified

Hematopoietic:
 Absolute neutrophil count at least 2,000/mm3
 WBC at least 4,000/mm3

Hepatic:
 ALT and AST less than 2.5 times upper limit of normal (ULN) (less than 5
  times ULN if liver metastasis present)
 Bilirubin less than 1.25 times ULN

Renal:
 Creatinine less than 1.5 times ULN
 Creatinine clearance greater than 60 mL/min

Cardiovascular:
 No evidence of severe or uncontrolled cardiovascular disease

Pulmonary:
 No evidence of severe or uncontrolled pulmonary disease

Protocol Outline

This is a randomized, double blind, placebo controlled, multicenter study.

Patients are randomized to one of three treatment arms.  Patients receive
gemcitabine and cisplatin combined with lower dose oral ZD 1839 (arm I),
higher dose oral ZD 1839 (arm II), or placebo (arm III).

Stratification By

Not abstracted

Special Study Parameters

Not abstracted

End Points

Not abstracted

Projected Accrual

A total of 1,029 patients (343 per arm) will be accrued for this study.

Warning

The purpose of most clinical trials listed in this database is to test new
cancer treatments, or new methods of diagnosing, screening, or preventing
cancer.  Because all potentially harmful side effects are not known before a
trial is conducted, dose and schedule modifications may be required for
participants if they develop side effects from the treatment or test.  The
therapy or test described in this clinical trial is intended for use by
clinical oncologists in carefully structured settings, and may not prove to be
more effective than standard treatment.  A responsible investigator associated
with this clinical trial should be consulted before using this protocol.

Dosage Schedule

Not abstracted

Dosage Forms

Not abstracted

Participating Organizations/Investigators

Patient Inquiries (In the US & Canada) AstraZeneca Pharmaceuticals LP, Chair, Ph: 1-800-236-9933 AstraZeneca Pharmaceuticals LP

Principal Investigators

U.S.A.

Delaware

Patient Inquiries (In the US & Canada) AstraZeneca Pharmaceuticals LP, Principal Investigator, Ph: 1-800-236-9933 AstraZeneca Pharmaceuticals LP Wilmington, Delaware, U.S.A.

_______________________________________________________

The second study also tests Iressa combined with a chemotherapy drug.  Al study participants will receive carboplatin and Taxol, standard treatments.  Some will receive small doses of Iressa, some larger doses, and others placebo.  The fact that we are at stage 3 testing confirms to a large extent the efficac of the drug to date. 

ZD1839 Plus Chemotherapy in Treating Patients With Non-Small Cell Lung Cancer

This study is currently recruiting patients.

Sponsored by
AstraZeneca Pharmaceuticals

bullet Purpose

RATIONALE: Some tumors need growth factors produced by the body's white blood cells to keep growing. ZD1839 may interfere with the growth factor and stop the tumor from growing. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known whether combination chemotherapy is more effective with or without ZD1839 for non-small cell lung cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of combination chemotherapy with or without ZD1839 in treating patients who have stage III or stage IV non-small cell lung cancer.

Condition Treatment or Intervention Phase
 
stage IV non-small cell lung cancer
stage IIIB non-small cell lung cancer
recurrent non-small cell lung cancer
quality of life
Drug: carboplatin
Drug: paclitaxel
Drug: ZD 1839

Study Type: Treatment

Official Title: Phase III Randomized Study of ZD 1839 Combined With Paclitaxel and Carboplatin in Chemotherapy Naive Patients With Stage IIIB or IV Non-Small Cell Lung Cancer

Further Study Details: 

OBJECTIVES: I. Compare the 1 year survival rate, time to worsening of disease related symptoms, and progression free survival in chemotherapy naive patients with stage IIIB or IV non-small cell lung cancer treated with one of two doses of ZD 1839 or placebo combined with paclitaxel and carboplatin.

II. Compare the quality of life of patients treated with these three regimens.

PROTOCOL OUTLINE: This is a randomized, double blind, placebo controlled, multicenter study.

Patients are randomized to one of three treatment arms. All patients receive paclitaxel IV over 3 hours followed by carboplatin IV over 15-30 minutes on day 1. Patients receive lower dose oral ZD 1839 (arm I), higher dose oral ZD 1839 (arm II), or placebo (arm III) twice on day 1, and then once daily thereafter. Chemotherapy repeats every 3 weeks for a maximum of 6 courses. ZD 1839 or placebo continues daily in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed prior to study, then every 3 weeks until completion of chemotherapy, then every 4 weeks until completion of oral ZD 1839 or placebo, and then every 8 weeks thereafter.

Patients are followed every 8 weeks.

PROJECTED ACCRUAL: A total of 1,029 patients will be accrued for this study.

Eligibility

Ages Eligible for Study:  18 Years  and above
Criteria  

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

Histologically proven non-small cell lung cancer Stage III disease that is not curable with surgery or radiotherapy OR Stage IV disease

Chemotherapy naive--Prior/Concurrent Therapy--

Biologic therapy: Not specified Chemotherapy: See Disease Characteristics

Location and Contact Information

Delaware
AstraZeneca Pharmaceuticals LP, Wilmington,   Delaware,   19850-5437,   United States; Recruiting Patient Inquiries (In the US & Canada) AstraZeneca Pharmaceuticals LP  1-800-236-9933   
Study ID Numbers  199/15265;  ZENECA-1839IL/0017; MSKCC-00100
NLM Identifier  NCT00006049  

1.6 OTHER TYRONISE KINASE INHBITORS FOR LUNG CANCER

    1.61 OSI 771

OSI 771 is another Tyrosine Kinase Inhibitor which has shown modest results in Phase 2 trials.

A recent presentation to the American Society of Clinical Onoclogy stated:

"The EGFR is over-expressed in many solid tumors including NSCLC. Pre-clinical studies with OSI-774 revealed potent and selective inhibition of EGFR autophosphorylation and cell proliferation in vitro and in mouse xenograft models. The objectives of this trial were to determine the objective tumor response rate, time to progression, survival, pharmacokinetics, safety and quality of life associated with the oral administration of 150mg OSI-774 given daily until disease progression....  Fifty-six pts (23 males and 33 females) were enrolled with a median age of 61 (range 31-79)....

 Seven pts achieved a partial response at 8 weeks, six confirmed at 12 weeks (11%), 19 pts (34%) had stable disease, and 31 pts tumor progression. All 6 responders developed cutaneous rash versus 15 of 19 with stable disease and 23 of 31 with progressive disease. .. OSI-774 as daily oral therapy is well tolerated and has significant anti-tumor activity in pts with advanced NSCLC after failing platinum-based combination chemotherapy. Time to progression and survival data will be presented.

Sololer, Phase II Trial of the Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor OSI-774, Following Platinum-Based Chemotherapy, in Patients (pts) with Advanced, EGFR-Expressing, Non-Small Cell Lung Cancer (NSCLC).
\

1.62 C225 Monoclonal Antibody

1.63 Herceptin

1.65 Effectiveness Questions

It is unclear which of these drugs is the most effective and why.   Why do certain anti-egfr drugs work in certain areas?


APPENDIX 2 REFERENCES- DEALING WITH IRESSA

FDA Website, initial evaluation of Iressa.

http://www.fda.gov/ohrms/dockets/ac/02/briefing/3894B1_01_AstraZeneca.pdf
(comprehensive report on Iressa).

1. ZD1839 ('Iressa') as an anticancer agent. Drugs (New Zealand), 2000, 60 Suppl 1 p33_40; discussion 41_2

2. Lynch, Lung cancer highlights. Oncologist (United States), 2000, 5(4) p274-9

3. Ciardiello F. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD_1839 (Iressa), an epidermal growth factor receptor_selective tyrosine kinase inhibitor. Clin Cancer Res (United States), May 2000, 6(5) p2053_63

4. Meric JB, Zd 1839 Iressa Bull Cancer (France), Dec 2000, 87(12) p873_6 

5. Sirotnak FM, Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res (United States), Dec 2000, 6(12) p4885_92

6. Faivre S, Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs (New Zealand), 2000, 60 Suppl 1 p15_23; discussion 41_2

7. Ciardiello F Epidermal growth factor receptor tyrosine kinase inhibitors as anticanceragents. Drugs (New Zealand), 2000, 60 Suppl 1 p25_32; discussion 41_2

 8.  Fortunato, Inhibition of Growth Factor Production and Angiogenesis in Human Cancer Cells by ZD1839 (Iressa), a Selective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor. Clin Cancer Res (United States), May 2001, 7(5) p1459-1465

9. Denny The 4-anilinoquinazoline class of inhibitors of the erbB family of receptor tyrosine kinases. Farmaco (Italy), Jan_Feb 2001, 56(1_2) p51_6

10. Iressa Shows Promising AntiTumor Activity and is Well Tolerated with Minimal Side Effects: Oncology News, Vo. 9, no. 7, Supp 3 (July 2000).

11. Zhonghua, The growth inhibition of anti-EGF receptor monoclonal antibody to human lung adenocarcinoma cells 1998 Apr;21(4):233-5

12.  Sudbeck, Tyrosine kinase inhibitors against EGF receptor-positive malignancies.Methods, Mol Biol 2001;166:193-218

 

APPENDIX 3 OSI 774 PRESS RELEASE
 

OSI, Genentech's OSI-774 Does Well Against Lung Tumor (Update1)
 
 

5/12/01 6:36 PM
Source:Bloomberg News

San Francisco, May 12 (Bloomberg) -- OSI Pharmaceuticals Inc.'s and Genentech Inc.'s experimental cancer drug OSI-774 performed well enough against a common type of lung tumor for final testing to start later this year, researchers said.

OSI-774, also known as Tarceva, was given to 57 people with advanced non-small-cell lung cancer that wasn't responding to other treatments. Tumors disappeared or shrank by at least half in 16 percent of the patients, and stopped growing for at least three months in another 26 percent.

''The data continue to show a very positive picture for the drug,'' said Colin Goddard, OSI's chief executive. The study was presented at the annual meeting of the American Society of Clinical Oncology.

Median survival for patients in the study was 257 days and about 48 percent of patients survived for at least a year, he said.

In a separate study of OSI-774 in inoperable head-and-neck cancer, the drug performed worse than the company reported in November, leaving some analysts to question the drug's potential for that disease. The study showed that tumors stopped growing in 39 percent of 124 patients, though tumors shrank by at least half in just 6 percent of patients.

South San Francisco-based Genentech and its majority owner, Roche Holding AG, agreed in January with Uniondale, New York-based OSI to co-develop and market OSI-774. They are racing with makers of similar drugs that target a substance called EGF linked to cancer-cell growth, such as ImClone Systems Inc. and AstraZeneca Plc.

First in Class

ImClone's drug, IMC225, could be the first in the new class to be approved. The company plans to first seek approval in June for IMC225 for colorectal cancer, though it's also studying it in diseases including lung cancer.

For OSI-774, the most direct competition in the class is AstraZeneca's drug, Iressa, which Goddard said is one year ahead in development for lung cancer.

''There's certainly advantages to being first,'' he said, adding that the large potential patient population leaves room for both drugs to compete.

Lung cancer is the leading cause of cancer death and has about 169,500 new cases each year, according to the American Cancer Society.

Both studies are from the second of three phases of testing generally required for U.S. approval. The U.S. Food and Drug Administration traditionally approves cancer drugs on the basis of tumor shrinkage.

OSI-774's most common side effects are rash and diarrhea, researchers said. OSI presented preliminary data on the drug in both diseases at a European medical conference last year. The company will report the results of an ovarian cancer trial later at the ASCO meeting.

OSI and Genentech said they will start so-called phase III trials on the drug as a first-line treatment for non-small-cell lung cancer later this year.

Genentech shares fell $1.60 to $50.60 yesterday. OSI fell $1.75 to $43.55.

APPENDIX 3A OSI 774 REFERENCES FROM MANUFACTURER'S WEBSITE

Presented at the American Society of Clinical Oncology’s (ASCO) 37th Annual Meeting, San Francisco, California, May 12-15, 2001

#1235 A phase II trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor OSI-774, following platinum-based chemotherapy, in patients (pts) with advanced EGFR-expressing, non-small cell lung cancer (NSCLC). 1R Perez-Solar, 1A Chachoua, 2M Huberman, 2D Karp, 3J Rigas, 4L Hammond, 4E Rowinsky, 4G Preston, 5KJ Ferrante, 5LF Allen, 6PI Nadler, 7P Bonomi, 1NYU School of Medicine, NYC, 2Beth Israel Deaconess Med Ctr, Boston, MA; 3Dartmouth-Hitchcock Med Ctr, Lebanon, NH; 4Institute for Drug Development, San Antonio, TX; 5Pfizer Inc., Groton, CT; 6OSI Pharmaceuticals, Inc., Uniondale, NY; 7Rush Cancer Inst., Chicago, IL.

#6 Phase 2 Evaluation of OSI-774, a Potent Oral Antagonist of the EGFR-TK in Patients with Advanced Squamous Cell Carcinoma of the Head and Neck. N. Senzer, D. Soulieres, L. Siu, S. Agarwala, E. Vokes, M. Hidalgo, S. Silberman, L. Allen, K. Ferrante, D. Fisher, C. Marsolais, and P. Nadler, Texas Oncology, Dallas, TX, Hospital Notre Dame, Montreal, Princess Margaret Hospital, Toronto, University Pittsburgh Cancer Center, Pittsburgh, PA, University of Chicago, Chicago, IL, Cancer Therapy and Research Center, San Antonio, TX, Pfizer, Inc., Groton, CT, Pfizer, Canada, and OSI Pharmaceuticals, Inc., Uniondale, NY.

#831 Phase 2 Evaluation of OSI-774, A Potent Oral Antagonist of the EGFR-TK in Patients with Advanced Ovarian Carcinoma. Neil Finkler, Walt Disney Memorial Cancer Institute, Orlando, FL, Alan Gordon, US Oncology, Dallas, TX, Mark Crozier, Robert Edwards, Magee-Women’s Hospital, Pittsburgh, PA, Jose Figueroa, Joe Arrington Cancer Research and Treatment Center, Lubbock, TX, Agustin Garcia, USC/Norris Cancer Hospital, Los Angeles, CA, John Hainsworth, The Sarah Cannon Cancer Center, Nashville, TN, David Irwin, Alta Bates Comprehensive Cancer Center, Berkeley, CA, Sandra Silberman, Lee Allen, Karen Ferrante, Douglas Fisher, Pfizer, Inc., Groton, CT, Paul Nadler, OSI Pharmaceuticals, Inc., Uniondale, NY.

#5 Dose-Schedule-Finding, Pharmacokinetic (PK), Biologic, and Functional Imaging Studies of OSI-774, a Selective Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase (TK) Inhibitor. E. Rowinsky, L. Hammond, L. Siu, P. Jerabek, J. Rizzo, L. Denis, J. Nemunatis, A. Patnaik, S. Eckhardt, A. Tolcher, C. Takimoto, K. Ferrante, L. Allen, S. Silberman and M. Hidalgo. Cancer Therapy and Research Center, San Antonio, TX, US Oncology, Houston, TX, Pfizer, Inc, Groton, CT, and OSI Pharmaceuticals, Uniondale, NY.

# 281 Inhibition Of The Epidermal Growth Factor Receptor (EGFR) By OSI-774, A Specific EGFR Inhibitor, In Malignant And Normal Tissues Of Cancer Patients. Manuel Hidalgo, Shazly Malik, Erik Rowinsky, Alexander Miller, Dianne Duffey, Linda de’Grafenried, University of Texas Health Science Center at San Antonio; Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, Lillian Siu, Princess Margaret Hospital, Toronto, Canada, Cecelia Simmons, Jeffrey Kreisberg, Paul Nadler, OSI Pharmaceuticals, Uniondale, NY; Michael Brattain, University of Texas Health Science Center at San Antonio; Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX.

Presented at the 92nd American Association for Cancer Research (AACR) Annual Meeting in New Orleans, March 24-28, 2001

#4565 - Inhibition of the Epidermal Growth Factor Receptor (EGFR) Activation and Signaling by OSI-774, a Novel EGFR Inhibitor, in Clinical Specimens of Head and Neck Carcinoma. Shazli Malik, Michael Brattain, Eric Rowinsky, Alexander Miller, Diane Duffey, Linda deGraffenried, Lillian Siu, Cecelia Simmons, Jeffrey Kreisberg, Paul Nadler, Manuel Hidalgo, University of Texas Health Science Center at San Antonio, San Antonio, TX; Institute for Drug Development, San Antonio, TX; Princess Margaret Hospital, Toronto, Canada; OSI Pharmaceuticals, New York.

#4578 – Antiproliferative Effect of CP 358, 774, an Inhibitor of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase, on Glioblastoma Multiforme (GBM) Cells in Vitro. Marc-Eric Halatsch, Esther E. Gehrke, Ursula Schmidt, Herbert Kolenda, Georg-August-University, Goettingen, Germany; Medizinische Hochschule, Hannover, Germany.

#5140 – Probing EGFR Signaling in HN5 Squamous Carcinoma Using the Quinazoline EGFR Inhibitor OSI-774 and Coupled Affinity Chromatography and Mass Spectrometry. John D. Haley, April Theleman, Heng Pan, David Fenyo, Kenneth Iwata, Arthur Bruskin, OSI Pharmaceuticals Inc, Uniondale, NY; Proteometrics LLC, New York, NY.

 

Presented at the 11th NCI-EORTC-AACR Symposium on New Drugs in Cancer Therapy (Amsterdam), November 7-10, 2000

#387 A Phase II, Multi-Cancer Study Of The Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI), OSI-774 (Formerly CP-358,774), In Patients (Pts) With Advanced Squamous Cell Carcinoma Of The Head Neck (SCCHN). LL Siu, D Soulieres, N Senzer, S. Agarwala, E Vokes, D Fisher, C Marsolais, KJ Ferrante, LF Allen.

#386 Phase II trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), OSI-774 (formerly CP-358,774), following platinum-based chemotherapy in patients (pts) with advanced non-small cell lung cancer (NSCLC). PD Bonomi, R Perez-Soler, A Chachoua, M Huberman, D Karp, J Rigas, L Hammond, E Rowinsky, G Preston, KJ Ferrante, LF Allen.

#385 18FDG-PET evaluation of patients treated with epidermal growth factor (EGFR) tyrosine kinase (TK) inhibitor, OSI-774 (formerly CP-358,774). Hammond, LJ Denis, UA Salman, K Chintapalli, M Hidalgo, P Jeraback, A Patnaik, LF Allen, KJ Ferrante, WO Carter, J Kuhn, R Drengler, S Silberman, EK Rowinsky.

#384 Investigation of the effects of OSI-774 (formerly CP-358,774) on various human tumor specimens taken directly from patients. LF Allen, C Cerna, L Gomez, M Yochmowitz, L Medina, S Weitman.

Presented at the 9th World Conference on Lung Cancer (Tokyo, Japan) September 11- 15, 2000

#208 A Phase I Dose Escalation Study of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase (TK) Inhibitor CP-358,774 in Patients (pts) with Advanced Solid Tumors. Karp DD, Ferrante KJ, Tensfeldt TG, Thurer RL, LoCicero III J, Huberman MS. Wirth F, Hellman R, Poulin P, Silberman SL, Redifer P, Allen LF, Posner M, Schnipper LE (Boston, MA, USA).

Presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO) May 15-18, 1999

#1499 Phase I Dose Escalation Study of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase (TK) Inhibitor CP-358,774 in Patients with Advanced Solid Tumors. D.D. Karp, S.L. Silberman, R. Csudae, F. Wirth, L. Gaynes, M. Posner, G. Bubley, H. Koon, M. Bergman, M. Huang, L.E. Schnipper. Beth Israel Deaconess Medical Center, Boston, MA; Pfizer Inc. Groton, CT.

#1498 Dose and Schedule-Duration Escalation of the Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase (TK) Inhibitor CP-358, 774: A Phase I and Pharmacokinetic (PK) Study. L.L. Siu, M. Hidalgo, J. Nemunaitis, J. Rizzo, J. Moczygemba, S.G. Eckhardt, A. Tolcher, L. Smith, L. Hammond, A. Blackburn, T. Tensfeldt, S. Silberman, D.D. Von Hoff, E.K. Rowinsky. Cancer Therapy and Research Center, San Antonio, TX.; PRN Research, Inc., Dallas, TX.; Pfizer Inc., Groton, CT.

Presented at the American Association for Cancer Research Annual Meeting April 12-16, 1997

#3143 Induction of cell cycle arrest by inhibitors of epidermal growth factor receptor (EGFR) kinase activity. Barbacci, E.G., Cunningham, A., lwata, K., Moyer, J.D., and Miller, P.E. Pfizer Central Pesearch, Groton, CT 06340, Oncogene Science Inc., Uniondale, NY

#4248 CP-358,774: A selective EGFR kinase inhibitor with potent antiproliferative activity against HN5 head and neck tumor cells. lwata, K., Miller, P.E., Barbacci, E.G., Arnold, L., Doty, J., DiOrio, C.I., Pustilnik, L.R., Reynolds, M., Thelemann, A., Sloan, D., and Moyer, J.D. Oncogene Science Inc., Uniondale, NY 1 1553-3649, Pfizer Central Research, Groton, CT 06340

#4010 Pharmacokinetics and metabolism of CP-358,774, a potent and selective EGF receptor tyrosine kinase inhibitor. Smolarek, T.A., Vaidya, M.P., Davis, J., Turncliff, R., Pollack, V.A., Savage, D.M., Baker, D.A., Tsaparikos, K.E., Pustilnik, L.R., Moyer, J., Cole, M.J., Arnold, L.D., and Doty, J.L. Pfizer Central Pesearch, Groton, CT 06340

#3139 Tissue distribution of CP-358,774, a selective and potent EGF receptor tyrosine kinase inhibitor in HN5 tumor-beafing, athymic nu/nu (nude) mice. Potchoiba, M.J., West, M., Smolarek, T.A., Pollack, V., and Baker, D. Pfizer Central Pesearch, Groton, CT 06340

#3140 Pre-clinical safety assessment of CP-358,774, an epidermal growth factor receptor tyrosine kinase inhibitor. Updyke, L., Smolarek, T., Guzzie, P., Newton, R., Muelbauer, P., Sanders, M., Gonsalves, S., Fossa, A., Zorn, S., Migliaccio, J., Vaidya, M., Miller, M., Floyd, E., Emeigh-Hart, S., and Hakkinen, J. Pfizer Central Research, Groton, CT 06340

#4249 Therapy of human carcinomas in athymic mice by inhibition of EGF receptor-mediated signal transduction with CP-358774: Dynamics of receptor inhibition and anti-tumor effects. Pollack, V.A., Savage, D.M., Baker, D.A., Tsaparikos, K.E., Sloan, D.E., Barbacci, E.G., Pustilnik, L.R., Smolarek, T.A., Davis, J.A., Vaidya, M.P., and lwata, K. Dept. of Cancer, Pfizer Central Research, Groton, CT 06340, Oncogene Science, Inc., Uniondale, NY II 553

CANCER RESEARCH 57, 4838-4848, November 1, 1997

Induction of Apoptosis and Cell Cycle Arrest by CP-358,774, an Inhibitor of Epidermal Growth Factor Receptor Tyrosine Kinase. James D. Moyer,1 Elsa G. Barbacci, Kenneth K. Iwata, Lee Arnold, Bruce Boman, Ann Cunningham, Catherine DiOrio, Jonathan Doty, Michael J. Morin, Mikel P. Moyer, Mark Neveu, Vincent A. Pollack, Leslie R. Pustilnik, Margaret M. Reynolds, Don Sloan, April Theleman, and Penny Miller

The Journal of Pharmacology and Experimental Therapeutics JPET 291:739-748, 1999

Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. Pollack VA, Savage DM, Baker DA, Tsaparikos KE, Sloan DE, Moyer JD, Barbacci EG, Pustilnik LR, Smolarek TA, Davis JA, Vaidya MP, Arnold LD, Doty JL, Iwata KK, Morin MJ

1.23 What are tyrosine kinase inhibitors

"scientists have been able to develop a new group of cancer therapy agents known as tyrosine kinase inhibitors. By blocking the ability of protein tyrosine kinase to function, these compounds provide a valuable tool for controlling cancerous cell growth

Tyrosine kinase are enzymes within the cell that function to attach phosphate groups to the amino acid tyrosine. This process of phosphorylation serves two primary roles, as a molecular on_off switch and as a connector that binds proteins to one another. In these roles, tyrosine kinase can trigger a cascade of cellular events when phosphorylation stimulates additional enzymes, or when it prompts proteins to change their location. Tyrosine phosphorylation is therefore an early event in a complex signaling system that transfers information from the outside of the cell into the nucleus....

It is in this manner that cells react to molecular cues, such as hormones and growth factors that bind to receptors on the cell surface. When these ligand bind to receptors, tyrosine kinase are activated and the signaling cascade begins. Many receptors are tyrosine kinase themselves, or are located close to other tyrosine kinase, so signals can be quickly transmitted after ligand binding at the cell surface way that cancer cells achieve their excessive proliferation is due to mutations in genes that code for signaling proteins. Such mutations often result in a continual "on" signal for cell proliferation. When this happens, the signaling cascade acts as a survival mechanism that allows the tumor cells to grow out of control. With their survival assured, these tumor cells are particularly aggressive and often resistant to standard forms of chemotherapy.

Because phosphorylation triggers the signaling cascade, researchers have developed tyrosine kinase inhibitors in an attempt to turn cell growth "off". Studies have shown that these inhibitors cause rapid cell death when the cancerous survival mechanism is deactivated. Thus, for tumors that use tyrosine kinase signals to maintain constant proliferation, these inhibitors are promising therapeutic agents. Certain leukemias, as well as cancer of the breast, prostate, ovary, bladder, liver, and lung are within the category of tumors that may be successfully treated with tyrosine kinase inhibitors.." www.parkerhughes.org/pages/tyrosine_kinase_inhibitors.html

BOOKS 

1. Pass, Lung Cancer Principles and Practice (Lippincott 2000) (Book)

PERIODICALS DEVOTED TO IRESSA AND EGFR

1. Signal, The Journal of EGFR-Targeted Cancer Therapy, available online through Astra-Zeneca's website, www.EGFR-Info.com

FURTHER INFORMATION

1. www.egfr-info.com (informative site devoted to epidermal growth factor research, includes
Signal magazine.

2. www.AstraZenecaus.com

3. www.asco.org Online support groups, subscribe to non-small cell lung cancer and Iressa.

4. Although it is not directed solely to Iressa, the New England Journal of Medicine permits free use of its volume excepting those written during the last six months.  This is an excellent way of reviewing medical literature by the leading journal.

Books

The best book on lung cancer is Harvey Pass, et. al., Lung Cancer, Principles and Practice.  Superbly researched and compiled, the book covers virtually every major topic about lung cancer including chemotherapy, radiation, P-53 gene therapy, and surgery.   If you want to know how your physician will address a particular problem or situation, the book will provide considerable information.  The book is however expensive (about 175.00), designed for physicians, and has only limited coverage of Iressa because it was completed in 2000.  Nonetheless, taking a half day, with a dictionary, to read some of the material is the course I would recommend for patients interested in lung cancer research and study.   It is available at Amazon through the link below or at most medical school libraries.  Start at page 367 and skip chapter one which is unnecessarily technical.   Another excellent book is Devita, Cancer Principles and Practice of Oncology, but also expensive. 

More reasonably priced and designed for patients and family members is Lorraine Johnson's book, Lung Cancer, Making Sense of  Diagnosis.  The book review different treatments and other issues.

www.amazon.com

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