Lung Cancer Newsletter Spring 2007

                                              Review of Tarceva and EGFR Inhibitors

 

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I. Tarceva and EGFR Inhibitors

A. Response to Tarceva and Iressa- EGFR Mutation

Studies have shown that response to Iressa and Tarceva* correlates with the existence of a mutation in the epidermal growth factor receptor. (EGFR).  These drugs are EGFR inhibitors with the EGFR the target of recent medical research.  Lynch first found in 2004, "mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response." Lynch (1).  We now see:                    

"Targeting the epidermal growth factor receptor (EGFR) has played a central role in advancing NSCLC research initiatives, treatment, and patient outcome over the last several years. Novel targeted therapeutic agents, including the small-molecule tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib and the monoclonal antibody cetuximab, have been developed to interfere with EGFR signaling Soon after the TKIs were introduced, it became apparent that certain patient characteristics, including a never-smoking history, adenocarcinoma tumor histology, female gender, and East Asian origin, were correlated with improved response to the drugs and improved survival after treatment  One of the explanations for the improved outcome in these patient subsets was elucidated in 2004, when somatic mutations within the EGFR  gene itself were discovered   EGFR mutations are associated with both TKI response and prolonged survival and occur more frequently in the NSCLC patient subsets mentioned above . The mutations cause EGFR to transduce an intracellular antiapoptotic signal, upon which the cancer cells become "addicted" .  Administered EGFR TKIs interrupt the necessary survival signal, thus rendering the cell exquisitely susceptible to apoptosis."  Seequist (14).

The mutation is shown in a test pioneered at Harvard and Dana Farber and now commercially available. Lynch (1).   Let me first review the medicine behind these new drugs.

B. Overview of the EGFR

       
   1. Erb Family

EGFR or Erb 1 is a member of the ErbB family of RTKs,  which includes ERB2, ERB3,  and ERB4.   The EGFR gene is located at chromosomal region 7p12.      

           2.  The Tyrosine Kinase Family

EGFR is  a member of the  receptor tyrosine kinase (RTK) family.  These are called cell-surface receptors which receive and transmit signals for other cells.  "Phosphorylated tyrosines lead to the activation of the downstream pathways of EGFR thus resulting in cell proliferation, differentiation, migration/motility, protection from apoptosis (cell death), or angiogenesis (formation of tiny blood vessels which facilitates metastasis ."  (Sugio (16).  Cancer is really a communication malfunction among cells or defect in cell regulation. 

EGFR is normally found on the surface of epithelial cells and has been found to be commonly overexpressed in a variety of human malignancies  Different ligands can lead to EGFR activation and subsequent signal transduction, including the epidermal growth factor, the transforming growth factor {alpha}, and neuregulins. After ligand binding to the extracellular receptor domain, EGFR undergoes homo- or heterodimerization and autophosphorylation of its intracellular tyrosine kinase domain. These autophosphorylation events trigger a cascade of downstream signals that ultimately result in an increase of cellular motility, proliferation and invasion, and a block of apoptosis, contributing to cancer development and progression Toschi (21).   

 3. Mutation

Cells have a long-string of commands.  A small deviation in one of these commands. observable only through detailed testing, may contribute to carcinogenic behavior.   After finding a series of mutations in patients who responded, scientists presented the hypothesis that response is connected with mutation.

            4. Mechanisms of Iressa

Lynch explains the mechanism of Iressa ( generic name gefitinib) :

Gefitinib targets the ATP cleft within the tyrosine kinase epidermal growth factor receptor (EGFR), which is overexpressed in 40 to 80 percent of non–small-cell lung cancers and many other epithelial cancers.  EGFR signaling is triggered by the binding of growth factors, such as epidermal growth factor (EGF), resulting in the dimerization of EGFR molecules or heterodimerization with other closely related receptors, such as HER2/neu.  Autophosphorylation and transphosphorylation of the receptors through their tyrosine kinase domains leads to the recruitment of downstream effectors and the activation of proliferative and cell-survival signals.  Lynch 1

Apoptosis or cell death is one method by which the body rids itself of malfunctioning or defective cells.  One method by which a malfunctioning  EGFR promotes cancer, is to send anti-apoptotic signals so that these defective cells do not undergo cell death but instead proliferate.

 C.  Response and the EGFR 

        1. Response Rates for those with the EGFR Mutation

Conventional chemotherapy response rates are generally in the 20-25% rates for non-small cell lung cancer patients.   However the response rate for patients with the mutation is much greater frequently exceeding 60%.   Han found response rate for patients with the mutation of 61.5%. (2).  One study found in an astounding 91% response among Asian non-smokers with the mutation:

Sharma just published a comprehensive overview on Tarceva and Iressa treatment and states,  "Most retrospective studies to date have reported that 50-80% of EGFR-mutant NSCLCs respond to gefitinib or erlotinib, and more recent studies from Asia, where EGFR mutant NSCLC is 2-3 times more prevalent, have reported responses in more than 75% of NSCLC cases with mutant EGFR." Sharma (5).

        2. Why Those with the Mutation Respond to Tarceva

Studies first showed that EGFR mutation played a substantial role in some lung cancers.  Scientists then found the EGFR drugs were able to interrupt that aberrant signal.

"EGFR mutations are associated with both TKI response and prolonged survival and occur more frequently in the NSCLC patient...  The mutations cause EGFR to transduce an intracellular antiapoptotic signal, upon which the cancer cells become "addicted."   Administered EGFR TKIs interrupt the necessary survival signal, thus rendering the cell exquisitely susceptible to apoptosis." Sequist (14)

However, there are possible limitations to Tarceva.  Even if a tumor is EGFR driven, other methods of signaling are conceivable:

Gefitinib and erlotinib are both fairly selective for the EGFR TK domain . However, the signaling network that emerges from the ErbB family of transmembrane TK receptors (of which EGFR is a member) is large, interconnected, and redundant, with many possible routes between the ligand at the cell surface and the message destination within the nucleus . It is this diversity in possible signal transduction routes that allows a cell to have flexibility and, in the case of cancer cells treated with targeted anticancer agents, allows for the emergence of resistant cell clones that bypass the inhibited receptor.    Blocking multiple signaling pathways with either a combination of agents or a single multi-targeted drug has been synergistic in preclinical models . Second-generation EGFR TKIs have been developed that, in addition to blocking EGFR signaling, target additional members of the ErbB family such as HER-2 or other downstream or parallel pathways such as the vascular endothelial growth factor receptor (VEGFR) pathway.  (Sequist 14).

D. Who has the Mutation

                            1. Smoking History

Non-smokers and very light former smokers are the predominant groups with the mutation. Analyses showed an association between EGFR mutation and ... never smoker status. Riely (20)  Sharma (6) .   "A minimal smoking history was the strongest clinical predictor of harboring a mutation. In multivariable analyses, each pack-year of smoking corresponded to a 5% decreased likelihood of having an EGFR mutation."
Seequist (14).  "The mean number of pack-years smoked was significantly lower among EGFR mutation-positive patients (5.9 pack-years) compared with EGFR mutation-negative patients (30.8 pack-years)."  Seequist (14).   Yet there is no specific threshhold or breaking point, above which a mutation is not possible.  Instead there are estimates and probabilities.  Some non-smokers do not have the mutations, and and occasionally a heavy smoker will.  

                                        a. Non-smokers

Sugio (16) found 57% of non-smokers with the mutation.

                                        b. Light Former Smokers

The lower the amount of smoking the more likely there will be mutation.   Riely (2) found a median smoking history of 9 pack years, a smoker of limited duration, or amount.  (Years smoked x packs per day = pack years).   The association between limited history and mutation is  generally seen in various studies, but the studies vary and most do not show a clear dose relationship  Sugio (16).   

                                        c. Current and + 25 year smokers

EGFR mutation predominates among non-smokers and light former smokers.  Yet there remains some data finding the mutation among those who have substantial smoking history and even current smokers. 

Study Author                                             Results                                                                       Comments

Sugio (16) Sugio found 15% of smokers with the mutation. (16)  
Riely (20) 70 of 291 samples with found with the EGFR mutation.  Of this group, 6 current or former smokers with over 25 pack years of exposure were found.   
Horiike (19 )    
     

Riely likewise found most with the mutation to be non-smokers or light smokers, but nonetheless found some heavy smokers with the mutation including 3 heavy-smoking patients with over 70 pack years of exposure.

                             2.  Type of Cancer- Adenocarcinoma versus other subtypes

                                        a. Squamous cell mutations 

Adenocarcinoma is the predominant type of lung cancer with the mutation.  Whether squamous cell tumors have the EGFR mutations continues to be investigated with varying, sometime conflicting results.

Study Author                                             Results                                                                       Comments

Sugio (16) Sugio tested 102 specimens of squamous cell carcinoma and found none with the mutation. Various aspects of this study must be questioned, since low rate of non-smokers with mutation and high rate of smokers conflict with data elsewhere.
Horiike (19 ) "Mutations were detected in 31 patients ...  Of these, 23 patients had adenocarcinoma, 4 had squamous cell carcinoma." Test used transbronchial tissue rather than biopsy; whether that is significant remains to be seen.


                                        b.   Small cell

Sugio tested 13 pathological sample of small cell and found none had the mutation.   Lynch (1) tested 6 cell lines and found none with the mutation.

                                        c. Large Cell

None of the 3 large cell samples Lynch tested had the mutation.  Lynch (1) .  Sugio tested 27 samples of large cell carcinoma and found one with the mutation.

                                         d. Adenocarcinoma

Sugio tested 322 sample and found 136 cases (42.2%) with EGFR mutations.  These were primarily non-smokers and light former smokers.   

                                          e. Bronchoalveolar cancer

                              3. Gender

Studies have found more women with the mutation.  Sugio found only 20% of men with the mutation, but 45% of women.  (16).  While there is a consensus that more mutations exist among women, there is no agreement about the reason and even limited speculation.    

                              4. Race and Location

Asians have a greater proportion of mutations, but the reasons likewise remains unclear.  

                              5. Kras Mutation as a Negative Indication

It appears the existence of an EGFR and KRas mutation are usually mutually exclusive.   "We analysed the mutations of K-ras codon 12 in patients with adenocarcinoma, and detected a mutation in 29 cases (9.0%), but none of them had the EGFR mutations." Sugio (16)                                          

                                          a. Non-smokers with the Kras Mutation

The Kras mutation is associated with smoking.   Five of 129 patients who were never smokers had the K-ras mutation, while 24 of 193 patients who were current/former smokers had the mutation." Sugio (16).                    

                 4. Response and Survival benefit

Clearly those with the mutation have impressive partial and complete responses exceeding other treatments. It is not clear to what extent Iressa increases survival, and in which groups.

Additionally some responders may not have an EGFR mutation. Not all patients who carry an EGFR mutation respond to gefitinib and, conversely, there are patients who respond to gefitinib without an EGFR mutation, making somewhere complicating drug selection.  Sharma  (5).   Generally those who respond will have the mutation and be non-smokers or less frequently light former smokers.  Scientists are now dividing EGFR mutations to determine which predictor response and resistance.

D. Location and Prevalence of EGFR Mutations

Non-small cell lung cancer (NSCLC) mutations are concentrated in exons 18-21 of the EGFR.  Glioma,  another type of cancer, involve another part of the EGFR, the extra-cellular domain.  Lynch (1). 

Sharma explains the mutations locations in NSCLC :

The question arises, can we further delineate predictors of response among these various exons. Which exons are likely to experience responses, which are less likely to respond, and what particular mutations will confer resistance to Iressa.

                1. Exon 18

Exon 18 is the nucleotide binding group and comprises only about 5% of mutations. Sharma (5).  The mutation involves substitution of G719 in the nucleotide-binding loop of exon 18,

                2. Exon 19

                       a. Prevalence

Exon 19 mutations comprise at least 40% of mutations.  Sugio found an in-frame deletion in exon 19 was found in 62 of 136  cases of mutations. (16).   Riely (20) found 43 or 61% of tissue samples had an EGFR exon 19 deletion. 

                       b. Response and Survival Rates

The exon 19 mutations generally respond to Iressa. They appear to play a role in cancer formation and spread:

Jackman found,

Patients with an exon 19 deletion had a significantly longer overall survival compared with patients with an L858R mutation (38 versus 17 months; P = 0.04). There were also trends toward higher response rate (73% versus 50%) and improved time to progression (24 versus 10 months) for the patients with an exon 19 deletion, although these were not independently significant in a multivariate analysis

                       a. L858R

The most frequently EGFR mutations are L858R and deletions in exon 19.  These two mutations have been confirmed to be activating mutations and are extremely sensitive to gefitinib. (Iressa) Han, (2).  Patients with an exon 19 deletion had a significantly longer overall survival... There were also trends toward higher response rate (73% versus 50%) and improved time to progression (24 versus 10 months) for the patients with an exon 19 deletion. See Jackman (6).   6 patients had a deletion in exon 19 (3 E746-A750, 1 L747-A750, 1 L747-P751insP, and 1 E746... {All six} patients with a mutated EGFR responded to gefitinib (100%). Han (2).

                      b. D761Y

A D761Y a T790M-like secondary mutation in exon 19 of EGFR (at the border of exon 19 and exon 20), was also reported to be associated with resistance to gefitinib and erlotinib in NSCLC cells that contain the L858R-EGFR mutation. A Medscape (5).

        3. Exon 20

                     a. T790M Iressa-resistant mutation

Scientists have found a second mutation develops at exon 20 T790M which provides resistance to Iressa/Tarceva. This microspopic and small change at one exon can mean that Iressa or Tarceva will no longer be effective for many patients.

There may be a hereditary component in the development of this mutation:                                                        

                   
"mutations in EGFR identify a subset of non-small cell lung cancer that respond to tyrosine kinase inhibitors. Acquisition of drug resistance is linked to a specific secondary somatic mutation, EGFR T790M. Here we describe a family with multiple cases of non-small cell lung cancer associated with germline transmission of this mutation.  Four of six tumors analyzed showed a secondary somatic activating EGFR mutation, arising in cis with the germline EGFR mutation T790M.  These observations implicate altered EGFR signaling in genetic susceptibility to lung cancer."  Bell (15)

         b. Other characteristics 

Patients with T790M tended to be women, never smokers, and carrying deletion mutations, but the T790M was not associated with the duration of gefitinib administration.

         c. Treatment for the Cell Mutation

Studies of pan-inhibitors suggests that they may be able to inhibit aberrant cell-signaling by this mutation.  T790M mutations block binding of erlotinib and gefitinib to the receptor.  New irreversible EGFR bind to the mutated EGFR and have preclinical activity in such tumors.  Sharma writes,

Testing and identifying T790M mutation is becoming an important goal. Once the mutation is identified, continued use of Tarceva becomes questionable with pan-inhibitors now important alternatives.

                        d. Smoking status and Exon 20

Generally EGFR mutations have been found in non-smokers. Lynch (1). However, one researcher observed, A the exon 20 insertion mutations showed no bias for sex (seven in males versus eight in females) or smoking status (seven in smokers versus eight in never smokers). Shigematzu (11).

        3. Exon 21

            a. L858R substitution

A point deletion at exon 21 at L858R has been identified. A recurrent mutation is the L858R substitution in exon 21 within the activation loop of EGFR, which comprises approximately 40-45% of EGFR mutations.  Sharma (5).   "Paez  reported that the lung cancer cell line H3255 harboring the L858R mutation in EGFR exon 21 was also highly sensitive to gefitinib  and also that both Akt and ERK1/2 pathways in H3255 were highly susceptible to the inhibitory effect of gefitinib."  Ono 22. 

D. Other Predictors of Response to Iressa/Tarceva K-Ras Mutations and Iressa

"K-ras is a downstream mediator of EGFR-induced cell signaling, and ras mutations confer constitutive activation of the signaling pathways without EGFR activation. Growing evidence indicates that K-ras mutations are important in the development of lung carcinomas (19). Pao et al. (20) examined 60 lung adenocarcinoma patients and showed that K-ras mutations are associated with a lack of sensitivity to gefitinib or erlotinib. K-ras mutations seem to be resistant to EGFR-targeting agents and are reported to be mutually exclusive to EGFR or HER2 gene mutations." (Ono 22).

E. Use of Tarceva/Iressa for those without EGFR mutations

Lynch' s seminal study found that those who responded to Iressa had EGFR mutations. Typically those who are non-smokers and light-former smokers with adenocarcinoma. Can Iressa be used outside that target group, and can those without the EGFR mutation benefit from Iressa and Tarceva.

        1. Response to Iressa for those without the mutation

Beginning with Lynch, studies have generally found response concentrated within the EGFR mutation group. Lynch (1). Some studies have questioned whether Tarceva increases survival, partly because the studies have included smokers without the mutation who did not responds. Evidence showing a survival advantage for smokers without the mutation is questionable.

There is nonetheless some evidence supporting the use of Tarceva for smokers. Daniele wrote, A of the 35 patients without EGFR mutation, 14% responded to gefitinib.  Danieli (3)

F. Addressing Resistance and Irreversible Inhibitors

            1. Mechanisms of Resistance

Many patients who initially respond to Iressa develop resistant cells.   What is the mechanism by which cells become resistant to Tarceva. A study examined a primary resistant cell mutation, L858R, and found the resistance associated with the development of the Kras mutation:

           2. HKI 272

HKI 272 is a new drug now undergoing clinical trial.  It has shown the ability to prevent aberrant EGFR signalling among cells with the EGFR mutation.

G. Types of EGFR Detection Programs

        1 Harvard EGFR Program

Its tough to start starting of a program but two years old as the father of detection programs, but that accurate here.  The Harvard/ Massachusetts General program was pioneered by Lynch (1) and later became commercially available. 

        2. Manchester        

Another program was featured in the June 2007 Chest Journal and was able to detect EGFR mutations from less invasive transbrochial secretions, rather than biopsied lung material:                      

The aim of this study was to detect EGFR mutations in transbronchial needle aspiration (TBNA) samples using both direct sequencing and a highly sensitive assay (Scorpions Amplified Refractory Mutation System; DxS; Manchester, UK) [ARMS], and to compare the sensitivity of these methods. Methods: We enrolled 94 patients (63 men and 31 women) with NSCLC in this study. Cytologic diagnoses were adenocarcinoma (n = 58), squamous cell carcinoma (n = 24), and other types of NSCLC (n = 12). We extracted DNA from the TBNA samples, and EGFR mutations were analyzed using both direct sequencing (exons 19 and 21) and the Scorpions ARMS method (E746 A750del and L858R). Results: Mutations were detected in 31 patients (33%; 14 women and 17 men). Of these, 23 patients had adenocarcinoma, 4 had squamous cell carcinoma, and 4 had other types of NSCLC. Direct sequencing detected 13 mutations (14%) in 13 patients (E746-A750del, n = 6; L858R, n = 7), and the Scorpions ARMS method detected 27 mutations (29%) in 27 patients (E746 A750del, n = 16; L858R, n = 11 patients).  Conclusions: Both methods detected EGFR mutations in TBNA samples, but Scorpions ARMS is more sensitive than direct sequencing.  

           3. Sloan-Kettering, New York 

Sloan-Kettering appears to be able to detect mutations by testing within its laboratory-  "We have included all patients with NSCLC on whom successful EGFR genotyping was done in the Laboratory of Diagnostic Molecular Pathology at Memorial Sloan-Kettering Cancer Center. The results of the EGFR mutational analysis, tumor stage, pathologic subtype, and survival were obtained by retrospective chart review. "   Riely (20).

 

Footnotes and References

* I refer to Iressa and Tarceva interchangeably since there are similar results in studies and leave to another day an analysis of possible differences.  Note that Iressa's generic name is Gefitinib.    I use the term mutation to refer to damage to exons 18-21 of the EGFR. 

 

1. Lynch, T. J. 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 2004, 350:2129-39

2. Han, Optimization of Patient Selection for Gefitinib in NonB Small Cell Lung Cancer byCombined Analysis of Epidermal Growth Factor Receptor Mutation, K-ras Mutation, and Akt Phosphorylation, Clinical Cancer Research Vol. 12, 2538-2544, April 15, 2006

3. Daniele, Predicting gefitinib responsiveness in lung cancer by fluorescence in situ hybridization/chromogenic in situ hybridization analysis of EGFR and HER2 in biopsy and cytology specimens, Mol Cancer Ther 2007;6(4):1223B 9.

4. Eberhard, Mutations in the Epidermal Growth Factor Receptor and in KRAS Are Predictive and Prognostic Indicators in Patients With NonB Small-Cell Lung Cancer Treated With Chemotherapy Alone and in Combination With Erlotinib, Journal of Clinical Oncology, Vol 23, No 25 (September 1), 2005: pp. 5900-5909, Journal of Clinical Oncology, Vol 23, No 25 (September 1), 2005: pp. 5900-5909

5. Sheema, Epidermal Growth Factor Mutations in Cancer, www.medscape.com

6. Jackman, D. M. et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin. Cancer Res. 12, 3908-3914 (2006).

7. Yoshida, Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer, J Thorac Oncol. 2007 Jan;2(1):22-8

8. Tang, EGFR Tyrosine Kinase Domain Mutations Are Detected in Histologically Normal Respiratory Epithelium in Lung Cancer Patients, Cancer Res 2005; 65: (17). September 1, 2005

9. Tracy, Gefitinib induces apoptosis in the EGFR[l858r] non-small-cell lung cancer cell line H3255, Cancer Research 64, 7241-7244, October 15, 2004]

10. Gazdar, Inhibition of EGFR Signaling: All Mutations Are Not Created Equal PLoS Medicine Vol. 2, No. 11, (2005).

11. Shegamatzu, The Need for an Individual Approach to Lung Cancer Treatment, PLoS Med. 2006 April; 3(4): e206.

12. Pao, Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain, PLOS Med, 2005 Mar;2(3):e73. Epub 2005 Feb 22.

13. Uchida, Activation of downstream epidermal growth factor receptor (EGFR) signaling provides gefitinib-resistance in cells carrying EGFR mutation, Cancer Sci 2007; 98: 357B 363

14. Sequeist , Response to Treatment and Survival of Patients with Non-Small Cell Lung Cancer Undergoing Somatic EGFR Mutation Testing, The Oncologist, Vol. 12, No. 1, 90-98, January 2007

15. Bell, Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR
Nature Genetics 37, 1315 - 1316 (2005)
 
16. Sugio, Mutations within the tyrosine kinase domain of EGFR gene specifically occur in lung adenocarcinoma patients with a low exposure of tobacco smoking, British Journal of Cancer (2006) 94, 896-903.

17.  Sasaki, EGFR Mutation Status in Japanese Lung Cancer Patients: Genotyping Analysis Using Light Cycler Linical Cancer Research Vol. 11, 2924-2929, April 15, 2005

18. Riley, Update on Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer
Clin. Cancer Res., December 15, 2006; 12(24): 7232 - 7241.

19.  Horiike, Detection of Epidermal Growth Factor Receptor Mutation in Transbronchial Needle Aspirates of Non-Small Cell Lung Cancer . 2007; 131:1628-1634. 

20.  Riely, Clinical Course of Patients with Non–Small Cell Lung Cancer and Epidermal Growth Factor Receptor Exon 19 and Exon 21 Mutations Treated with Gefitinib or Erlotinib, Clinical Cancer Research Vol. 12, 839-844, February 2006.

21.  Toschi, Understanding the New Genetics of Responsiveness to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
The Oncologist, Vol. 12, No. 2, 211-220, February 2007

22.  Ono, Molecular Mechanisms of Epidermal Growth Factor Receptor (EGFR) Activation and Response to Gefitinib and Other EGFR-Targeting Drugs,  Clinical Cancer Research Vol. 12, 7242-7251, December 15, 2006


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