- Email: [email protected]
Getting to grips with gefitinib
Reflection & Reaction many trials because of the complexity of the treatment regimens and the difficulty in ascertaining the relative contributions of polychemotherapy, radiotherapy, etc, to clinical outcome. This exemplifies one of the problems inherent within this Directive; in an attempt to make one regulation applicable to all eventualities it has become too focused on information and process management. The Directive is a minefield of bureaucratic process masquerading as intelligent regulation. This Directive was meant to harmonise and simplify procedures for doing clinical trials across Europe; instead it is very likely that it will have the opposite effect. Proponents will cite the enhanced protection of patients as a fundamental principle behind the Directive but, if it was really about patient protection, why does it only regulate trials investigating drugs? The ‘Clinical Trials’ Directive is a further example of the precautionary principle of risk management that pervades Europe where, irrespective of whether there is any evidence, patients must be protected against some ‘notional’ harm. This attitude is even more harmful to patients than the risks it claims to protect them against, and it is damaging the future of European research. Richard Sullivan and Kate Law Cancer Research UK, 61 Lincoln’s Inn Fields, London, UK.
Association of the British Pharmaceutical Industry says . . . Much concern has been voiced about the implications of the Clinical Trials Directive (2001/20/EC) following
publication of draft UK legislation transposing the ordinance. These concerns have been heightened by the lack of concise information on how the Directive’s implementation will actually be done because of the failure by the European Commission to publish all of its supportive guidance—in particular, the Directive on Good Clinical Practice. It is unlikely, therefore, that final UK legislation will be in place before February, 2004, which allows researchers and sponsors about three months to prepare. The Association of the British Pharmaceutical Industry, however, believes that the final legislation could provide new opportunities. Most phase I cancer trials in the UK are reviewed by the Medicines and Healthcare Products Regulatory Agency (MHRA). For trials involving patients (rather than healthy volunteers) this process takes 60 days, which includes, 30 days for the MHRA to review the proposal, 14 days for sponsors and investigators to answer any questions raised by the MHRA, and 16 days for the MHRA to consider the answers before issuing a clinical trial authorisation (CTA). Following implementation of the EU directive, the MHRA aims to complete at least 80% of all CTA applications within 30 days. For healthy volunteers participating in phase I studies, the timeline will be faster still—with a projected average of just 14 days and a 21-day maximum. Ethics committees will have to complete their work within 60 days. Consequently, UK patients will benefit because clinical trials will start much earlier than currently possible. However, the new accelerated process will lead to more protocol rejections, so investigators and
sponsors will need to be meticulous in their applications. The role of the sponsor is also central to the new legislation. From May 2004, all clinical trials must have a sponsor in order to continue, although funders of individual trials will no longer have to be referred to as sponsors, expanding the potential for closer collaboration between the pharmaceutical industry, investigators, and other funders, such as the UK Medical Research Council. Importantly, pharmaceutical companies with cancer portfolios will be able to fund investigator-lead trials without becoming the actual sponsor. However, the new legislation will cause problems for charities currently providing funds for clinical trials and it is likely that these organisations will be unable to take on the role of sponsor—a consequence that may compel many host institutions to take on this role themselves. The Directive is far from doom and gloom. Indeed, it offers partnership opportunities that could improve the UK as a location for cancer trials. It will be a challenge, but by working together, UK researchers and funders can face it optimistically. Richard Tiner Association of the British Pharmaceutical Industry, 12 Whitehall, London, UK. References
1 Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001. http://europa.eu.int/eurlex/pri/en/oj/dat/2001/l_121/l_121200105 01en00340044.pdf, accessed November 2003. 2 Flavell DJ, Flavell SU, and Sullivan R. European Clinical Trials Directive: responses made to the MHRA consultation letter MLX 287. Lancet 2003; 362: 1415.
Getting to grips with gefitinib A recent article in The Lancet Oncology called into question the mechanism of action of the tyrosine kinase inhibitor gefitinib,1 stating that results presented at the American Association of Cancer Research (Washington, DC, USA, July 11–14, 2003) confirmed that this agent did not act through the epidermal growth factor receptor (EGFR). In fact, THE LANCET Oncology Vol 4 December 2003
this is an incorrect interpretation of the data presented by us at this meeting.2,3 Extensive preclinical studies of gefitinib have shown that this agent blocks signal transduction pathways implicated in the proliferation and survival of cancer cells,4–6 and that EGFR is the target. Gefitinib
inhibited the tyrosine kinase activity of EGFR (prepared from the human vulval squamous carcinoma cell-line A431) with an IC50 of 0·033 M, compared with an IC50 of 3·7–10 M for ERBB2.4 Further evidence that gefitinib acts via EGFR comes from work on KB cells, the growth rate of which is increased by the addition of
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
719
Reflection & Reaction EGF. Gefitinib inhibited growth of KB cells with an IC50 of 0·054 M in the presence of EGF, compared with an IC50 of 8·8 M in the absence of EGF.4 This paper also highlighted that the extent of EGFR expression may not indicate the degree to which the individual tumour cells are dependent on the EGFR signalling pathway for growth. Articles reviewing EGFR signalling pathways gave the expectation that response to gefitinib would not simply be predicted by EGFR expression.7,8 EGFR acts as part of a signalling pathway comprising many other components, each of which will influence activation of the pathway and response to gefitinib. Receptor mutations, increased expression of ligands, and heterodimerisation of EGFR with other members of this receptor family are all mechanisms by which EGFR signalling may be increased. Therefore, simply measuring EGFR may not be a true reflection of the extent of activation of this pathway. In addition, irrespective of the degree of EGFR signalling, tumour cells may not necessarily be dependent on the EGFR pathway for proliferation. Clinical studies of gefitinib have concentrated on tumour types that have previously been shown to express EGFR, although evaluation of the EGFR status of individual patients was not carried out at recruitment. Phase II trials (IDEAL 1 and 2) of gefitinib monotherapy in previously treated patients with non-small-cell lung cancer showed unprecedented activity, with response rates of 11·8–18·4% with 250 mg gefitinib per day and about 40% of symptomatic patients experiencing symptom relief.9,10 Our own studies used tumour samples from IDEAL 1 and 2 to evaluate the reproducibility of immunohistochemical determination of EGFR, and to estimate the correlation of baseline EGFR mem-
brane staining intensity with the probability of objective response or symptom improvement. We concluded that visual scoring of immunohistochemical stains for EGFR by experienced observers is highly reproducible3 and that tumour EGFR membrane staining is not clinically relevant for predicting response to gefitinib.2 Some patients with no detectable EGFR staining had objective responses or symptom relief, whereas some patients with intense EGFR staining had neither. Of note is that most samples came from diagnostic tissue that may or may not reflect EGFR status at the time of gefitinib treatment, which was second line or beyond. Another area for consideration is the threshold of sensitivity of the methods used to detect EGFR expression. There is no standard universally accepted method for measuring EGFR, and results may vary substantially between assays. The failure to detect EGFR does not necessarily mean that low concentrations are not there, as each method has a limit for detection of EGFR. Therefore, response to gefitinib in the absence of detectable EGFR does not mean that gefitinib is not acting through EGFR. In conclusion, EGFR has an integral role in the development of a range of cancers and it has been shown unequivocally that gefitinib targets this receptor. What is currently unclear is which markers most accurately predict response to gefitinib. The lack of a universally accepted method for assessing EGFR expression, together with the complex interaction between different components of the EGFR signalling pathway and associated networks, help explain why EGFR does not seem to be a useful predictor of response. Future studies on other potential biological markers downstream of EGFR, eg, Ki67, STAT, and
MAPK, may help clarify the situation and such studies are underway. Lisa Renee Bailey* and Mette Janas† *AstraZeneca, Wilmington, DE, USA. †Dakocytomation, Copenhagen, Denmark.
References
1 Brown H. Does hope match the hype for targeted drugs? Lancet Oncol 2003; 4: 452. 2 Bailey LR, Kris M, Wolf M, et al. Tumor EGFR membrane staining is not clinically relevant for predicting response in patients receiving gefitinib (‘Iressa’, ZD1839) monotherapy for pretreated advanced non-small-cell lung cancer: IDEAL 1 and 2. Proc Am Assoc Cancer Res 2003; 44: 1362. 3 Janas M, Franklin WA, Schmidt K, et al. Interobserver reproducibility of visually interpreted EGFR immunohistochemical staining in non-small-cell lung cancer. Proc Am Assoc Cancer Res 2003; 44: abstr LB-171. 4 Wakeling AE, Guy SP, Woodburn JR, et al. ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 2002; 62: 5749–54. 5 Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther 1999; 82: 241–50. 6 Woodburn JR, Kendrew J, Fennell M, et al. ZD1839 (‘Iressa’) a selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TK1): inhibition of c-fos mRNA, an intermediate marker of EGFR activation, correlates with tumor growth inhibition. Proc Am Assoc Cancer Res 2000; 41: 402. 7 Arteaga CL. Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist 2002; 7 (Suppl 4): 31–39. 8 Ciardiello F, Tortora G. Epidermal growth factor receptor (EGFR) as a target in cancer therapy: understanding the role of receptor expression and other molecular determinants that could influence the response to anti-EGFR drugs. Eur J Cancer 2003; 39: 1348–54. 9 Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003; 21: 2237–46. 10 Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib (ZD1839, Iressa), an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer previously treated with cisplatin or carboplatin and docetaxel. JAMA 2003; in press.
If you would like to respond to an article in The Lancet Oncology, or share your views on a current topic of interest or concern in oncology, please email your submission to the Editor at: [email protected]
720
THE LANCET Oncology Vol 4 December 2003
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
Association of the British Pharmaceutical Industry says . . . Much concern has been voiced about the implications of the Clinical Trials Directive (2001/20/EC) following
publication of draft UK legislation transposing the ordinance. These concerns have been heightened by the lack of concise information on how the Directive’s implementation will actually be done because of the failure by the European Commission to publish all of its supportive guidance—in particular, the Directive on Good Clinical Practice. It is unlikely, therefore, that final UK legislation will be in place before February, 2004, which allows researchers and sponsors about three months to prepare. The Association of the British Pharmaceutical Industry, however, believes that the final legislation could provide new opportunities. Most phase I cancer trials in the UK are reviewed by the Medicines and Healthcare Products Regulatory Agency (MHRA). For trials involving patients (rather than healthy volunteers) this process takes 60 days, which includes, 30 days for the MHRA to review the proposal, 14 days for sponsors and investigators to answer any questions raised by the MHRA, and 16 days for the MHRA to consider the answers before issuing a clinical trial authorisation (CTA). Following implementation of the EU directive, the MHRA aims to complete at least 80% of all CTA applications within 30 days. For healthy volunteers participating in phase I studies, the timeline will be faster still—with a projected average of just 14 days and a 21-day maximum. Ethics committees will have to complete their work within 60 days. Consequently, UK patients will benefit because clinical trials will start much earlier than currently possible. However, the new accelerated process will lead to more protocol rejections, so investigators and
sponsors will need to be meticulous in their applications. The role of the sponsor is also central to the new legislation. From May 2004, all clinical trials must have a sponsor in order to continue, although funders of individual trials will no longer have to be referred to as sponsors, expanding the potential for closer collaboration between the pharmaceutical industry, investigators, and other funders, such as the UK Medical Research Council. Importantly, pharmaceutical companies with cancer portfolios will be able to fund investigator-lead trials without becoming the actual sponsor. However, the new legislation will cause problems for charities currently providing funds for clinical trials and it is likely that these organisations will be unable to take on the role of sponsor—a consequence that may compel many host institutions to take on this role themselves. The Directive is far from doom and gloom. Indeed, it offers partnership opportunities that could improve the UK as a location for cancer trials. It will be a challenge, but by working together, UK researchers and funders can face it optimistically. Richard Tiner Association of the British Pharmaceutical Industry, 12 Whitehall, London, UK. References
1 Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001. http://europa.eu.int/eurlex/pri/en/oj/dat/2001/l_121/l_121200105 01en00340044.pdf, accessed November 2003. 2 Flavell DJ, Flavell SU, and Sullivan R. European Clinical Trials Directive: responses made to the MHRA consultation letter MLX 287. Lancet 2003; 362: 1415.
Getting to grips with gefitinib A recent article in The Lancet Oncology called into question the mechanism of action of the tyrosine kinase inhibitor gefitinib,1 stating that results presented at the American Association of Cancer Research (Washington, DC, USA, July 11–14, 2003) confirmed that this agent did not act through the epidermal growth factor receptor (EGFR). In fact, THE LANCET Oncology Vol 4 December 2003
this is an incorrect interpretation of the data presented by us at this meeting.2,3 Extensive preclinical studies of gefitinib have shown that this agent blocks signal transduction pathways implicated in the proliferation and survival of cancer cells,4–6 and that EGFR is the target. Gefitinib
inhibited the tyrosine kinase activity of EGFR (prepared from the human vulval squamous carcinoma cell-line A431) with an IC50 of 0·033 M, compared with an IC50 of 3·7–10 M for ERBB2.4 Further evidence that gefitinib acts via EGFR comes from work on KB cells, the growth rate of which is increased by the addition of
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
719
Reflection & Reaction EGF. Gefitinib inhibited growth of KB cells with an IC50 of 0·054 M in the presence of EGF, compared with an IC50 of 8·8 M in the absence of EGF.4 This paper also highlighted that the extent of EGFR expression may not indicate the degree to which the individual tumour cells are dependent on the EGFR signalling pathway for growth. Articles reviewing EGFR signalling pathways gave the expectation that response to gefitinib would not simply be predicted by EGFR expression.7,8 EGFR acts as part of a signalling pathway comprising many other components, each of which will influence activation of the pathway and response to gefitinib. Receptor mutations, increased expression of ligands, and heterodimerisation of EGFR with other members of this receptor family are all mechanisms by which EGFR signalling may be increased. Therefore, simply measuring EGFR may not be a true reflection of the extent of activation of this pathway. In addition, irrespective of the degree of EGFR signalling, tumour cells may not necessarily be dependent on the EGFR pathway for proliferation. Clinical studies of gefitinib have concentrated on tumour types that have previously been shown to express EGFR, although evaluation of the EGFR status of individual patients was not carried out at recruitment. Phase II trials (IDEAL 1 and 2) of gefitinib monotherapy in previously treated patients with non-small-cell lung cancer showed unprecedented activity, with response rates of 11·8–18·4% with 250 mg gefitinib per day and about 40% of symptomatic patients experiencing symptom relief.9,10 Our own studies used tumour samples from IDEAL 1 and 2 to evaluate the reproducibility of immunohistochemical determination of EGFR, and to estimate the correlation of baseline EGFR mem-
brane staining intensity with the probability of objective response or symptom improvement. We concluded that visual scoring of immunohistochemical stains for EGFR by experienced observers is highly reproducible3 and that tumour EGFR membrane staining is not clinically relevant for predicting response to gefitinib.2 Some patients with no detectable EGFR staining had objective responses or symptom relief, whereas some patients with intense EGFR staining had neither. Of note is that most samples came from diagnostic tissue that may or may not reflect EGFR status at the time of gefitinib treatment, which was second line or beyond. Another area for consideration is the threshold of sensitivity of the methods used to detect EGFR expression. There is no standard universally accepted method for measuring EGFR, and results may vary substantially between assays. The failure to detect EGFR does not necessarily mean that low concentrations are not there, as each method has a limit for detection of EGFR. Therefore, response to gefitinib in the absence of detectable EGFR does not mean that gefitinib is not acting through EGFR. In conclusion, EGFR has an integral role in the development of a range of cancers and it has been shown unequivocally that gefitinib targets this receptor. What is currently unclear is which markers most accurately predict response to gefitinib. The lack of a universally accepted method for assessing EGFR expression, together with the complex interaction between different components of the EGFR signalling pathway and associated networks, help explain why EGFR does not seem to be a useful predictor of response. Future studies on other potential biological markers downstream of EGFR, eg, Ki67, STAT, and
MAPK, may help clarify the situation and such studies are underway. Lisa Renee Bailey* and Mette Janas† *AstraZeneca, Wilmington, DE, USA. †Dakocytomation, Copenhagen, Denmark.
References
1 Brown H. Does hope match the hype for targeted drugs? Lancet Oncol 2003; 4: 452. 2 Bailey LR, Kris M, Wolf M, et al. Tumor EGFR membrane staining is not clinically relevant for predicting response in patients receiving gefitinib (‘Iressa’, ZD1839) monotherapy for pretreated advanced non-small-cell lung cancer: IDEAL 1 and 2. Proc Am Assoc Cancer Res 2003; 44: 1362. 3 Janas M, Franklin WA, Schmidt K, et al. Interobserver reproducibility of visually interpreted EGFR immunohistochemical staining in non-small-cell lung cancer. Proc Am Assoc Cancer Res 2003; 44: abstr LB-171. 4 Wakeling AE, Guy SP, Woodburn JR, et al. ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 2002; 62: 5749–54. 5 Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther 1999; 82: 241–50. 6 Woodburn JR, Kendrew J, Fennell M, et al. ZD1839 (‘Iressa’) a selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TK1): inhibition of c-fos mRNA, an intermediate marker of EGFR activation, correlates with tumor growth inhibition. Proc Am Assoc Cancer Res 2000; 41: 402. 7 Arteaga CL. Epidermal growth factor receptor dependence in human tumors: more than just expression? Oncologist 2002; 7 (Suppl 4): 31–39. 8 Ciardiello F, Tortora G. Epidermal growth factor receptor (EGFR) as a target in cancer therapy: understanding the role of receptor expression and other molecular determinants that could influence the response to anti-EGFR drugs. Eur J Cancer 2003; 39: 1348–54. 9 Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003; 21: 2237–46. 10 Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib (ZD1839, Iressa), an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer previously treated with cisplatin or carboplatin and docetaxel. JAMA 2003; in press.
If you would like to respond to an article in The Lancet Oncology, or share your views on a current topic of interest or concern in oncology, please email your submission to the Editor at: [email protected]
720
THE LANCET Oncology Vol 4 December 2003
http://oncology.thelancet.com
For personal use. Only reproduce with permission from The Lancet.