Abstract PL07-01: Rational cancer drug development for targeted drugs: Views from academia and the European Medicines Agency (EMA).
Authors: Bergh Jonas 
Published: June 2012

Abstract
Background: This extended abstract briefly described the cancer drug approval process within the European Union, a short description of the drug approvals made by the FDA and EMA, respectively, during the time period 1995 through 2008. Finally, this abstract will also make some comments and remarks regarding some view-points on the developments of targeted drugs - can we do better?
Since 2005, new cancer drugs within the EU, can only be approved via the so-called ‘Centralized Procedure’. In short that means that for new cancer drugs - you can no longer apply for an approval for a single country within the EU. However, pharmaceutical companies can still ask for scientific advice on both a national and European level from the European Medicines Agency (EMA).
When the EMA receives a new cancer drug application a rapporteur and co-rapporteur is appointed by the EMA. During the examination process the different committee members are asked to give their views and comments on the presented documents produced by the rapporteur/ co-rapporteur, respectively, at regular predefined time intervals, including questions to be answered by the applicant. After 210 days The Committee for Medicinal Products for Human Use (CHMP) must reach a decision, being either a positive or negative opinion based on a composite analysis of the benefit-risk balance, based on the majority vote within the CHMP, presently being 17 votes in one direction.
During this process other committees within the EMA can be activated, including the Scientific Advisory Group (SAG). The SAG is asked for advice on applications with a more uncertain-difficult benefit/risk balance or in those instances when an applicant asks for a re-examination. Finally, based on either the positive or negative opinion, respectively, by CHMP; this information is then submitted to the European Commission in Brussels for the final and formal decision to be made.
Results: During the time period 1995–2008, 42 anticancer drugs were approved by the EMA, corresponding to a total of 100 indications for these approved compounds, the two most frequent diagnostic groups were hematological malignancies and breast cancer. (Trotta et al 2011) Based on the 100 indications, no difference was recorded between the EMA and FDA in 52 instances (Trotta et all 2011). 19 indications were not approved by one of the two agencies. In 16 cases the indication was not approved in the United States and in 3 instances the indication was not approved in the European Union. (Trotta et al 2011) In 28 instances the indication description had different wordings. In 13 cases of the 28 instances, the FDA was more restrictive and in the other 15 cases the EMA was more restrictive. (Trotta et al 2011). Another observation was that the agency which approved drugs after the other agency was usually more restrictive with regards to the wording and indication than the first agency. It was also noted that FDA approves more compounds first, compared with the EMA (Trotta et al 2011).
Two examples of different indications approved by EMA and FDA, respectively, for two compounds can be mentioned. Panitumimab was approved within the EU; to be added to chemotherapy for colorectal cancer patients only for tumors with K-ras wild type status. The retrospective analysis of several randomized studies revealed quite similar hazard ratios, only being favorable for the addition of these EGF receptor monoclonal antibodies in those patients with K-ras wild type status. The FDA initially approved this compound irrespective of K-ras status, however, this was changed at a later date and, in order to optimize the benefit/risk ratio the indication was restricted to only patients with tumors with wild-type K-ras, for safety reasons.
Another example is the tyrosine kinase inhibitor gefitinib which was initially approved for whole group of non small lung cancer patients in the United States by the FDA. The drug is, however, no longer actively marketed in the United States because a later presented placebo controlled study could not reveal any statistically significant benefit for gefitinib in a study on an unselected lung cancer population. Within the EU gefitinib was never approved for the unselected lung cancer population, although gefitinib was later approved and restricted to patients with non-small cell lung cancer containing EGF receptor mutations since the benefit/risk balance was much more positive for this sub-group, because almost all anti-tumoral effects were confined to this group. The two agencies have also taken slightly different standpoints on bevacizumab for the breast cancer indication.
Discussion: The knowledge regarding tumor initiation, promotion and progression has increased exponentially in the last two or three decades (Hanahan & Weinberg, 2011). This expanding knowledge has been the corner stones and basis for the development of a long list of targeted drugs to more or less well defined drugs targets, frequently being tyrosine kinases (TKIs) and cellular receptors (Bergh 2009).
Some quite remarkable targeted drugs have reached the market and (dramatically) changed the panorama for some tumor types and sub-groups, e.g.:Imatinib for CML and GISTTrastuzumab for Her2/neu positive breast cancerRituximab for CD 20 positive lymphomas
One can mention that chemotherapy plus trastuzumab was approved for metastatic breast cancer based on a study with 469 randomized patients demonstrating a survival gain (Slamon et al 2001) A survival gain was also confirmed in a randomized phase II study with only 186 patients (Marty et al 2005). An Untargeted randomized study, with inclusion of all patients with metastatic breast cancer would have required 23586 randomized patients in order to demonstrate a survival gain (Simon and Maitournam 2004). These drugs mentioned above have mechanisms of actions, which are quite distinctly related to defined molecular targets, in many instances of importance for driving tumor progression.
A long list of other targeted drugs has also been developed for other indications. This list contains drugs with quite well defined drug targets, frequently a more or less long list of TKIs being inhibited to variable degrees by the different targeted agents (Bergh, 2009). Sunitinib can be mentioned as a drug inhibiting a very long list of potentially important TKIs. The side-effects of sunitinib are also quite marked.
The following targeted drugs have all been approved for the management of metastatic renal cell carcinoma, in comparative studies versus previous standard therapies or placebo in unselected patient cohorts. To the knowledge of the abstract author, none of these studies has included correlative biopsy from metastatic lesions and functional imaging studies as recommended by the present EMA Anti-cancer guidelines approved in 2005 (EMEA, 2005).SorafenibSunitinibTemsirolimusPazopanibBevacizumab
If such studies had been performed the selection of drugs could then have been made based on molecular markers, and the optimal sequence of usage of these drugs could then also have been investigated. Identification of such better-defined target populations would most likely have improved the benefit/risk balance.
Bevacizumab has also been approved for several other indications (advanced breast-colo-rectal- and non-small cell lung cancer) mostly resulting in improved progression free-survival, but rarely in survival gains. At long term follow-up this compound, as well as sunitinib, has resulted in the trend for worse overall survival (Bergh et al, 2010).
Ideally, targeted drugs should also (in humans receiving this drug) be investigated for the following critical points:
Is the target expressed in the tumor? Is the expression similar in the primary tumor compared with the corresponding metastatic lesion in the same patient? Is the target functional? Is the target expressed in other organs and at what levels? Is the target of importance for driving and preserving the malignant phenotype? Is the drug reaching the target? If the target is expressed in normal organs too - Correlation between side effects and anti tumoral effects? What is the optimal dose range rather than a specific dose? While individual dose adaptions-optimizations improve the benefit-risk balance?
These questions are sometimes difficult to investigate in humans but recent achievements in functional imaging can potentially be used to answer some of these questions together with biopsy analyses. Furthermore, we have shown that cytological sampling from metastatic lesions gives, from most patients, sufficient material for the analysis of the commonly used therapy predictive factors for breast cancer (Lindström et al, 2010 (a)). In a limited small study we have also shown that, for the majority of patients we also have sufficient material for comparative gene expression analysis studies (Lindström et al, 2010 (b)).
In order to improve the benefit/risk balance many studies of targeted agents would benefit from investigating the above mentioned items and dedicated efforts should be made to validate target functions aiming at identifying patients who would benefit to a greater or lesser degree from certain targeted agents.
Finally the present dosing strategy with one dose for each patient may be highly insufficient, since studies on conventional cytotoxic studies in retrospective studies have revealed a worse outcome for patients having less or no toxicities and the same type of retrospective observations have also been made regarding some targeted agents. Prospective studies using individually tailored doses to equivalent toxicity should therefore be warranted.
Footnote: The author is a full Professor at the Karolinska Institutet, consultant in oncology at the Karolinska University Hospital, Radiumhemmet. Professor Bergh was also Previously Professor at Manchester University and Honorary Consultant at the Medical Oncology Department, Manchester's Christie Hospital. The abstract writer has also served as a core member SAG, EMA, since 2004. He is presently vice-chairman of the SAG Group. The views presented in this abstract are the writer's personal views and not the official views of the EMA.
References:
Bergh J. Quo Vadis With Targeted Drugs in the 21st Century? Clin Oncol 27, 2–5, 2009
Bergh J, Greil R, Voytko N, Makhson A, Cortes J, Lortholary A, Huang X, Giorgetti C, Kern KA, Lichinitser M. Sunitinib (SU) in combination with docetaxel (D) versus docetaxel alone for the first-line treatment of advanced breast cancer. (Selected for oral presentation, late breaking abstract, ASCO June 4–8 2010, Chicago) Accepted J Clin Oncology.
European Medicines Agency – Guidelines on the evaluation of anticancer medicinal products in man. 2005. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/12/WC500017748.pdf
Hanahan D and Weinberg RA: Hallmarks of Cancer: The Next Generation. Cell 144, 646–674, 2011.
Lindström L, Karlsson E, Wilking U, Bergh J: Discordance in Hormone Receptor and Her2 Status in Breast Cancer During Tumour Progression: Oral Presentation San Antonio 2010 (a).
Lindström L, Giorgetii C, Smeds J, Borg A-L, Sköög L, Lilgren A, Kern KA, Bergh J: Understanding Targeted Activity Through Gene Expression Profiling: Analysis of Paired Biopsies in Patients with Advanced Breast Cancer in a Sub-Study of the Randomized Study of Docetaxel +/− Sunitinib (A6181064) Poster San Antonio, 2010 (b)
Marty M, Cognetti F, Maraninchi D, Snyer R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Antón A, Lluch A, Kennedy J, O'Byrne K, Conte PF, Green M, Ward C, Mayne K and Extra J-M. Randomized Phase II Trial of the Efficacy and Safety of Trastuzumab Combined With Docetaxel in Patients
With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer Administered As First-Line Treatment: The M77001 Study Group: J Clin Oncol 23:4265–4274, 2005.
Loges S, Mazzone M, Hohensinner P and Carmeliet P: Silencing or Fueling Metastasis with VEGF Inhibitors: Antiangiogenesis Revisited. Cancer Cell 15, 2009
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of Chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl J Med 344(11) 783–792, 2001
Simon R and Maitournam A: Evaluating the efficiency of targeted designs for randomized clinical trials. Clinical Cancer Res, 10, 6759–63, 2004
Trotta F, Leufkens H, Schellens J, Laing R and Tafuri G: Evaluation of Oncology Drugs at the European Medicines Agency and US Food and Drug Administration: When Differences Have an Impact on Clinical Practice. Clin Oncol 29:2266–2272, 2011
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr PL07-01.