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Originally published as JCO Early Release 10.1200/JCO.2008.18.8342 on December 1 2008 © 2009 American Society of Clinical Oncology.
Quo Vadis With Targeted Drugs in the 21st Century?Radiumhemmet and Karolinska Oncology, Karolinska Institutet & University Hospital, Stockholm, Sweden During the last few decades, a rapid development has taken place in the exploration and development of cancer drugs, including cytostatics, endocrine agents (first generation of targeted drugs), and more recently, a new generation of targeted drugs. This development was facilitated by a marked increase in knowledge on how to best run well-designed clinical studies within academic collaborative groups, mainly in the United States and Europe and frequently with the pharmaceutical industry as sponsors for the studies. The aims were and still are to register and establish new drugs and indications for broad groups of patients based on conventional morphologic classification systems of the primary cancers. The inclusion criteria are frequently aimed at defining a clinically homogeneous patient population, although the interpatient molecular signatures may be markedly different between patients included, not investigated, and not detected. More recent studies have had large sample sizes to be able to detect small differences. Another way to express this is that a positive effect in few patients will be recorded as a statistically significant finding, resulting in new indications for the whole group of patients, despite the fact that only a few patients experienced an advantage. We need to design our studies differently to be able to identify these few patients. Despite this, step by step, small but significant achievements have been observed for the major solid cancers with the use of new drugs, as well as their better use in the metastatic setting. For example, major achievements have been recorded in the adjuvant setting for colorectal and breast cancer. The impact on the general breast cancer patient should not be underestimated; during the last 15 years, the likelihood of dying from breast cancer for a middle-aged woman with a receptor-positive disease has been reduced by 50% with the use of chemotherapy and endocrine therapy.1 However, these successful strategies have been based on over- and undertreatment of large patient cohorts. In parallel with the clinical achievements we have observed, there have been remarkable improvements in molecular and functional understanding of malignant processes with focus on oncogenes, tumor suppressor genes, and loss of function of other growth regulatory processes involving receptors and secondary messengers with different tyrosine kinases (TKs). Breast cancer is no longer one disease entity; with RNA expression profiling and reverse transcriptase polymerase chain reaction–based studies, breast cancer can be separated into distinct subgroups with dissimilar prognosis and likely different clinical management.2-12 Two of the signatures are presently being tested in prospective randomized studies, Microarray in Node-Negative Disease May Avoid Chemotherapy (MINDACT) and Trial Assigning Individualized Options for Treatment (TAILORx). We cannot wait for these data when we design and run clinical studies. It should already be mandatory to prospectively save relevant tumor material and normal tissue for DNA extraction from all clinical studies, and this is particularly important for studies with new drugs, especially so-called targeted drugs including TK inhibitors (TKIs). This will require educational strategies and increased resources; these problems should by no means be neglected. Given the tidal wave of new targeted drugs, such as TKIs (Fig 1) and monoclonal antibodies, it is time to prospectively integrate more molecular and biologic knowledge into our oncology study designs.
The previous oncology strategy of "all for one and one for all" needs to be modified. The pharmaceutical industry and maybe some collaborative groups may not applaud such a development; new drug indications will potentially be limited to small subgroups based on prospectively proven effects in relation to certain marker signatures and functional characteristics rather than only morphology. This strategy will require readiness to perform biopsies, including from metastatic lesions, and improvement in functional imaging techniques for better patient selections in these studies. We need to work hard to obtain these goals. In this context, one should mention that if trastuzumab combined with chemotherapy had been developed without preselection of patients with HER-2/neu–positive cancers, such a study would have required up to 23,586 randomly assigned patients to demonstrate a 1-year survival improvement of 2.4%.14 By preselecting only patients with HER-2/neu–positive cancers, it was possible to detect significant survival benefits of 5 and 8.5 months in studies of 469 and 192 patients, respectively.15,16 The collaborative group involved in the sorafenib study published in this issue of Journal of Clinical Oncology was one of the important pioneers in the exploration of adjuvant trastuzumab.17
Sorafenib (BAY 43-9006) has been described to inhibit vascular endothelial growth factor receptor-1, -2, and -3; platelet-derived growth factor- Twenty-three breast cancer patients with a median age of 54 years who were previously treated with anthracyclines and/or taxanes and who had metastatic disease were included in the study by Moreno-Aspitia et al.17 Twelve and 13 of the patients had estrogen receptor–and progesterone receptor–negative disease, respectively; three patients had strongly positive immunohistochemistry for the HER-2/neu protein (not fluorescent in situ hybridization verified), likely in the primary biopsies. The new and interesting TKI sorafenib was administered orally at a dose of 400 mg twice daily for 4 weeks, to be repeated in 28-day cycles. Patients only received a median of two cycles (range, one to 15 cycles). The therapy was described to be well tolerated without any grade 4 and few grade 3 toxicities. No responses were recorded, but two patients had stable disease for 6 months or more. The authors correctly question whether "unidimensional tumor response is an appropriate measure of benefit."17 However, these data indicate that sorafenib seems to have minor efficacy in an unselected breast cancer patient population using a conventional phase II design with no preselection based on marker signatures and that other means for therapy evaluation should have been used. Is this the end of the story for sorafenib and breast cancer? Maybe so, but we likely have to design our studies differently in the future. How should we select the correct TKI from the long list of drugs for the single patient and to evaluate therapy effects? They cannot be tried one by one in each patient, as we tend to use most of our conventional cancer drugs today based on recorded mean and median effects for certain clinical situations, without a detailed knowledge of molecular characteristics. In the future, drug selections and dosage must realistically be based on the detailed molecular tumor characterization and single nucleotide polymorphism signatures from normal DNA. Single nucleotide polymorphism analyses may potentially give information on outcome and adverse effects as described for tamoxifen and CYP2D6, while others have not confirmed this.18,19 The lack of major toxicities in the study of sorafenib by Moreno-Aspitia et al17 raises concerns that a substantial number of the patients may have been underdosed. Eighteen patients stopped therapy as a result of tumor progression, and only one patient stopped therapy as a result of grade 2 skin rash. To highlight the potential importance of dosing targeted drugs to toxicity, consider, for example, a retrospective analysis of the degree of rash induced by the epidermal growth factor receptor (EGFR) inhibitor erlotinib, which was investigated in two randomized studies in patients with non–small-cell lung cancer and pancreatic cancer.20 Median survival time of patients without rash in the non–small-cell lung cancer group was 3.3 months, whereas it was 11.1 months in patients with grade 2+ rash (P < .001). The same principal findings were noticed in the study of pancreatic cancer.20 The correlation between skin rash and antitumoral effect may be a result of better targeting of EGFR both in normal skin and in the tumor, which may be related to certain EGFR polymorphisms or the immune system.20-22 The EGFR monoclonal antibody cetuximab was prospectively studied in patients with metastatic colorectal carcinoma, with escalated doses in one arm of cetuximab; in this study, skin toxicity was considered to be a potential surrogate marker of efficacy.23 The same type of escalating dose strategy for the individual patient could have been used in the study with sorafenib by Moreno-Aspitia et al,17 aiming at grade 2 or 3 toxicities for each patient and thereby potentially avoiding the risk of underdosing the patients. The view that targeted drugs, such as TKIs, have less toxicity compared with cytotoxic agents may not be correct if they are individually and correctly dosed. Targeted drug selections are already in routine use for breast cancer patients. Estrogen and progesterone receptor and HER-2/neu status should be known for each patient; however, status is frequently only based on analyses of the primary cancers, even though metastatic disease is treated. The levels of discordance, gain or loss, of these markers have been demonstrated to range from 0% to approximately 20% or more for HER-2/neu; receptors have been demonstrated to have up to a 44% discordance rate, although studies have been retrospective and mostly have had small sample sizes, and only one meta-analysis in abstract form has been published thus far.24-32 One small study has also revealed alterations in the metastatic lesions during therapy.33 Taken together, these data strongly indicate discordance between primary tumors and corresponding metastatic lesions in our routine therapy predictive factors, which indicates the need for prospective evaluation of TKs (being the presumed targets for TKIs) in metastatic lesions and not to rely on the status in the primary cancers; at least it should be investigated. Target identification is important, but it is also essential to obtain data on whether the targets drive the malignant process and whether the TKIs administered reach the targets and result in downregulation of their functions or loss of the malignant process. Repeated fine-needle aspiration may be one way to obtain these data, but we definitely need to develop further patient-friendly procedures for these strategies. The present focus on studies with molecular strategies in the neoadjuvant setting is an excellent research strategy and, for many institutions, more feasible, but we can likely not extrapolate all findings to the metastatic setting for reasons provided here. It would have been interesting to select and enrich the patient population in the present study with sorafenib, as for HER-2/neu–based therapies, based on expression of sorafenib-relevant TKs in the metastatic lesions. In practice, however, it will only be possible to biopsy one metastatic lesion per patient, which may not be sufficient to properly characterize each patient's disease regarding TK patterns. However, a single biopsy may miss important target heterogeneity in the metastatic lesions. Therefore, target-specific functional imaging techniques need to be developed in parallel. Studies have to be performed that relate the effects of the targeted therapies to the presumed targets of each drug. In vivo, in patients, other mechanisms may be involved and may be of greater importance, but we should start to analyze the nonclinically described targets for each drug. The importance of investigating molecular markers in solid tumors is also applicable to the recently approved EGFR-directed monoclonal antibody panitumumab. In the European Union, panitumumab was only approved for patients with colorectal cancer and with wild-type KRAS, whereas patients with the corresponding mutant oncogene received no benefit from panitumumab. The same observation has been made for cetuximab combined with irinotecan.23 The present European Medicines Agency guidelines for anticancer medicinal products urge investigators of noncytotoxic compounds to analyze biopsies of primary tumors, normal tissues, and metastatic lesions to understand the target and downstream effects and to make use of sensitive imaging techniques.34 These strategies will be valuable in the study of sorafenib. In conclusion, single-agent sorafenib is not a promising drug for an unselected and pretreated breast cancer population, as convincingly demonstrated in the study in this issue by Moreno-Aspitia et al.17 These authors propose the use of sorafenib in combination with other cancer drugs. That strategy has frequently been used for other targeted drugs, sometimes successfully. However, the potential value of sorafenib and other TKIs may be better explored by improved patient and target selection, as discussed in this editorial. It should not be long before we get started with these new strategies aimed at true tailored concepts when exploring new drugs and when investigating their most optimal use and at better patient selection of already approved targeted drugs. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Abraxis (C); Roche (C); Sanofi-aventis (C); Amgen Inc (C); GlaxoSmithKline (C); Pfizer Inc (C); AstraZeneca (C); Affybodies (C) Stock Ownership: None Honoraria: AstraZeneca; GlaxoSmithKline; Novartis; Pfizer Inc; Roche; Sanofi-aventis Research Funding: Pfizer; AstraZeneca; Merck & Co Expert Testimony: None Other Remuneration: None
ACKNOWLEDGMENTS I am grateful to Nils Wilking, MD, PhD, Johanna Smeds, PhD, and Eva Rossmann, MD, PhD, for help, comments, and excellent suggestions, and to Charlotte Larsson for excellent reference handling. REFERENCES 1. Early Breast Cancer Trialists’ Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] 2. Perou C, Sørlie T, Eisen M, et al: Molecular portraits of human breast tumours. Nature 406:747-752, 2000[CrossRef][Medline] 3. Sørlie T, Perou CM, Tibshirani R, et al: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869-10874, 2001 4. van't Veer LJ, Dai H, van de Vijver MJ, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530-536, 2002[CrossRef][Medline] 5. 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Santinelli A, Pisa E, Stramazzotti D, et al: HER-2 status discrepancy between primary breast cancer and metastatic sites: Impact on target therapy. Int J Cancer 122:999-1004, 2008[CrossRef][Medline] 33. Munzone E, Curigliano G, Rocca A, et al: Reverting estrogen-receptor-negative phenotype in HER-2-overexpressing advanced breast cancer patients exposed to trastuzumab plus chemotherapy. Breast Cancer Res 8:R4, 2006[CrossRef][Medline] 34. European Medicines Agency: Guideline on the evaluation of anticancer medicinal products in man. http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-3/pdfs-en/3cc23aen.pdf
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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and -β; RET; Flt3; and c-KIT (
