>> In Germany, the number of new cancer cases has almost doubled since the 1970s. One, but not the only, cause is increasing life expectancy. Lifestyle factors and increasing detection rates are also reasons for more frequent diagnosis. In the last 20 years, a significant decline in mortality has also been observed, so that more than half of patients no longer die from cancer (see RKI, 2016). A key reason is therapy options that take into account the newly gained knowledge about cancer and its molecular biological diversity. Personalized oncology and the innovative field of immuno-oncology show promising potential for efficient treatment and long-term therapeutic success. Nevertheless, it cannot be assumed in the future that an individually developed therapy will be available for every patient. Rather, using biomarkers, patients are divided into clinically relevant subpopulations that ultimately benefit from appropriate therapy, so that stratified medicine is increasingly being spoken of.
Classic and innovative therapies
As Figure 1 shows, in addition to surgical removal of the tumor, classic therapies such as radiation and chemotherapy are available. Since some tumor types use the body's own hormones for their growth, hormone therapy, or more correctly anti-hormone therapy, is another important treatment option, especially in patients.
inside with breast cancer depending on the stage of the disease and the menopause status. New opportunities in targeted therapy are emerging through the increasing decoding of a wide variety of signal transduction pathways that are responsible for tumor growth, angiogenesis and lack of apoptosis and are modulated with new substances via specific target molecules. The use of monoclonal antibodies is an integral part of numerous therapeutic strategies in cancer medicine. In addition, they are used in diagnostics to detect tumor markers in blood or tissue samples. Monoclonal antibodies such as angiogenesis inhibitors prevent tumor cells from gaining access to the bloodstream. Bevacizumab (ATC4 L01G0; see the following ATC code according to EphMRA with Figure 2) was the first to be approved in Europe in 2005 and is now used for the first-line treatment of numerous metastatic carcinomas. Other monoclonal antibodies, such as the signal transduction inhibitors pertuzumab (L01G0) and trastuzumab (L01G0), act specifically on cancer cells with HER2 receptor overexpression. About 20 percent of patients with breast cancer receive such stratified therapy, in which the receptor that mediates growth and division signals is inhibited by the antibody, which interrupts the signaling pathway and thus curbs tumor growth. In addition to monoclonal antibodies, targeted therapies also include mTOR inhibitors (L01H0; like everolimus), JAK inhibitors (L01H0; like ruxolitinib) and tyrosine kinase inhibitors (L01H0; like imatinib).
Future of immuno-oncology?
Immuno-oncology offers a new perspective in cancer therapy. The innovative generation of drugs activates the body's own immune system to attack the tumor. One of the most promising fields of research relies on so-called checkpoint inhibitors. These drug-like antibodies bind to central checkpoints and modulate them so that the immune system, which is altered in cancer, can recognize and fight the existing cancer cells again. The first checkpoint inhibitor ipilimumab (L01G0) has been approved for malignant melanoma since 2011; Nivolumab (L01G0) has been available for the treatment of non-small cell lung cancer since 2015. In practice, the new options also face challenges such as different response rates, high therapy costs and the prevention of autoimmune reactions (see German Cancer Society, 2017). On the other hand, there are some outstanding therapeutic successes and enormous development potential, which makes immuno-oncology another important component in tumor therapy. Attempts are being made to further improve the results using numerous substances that are still in the development phase as well as combination therapies.
From active ingredient to product
Drug development from the active ingredient candidate to the marketable product has grown into a complex system over the decades. Once an active ingredient has been found, preclinical development takes place alongside or after the patent application, in which the chemical and pharmacological properties, including toxicity, of the substance are examined and optimized. In clinical phase I, the active ingredient will be used for the first time in around 10-50 healthy volunteers to check its safety. In the subsequent phase II, effectiveness is tested in double-blind studies on around 100-500 patients. In the final clinical phase III studies, the drug will be tested on a larger collective of around 1,000-5,000 test subjects in order to confirm its effectiveness and safety in many different patients.
After positive completion of Phase III, the drug receives approval from the responsible medicines authority after submitting an application. With the approval and market launch, long-term tolerability, the occurrence of undesirable drug effects and the comparison of the benefit-risk ratio are documented and assessed in so-called market-accompanying studies (Phase IV). Since 2016, the central European drug regulatory authority EMA has implemented the “Prime” (Priority Medicines) program. The aim is to promote and accelerate the approval of medications with a high medical need in order to allow patients to benefit from new therapies as early as possible.
As Figure 2 shows, there are currently 68 substances in the pharmaceutical industry's advanced pipeline for the treatment of various types of cancer. In clinical phase III, the majority of the substances are in the ATC4 classes L01H0 (antineoplastic protein kinase inhibitors) and L01X9 (other antineoplastic agents), followed by the monoclonal antibodies L01G0. A similar picture emerges when it comes to the substances in the approval, although anti-TNF preparations are also represented here. Of the 44 substances in clinical phase III, 16 are currently genetically engineered drugs. There are currently 8 biologicals approved. However, this analysis does not allow any conclusions to be drawn as to how quickly the drugs will be approved and whether they will also be available on the German market after approval. Basically, it must be taken into account that even in Phase III, around 30 percent of the active ingredients do not meet the requirements and are abandoned. Ultimately, the reviewing committee CHMP (EMA's Committee for Medicinal Products for Human Use) can also express a “negative opinion” on the dossier and thus prevent approval. Despite these limitations, numerous new oncologic drugs with different principles of action are expected to increase the therapeutic options.
outlook
The analysis by INSIGHT Health shows that the oncological drug pipelines are well filled and research is being carried out into different therapeutic approaches. In addition, numerous substances are about to be approved and will therefore soon be available to patients. A milestone is the CAR T-cell therapy, which was only approved at the beginning of September. With this gene therapy approach, children and adolescents suffering from B-precursor cell acute lymphoblastic leukemia can be treated in the United States in the future. Approval for Europe could possibly take place this year (see German Cancer Society, 2017). However, not all of the more than 200 types of cancer will be treatable in the future. In addition to new oncologic drugs, tried and tested and different therapies continue to be combined, which are increasingly tailored to specific patient groups. The ultimate goal is to cure or stop the disease, which makes a decisive contribution to the entire solidarity system regardless of the expenses. The investment in patient health is also intended to be supported by the national cancer plan launched in 2013.
An early cancer detection and registration law was passed, which aims to introduce nationwide clinical cancer registries. The data from the treatment centers can provide valuable results on therapeutic measures, treatment successes and patient outcomes and ultimately also provide interesting insights for healthcare research. The German Consortium for Translational Cancer Research, founded in 2012, addresses a different point. The exchange of expertise is intended to bring research results into clinical development and application as quickly as possible in cross-site projects and clinical studies. This means that in the future it will be possible to recommend the treatment with the greatest chance of success to every patient. Making innovative therapies available quickly and using them efficiently are the goals of personalized oncology, the beginnings of which have long been made. <<
Authors:
Esther Zöllner and Kathrin Pieloth*