>> Malignant neoplasms of the bronchi and lungs are among the most common causes of death worldwide. Despite advances in diagnostics and therapy, lung cancer is the second most common cancer in men and the third most common cancer in women. The incidence in Germany is currently around 53,900 new cases annually (see Cancer Information Service). Most lung cancers are caused by smoking. While the rate of new cases among men has only increased slowly since the late 1980s, it continues to rise steadily and sharply among women (see German Cancer Society). On the one hand, an overall decreasing proportion of smokers has a positive effect on the number of cases. On the other hand, increasing average life expectancy is associated with a higher risk of developing lung cancer (see Lung cancer and older age, 2016).
About 85% of lung carcinomas are non-small cell
At the beginning of lung cancer, the symptoms are very general and uncharacteristic, so it can often only be diagnosed at an advanced stage. The symptoms include persistent or chronic cough, bloody and bloodless sputum, shortness of breath and chest pain, weight loss, swelling of the lymph nodes and bone pain, the severity and duration of which are of prognostic importance (see Diagnosis of Lung Carcinoma, 2014). Basically, two types of lung cancer can be distinguished. The most common form is non-small cell lung carcinoma (NSCLC), which affects around 85% of cases. Small cell lung carcinoma, which grows very quickly and often forms metastases in other organs at an early stage, is much rarer with around 12-15% (see MSD Manual Bronchial Cancer, 2018). Today, lung cancer is divided into at least two dozen biologically different entities that make targeted therapy possible (see Onkopedia guideline NSCLC, October 2019).
Targeted therapy for NSCLC
Conventional chemotherapy was the only option available until around 1995 and continues to be the treatment of first choice in the absence of evidence of a driver mutation. There are now treatment options individually tailored to the patient. Before the first-line therapy begins, tests are carried out to determine whether certain gene mutations are present and whether they respond to targeted therapy. In addition to the number of molecularly, histologically or clinically defined patient subgroups, this increases the diagnostic requirements for a type of cancer that is already generally characterized by a high number of genomic changes. Approved treatment options are currently available for at least three of these clinically relevant alterations. The drug blockade in the epidermal growth factor receptor (EGFR) gene, constitutional activation of the anaplastic lymphoma kinase (ALK) and activating translocations of the ROS1 (c-ros oncogene 1) receptor tyrosine kinase often lead to significantly longer tumor life.
respond compared to chemotherapy (see updated treatment recommendation for metastatic non-small cell lung cancer, 2017). Tyrosine kinase inhibitors, angiogenesis inhibitors and checkpoint inhibitors are predominantly used (see Table 1).
Innovation immuno-oncology
It has been known since 1890 at the latest that the body's immune system can destroy cancer cells (see Spektrum Kompakt, 2018). But it is only in recent years that cancer treatment through immunotherapy has made significant progress. However, only certain patient groups benefit from this - among lung cancer patients this is around 15 to 20% (see Cancer Information Service, 2018). In NSCLC therapy, the checkpoint inhibitors with a prescription share of 77.3% have the highest relevance in relation to the statutory health insurance market (see Fig. 1). Checkpoint inhibitors raise
immunosuppressive signals so that the body's immune system can recognize and fight diseased cells. For metastatic non-small cell lung cancer, checkpoint inhibitors can replace, or sometimes even surpass, chemotherapy that has many side effects (see Immunotherapy for Lung Cancer, 2016). An example is prembrolizumab. The antibody was originally only approved in the EU in 2015 for the treatment of advanced melanoma. To date, there has been a significant expansion of indications. In the USA, prembrolizumab is even approved as the third non-tissue-specific cancer drug. The drug can be used in various types of cancer as long as a certain mutation is present (see Pharmazeutische Zeitung, 2019). In Germany, however, the active ingredient is approved for certain types of cancer, including the treatment of NSCLC. In September of this year, prembrolizumab was approved as first-line therapy for patients with metastatic NSCLC with PD-L1-expressing tumors without activating EGFR and ALK mutations. In the early benefit assessment according to Section 35a SGB V, the drug was able to demonstrate a significant additional benefit for the patient group: Both progression-free survival and overall survival were improved compared to chemotherapy. However, the effects and side effects of immunotherapy are also close together. Checkpoint inhibitors can induce autoimmune side effects that can affect any organ system (see Deutsches Ärzteblatt, 2019).
Nintedanib with the highest
Prescription share
As of the beginning of November 2019, a total of eighteen active ingredients are available for NSCLC therapy. While eleven of these are approved exclusively for NSCLC, the remaining seven are also used for the treatment of other types of cancer (see Table 1). Looking at the eleven drugs that are approved solely for the treatment of NSCLC, Figure 1 clearly shows the four most commonly prescribed active ingredients. Nintedanib, durvalumab, osimertinib and afatinib share 86.5% of the GKV regulations. Nintedanib is an angiogenesis inhibitor that has been approved since 2014 and causes reduced blood flow and thus an undersupply of tumor tissue. The antibody durvalumab has been on the German market since October 2018 and belongs to the class of checkpoint inhibitors. The two EGFR-specific tyrosine kinase inhibitors osimertinib and afatinib have been approved since 2016 and 2013, respectively, and inhibit EGFR activity and thus tumor progression (see Cancer Information Service, 2018).
outlook
Figures from the vfa also show that cancer research is complex and always presents new challenges. Accordingly, ten new drugs were introduced in the area of lung cancer between 1998 and 2014. During the same period, however, 167 study programs had to be canceled. And yet numerous innovative medicines are now available or are on their way to market. At the end of November, the G-BA published the benefit assessment results for the ALK tyrosine kinase inhibitor lorlatinib. And for the tropomyosin receptor kinase inhibitor larotrectinib, the evaluation will be completed in April 2020. It is the first precision oncology drug approved in the EU that can be used independently of the tumor. In a basket study, the concept of which is to treat patients with different tumor entities in a common protocol with larotrectinib, long-term remissions were achieved in 17 different cancers, including lung carcinoma. The NTRK fusion genes, which are relevant as a therapy target for larotrectinib, have been found in more than 20 cancers so far, but in fewer than 1% of patients (see Deutsches Ärzteblatt, 2018). With the increasing importance of stratified therapy for tumor diseases, larotrectinib could set the next milestone in modern oncology. With PRIME status and an EU approval application submitted in January 2019, entrectinib, another tyrosine kinase inhibitor for the treatment of solid, tissue-nonspecific tumors and NSCLC, is expected to be available on the German market (see New cancer drugs in the EU approval process, vfa, October 2019 ). As the first gene-based rather than organ-based cancer therapy, these active ingredients are considered breakthrough innovations. Cancer treatment across disease boundaries and a focus on molecular genetic methods could create effective treatment options for an increasing number and differentiation of patient subgroups in the future. <<
Authors:
Sarah Meyer, Kathrin Pieloth*
Citation note:
