>> One disease, one treatment – for a long time this “one size fits all” idea dominated oncology. However, more is now known about how cancer develops and spreads: specific changes in the genes are responsible, which can provide information about whether a therapy will be successful or not. Therefore, patients with malignant diseases are now increasingly stratified based on the specific genetic changes in their tumor and treated in the spirit of precision medicine. For example, AOK Nordost now covers the costs of biomarker tests for early breast cancer on a case-by-case basis.
“In the future, therapies will increasingly be based on genomic rather than anatomical similarities. For us this means: treatment of ever smaller and more heterogeneous subgroups, differentiated based on individual genetic changes.” In these new concepts, tumor localization can only play a minor role in some cases, which is why Dr. Benedikt Westphalen, coordinator of clinical/translational research at the CCC Munich, explained during his lecture that it is to be expected that “treatment strategies that cross entity boundaries will become significantly more important in the future.”
The test substance entrectinib is a
cher, new therapeutic approach for the treatment of patients with NTRK fusion-positive solid tumors and ROS1 fusion-positive non-small cell lung carcinoma (NSCLC). NTRK fusion genes are known as oncogenic drivers, although they occur very rarely overall, they occur in many different
which tumor entities.
The efficacy of entrectinib has been evaluated in several basket studies (STARTRK-2, -1 and ALKA-372-001). “For patients with NTRK fusion-positive solid tumors
and ROS1 fusion-positive NSCLC is Entrec-
“tinib is a promising approach,” Westphalen made clear based on current data on the test substance. A pooled analysis of the basket studies would have shown that patients with CNS metastases in particular can benefit from entrectinib. In addition, therapy with entrectinib would have been associated with a very good intracranial response in patients with CNS metastases - in patients with NTRK fusion genes, the intracranial ORR was 54.5% (95% CI: 23.4 - 83.3%) and in patients with ROS1-
Fusion genes 55% (95% CI: 31.5 – 76.9%).1
“Together with the previous data on overall survival and the data now available on patients with brain metastases, we can say that entrectinib improves the prognosis of patients - regardless of the CNS status,” summarized Westphalen. In addition, initial data from the STARTRK-NG trial showed that entrectinib is also suitable for the treatment of children with NTRK,
ALK and ROS1 fusion positive solids
tumors is an effective option. All eleven patients with one of the relevant fusion genes - including five with a primary CNS tumor - responded well and quickly to entrectinib.2
New study designs are required
“The change from tumor-based to biomarker-based cancer therapy also means that study designs are changing,” added Dr. Susanne Schach, Real World Data
Director at Roche Pharma AG. The reason: the lower the prevalence of a disease, the smaller the potential study population. This is a particular challenge when a new active ingredient is to be examined in clinical studies.
“It is often not possible to set up randomized clinical trials for these few patients,” said Schach. There are also ethical aspects: Especially with targeted therapy options, a control group cannot always be represented due to differences in effectiveness and tolerability. Therefore, single-arm studies are increasingly being used for rare and previously undertreated diseases.
According to Schach, single-arm basket studies can provide evidence for new therapeutic approaches in small patient populations and regardless of the tumor location. The use of real world data (RWD) could also increase the significance of these studies by using them
equal arms are formed. It is important that the data is transparent and can be traced.
“The basket studies on entrectinib show that in the future the success of a therapy will increasingly not be measured against a large, selected population, but rather on an individual basis for individual patients,” emphasized Schach. “This is also recognized by various health authorities.” Entrectinib would be suitable for the treatment of adult and pediatric patients with NTRK fusion-positive, locally advanced or metastatic solid tumors that have either progressed after previous therapies or have not received acceptable standard therapies received “Priority Medicines” (PRIME)3 status from the EMA. The FDA has also granted entrectinib a “Breakthrough Therapy Designation” (BTD)4 in this indication and the Japanese regulatory authority has granted entrectinib Sakigake status.5 <<

Literature:

1: Siena S et al., J Clin Oncol 2019; 37: Abstract 3017
2: Robinson GW et al., J Clin Oncol 2019; 37: Abstract 10009
3: EMA. CHMP: Minutes of the meeting on 09–12 October 2017. EMA/CHMP/762846/2017
4: F. Hoffman La Roche Ltd. Data on file (https://www.roche.com/media/releases/med-cor-2019-02-19b.htm, accessed June 2019)
5: F. Hoffman La Roche Ltd. Data on fileessel/ Gersch/ Goeke 2010, p. 121 ff.