| Anders Mellemgaard, MD, Medical Oncologist from the Department of Oncology, Herlev University Hospital, Herlev, Denmark, spoke with The Oncology Pharmacist about his study, "Antiangiogenic-Specific Adverse Events in Patients with Non-Small-Cell Lung Cancer Treated with Nintedanib and Docetaxel," regarding the development of the new compound that is augmenting the effect of chemotherapy by treating the new vasculature. |
Nintedanib is an oral agent targeting all 3 cells that are present in the vasculature.
In a sense, targeting the new vasculature is not a novel idea; one of the most widely used drugs, bevacizumab, which is a monoclonal antibody, does exactly that. Antibodies are very specific, usually targeting only one type of receptor, whereas tyrosine kinase inhibitors have the ability to target multiple pathways. I think we can even hypothesize that tyrosine kinase inhibitors might be more effective than the monoclonal antibodies.
Nintedanib was developed to be used in conjunction with chemotherapy, and primarily in patients with lung cancer, although it has also been tested in other cancer types. It also has the potential to be used in other respiratory conditions, such as pulmonary fibrosis.
Nintedanib is certainly well-tolerated. As is the case with all drugs that target the vasculature, we were concerned about perforations and bleeding, because those adverse events-which were sometimes fatal-were seen in the development of bevacizumab, and had also been seen in other compounds that have been developed to target new vasculature, such as selumetinib.
In our study, we demonstrated that adding nintedanib to the standard chemotherapy of docetaxel clearly improved the overall survival of patients with adenocarcinoma histology. The other major group included in the study-patients with squamous-cell carcinoma-did not benefit to the same degree. Side effects were also seen slightly more often in that group. Future research and development of this drug will focus on patients with nonsquamous histology or adenocarcinoma.
When we looked at subgroups of patients, it appeared that the shorter the intervals in first-line therapy to initiation of second-line therapy, the greater the effect of nintedanib. This is most likely because the quicker a tumor progresses, the more dependent it is on new vasculature. That means that the vasculature becomes a more important target for tumors that grow rapidly, grow slowly (but are efficient), or are indolent.
It is a fixed, clinical observation of a bigger effect in early progression that fits in with biologic understanding of how vasculature-and drugs targeting the vasculature-work. Especially among patients who had < 9 months, and even among patients whose disease progressed after first-line therapy, there was a clear and pronounced effect from nintedanib, extending overall survival without reducing quality of life.
An interesting finding in the LUME-Lung 1 trial was that adverse events were not really found more frequently in the nintedanib group. We did see more hypertension, but hypertension is not a real worry, because it can be easily treated. The more serious adverse events (eg, gut perforation, thorax wall abscess, and other types of bleeding) were not increased. That is a great thing about a drug; you want the greatest effect that you can get, and you also want to see a drug work without significant adverse events. The strength of the study is in that it demonstrated an adverse event profile that is quite mild, and we actually did not see more patients dropping out of treatment when given nintedanib plus docetaxel, compared with patients who only received docetaxel.
