Interview: Anders Mellemgaard, MD, PhD, Clinical Associate Professor, Department of Oncology, Herlev University Hospital, Copenhagen, Denmark
How important is anti-angiogenesis in the treatment concept of lung cancer? Angiogenesis is a very important driver for cancer progression. Some cancers are particularly dependent on the development of new vasculature in order to grow and metastasise. Targeting the vasculature is therefore very useful. Anti-angiogenic compounds are available, such as bevacizumab, which is used primarily in first-line treatment, but now we also have second-line drugs that are applied together with chemotherapy, thus improving its efficacy. When the anti–VEGFR-2 antibody ramucirumab and the triple angiokinase inhibitor nintedanib are added to a common chemotherapeutic agent like docetaxel, they can actually improve OS. There are differences in terms of administration and toxicity profiles between these two compounds, but they are also a proof of concept that targeting angiogenesis is important, and that it can prolong the life of patients with metastatic lung cancer.
Where do you see anti-angiogenic drugs in the future, considering the plethora of new treatments, such as immunotherapies? That is a good question, because when everybody was thinking ahead two years ago, I do not think anybody anticipated that today we would be talking about immunotherapies that much. However, I believe that what we need to realize is that any cancer, and this is certainly true for lung cancer, has many subgroups that differ from a biological point of view. Some of these are amenable to immunotherapy, while for others, other kinds of therapy are more suitable. It appears that in the case of rapid progression after first-line therapy, immunotherapies do not work too well. In the CheckMate 057 trial , nivolumab was most effective in patients with a longer time interval since their last prior treatment. On the other hand, an analysis of the LUME-Lung 1 study showed that the OS effect of nintedanib plus docetaxel was stronger in patients who had experienced a shorter disease-free interval after first-line treatment (Table) . There was a pronounced OS benefit in the group who only showed progressive disease as best response or who were chemo-refractory in the first-line setting. In my opinion, the time interval from first-line to second-line therapy is therefore quite important for the selection of treatment. This has to be considered when discussing the further courses of action with the patient. Immunotherapy might be the best option if the interval is long, and antiangiogenic compounds are preferable if the interval is short.
Are there any biomarkers for anti-angiogenic drugs in the molecular sense yet? Research is still ongoing to identify biomarkers, but thus far there are no classical markers in the sense of parameters that can be tested in the laboratory. The problem is that angiogenesis is a normal function of the body and is just up-regulated in cancers. We cannot look for biomarkers in the cancer cell itself, because the cell is not involved in the mechanism of action of these agents, but rather the tumour microenvironment. What we do have is a clinical marker, which is the interval from firstline to second-line therapy.
1 Borghaei H et al., Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med 2015; 373: 1627- 1639
2 Heigener D et al., Efficacy and safety of nintedanib/ docetaxel in patients with lung adenocarcinoma: further analyses from the LUMELung 1 study. ESMO 2016, abstract 1276P