“Anti-angiogenesis in cancer is something of a conundrum where the unexpected is to be expected.”
Anti-angiogenesis in cancer is something of a conundrum where the unexpected is to be expected.
Clinical performance of therapies has failed to match the potential and there remain questions about how they are best used. Combinations appear to be the answer with novel agents and immunotherapies seen as providing new options.
The subject was explored by Raffaella Giavazzi when she gave the 5th Simon Karpatkin Memorial Lecture at the 9th ICTHIC in Bergamo in April. Her talk was titled ‘Anti-angiogenesis for cancer: current status and prospects.’
Cancer cells stimulate growth of new vessels from existing ones which feed tumors with oxygens and nutrients so they can develop. Sustained angiogenesis is one of six ‘hallmarks of cancer’ identified in 2000. As a result, inhibiting angiogenesis was seen as an important objective in developing new treatments. By ‘normalizing’ abnormal blood vessels it was thought that anti-angiogenesis therapies could block the supply to tumors.
Research focussed on vascular endothelial growth factors (VEGF) and their receptors as the target for therapies. Development of a number of VEGF inhibitors by pharmaceutical companies followed. Bevacizumab, a monoclonal antibody, was the first anti-angiogenesis therapy to be approved by the FDA in the US. It was followed by several other anti-VEGF therapies, such as ramucirumab, aflibercept and axitinib for other types of tumor.
They became a standard treatment for many types of solid tumours. The new therapies appeared to herald a bright new future where progress of the tumour could be halted and the disease might be transformed into a manageable one. The reality was different.
In her talk, Giavazzi outlined how the promising results of VEGF pathway inhibitors in mouse models led to hopes of successful treatments. But the results from medical practice showed that they delayed tumor growth rather than bring about regression. Bevacizuamb and tyrosine kinase inhibitors (TKI) have shown significant improvement in progression free survival (PFS) but only modest results for overall survival (OS).
Using anti-VEGF agents as monotherapies has proved effective only in a small number of cancers. But adding them to chemotherapy has significantly improved clinical outcomes on different malignancies despite reducing the amounts reaching the tumour. It had been assumed that by normalising abnormal blood vessels, this would increase the amount of chemotherapy that could be delivered. Instead, the anti-VEGFs reduce its uptake.
Giavazzi highlighted how, even though bevacizumab reduces the delivery of chemotherapy agents such as placitaxel, the combination still delayed tumor growth significantly more than the single agents. This may be because bevacizumab provides for a better distribution of the chemotherapy despite the reduced uptake. Current thinking suggests that more appropriate scheduling of therapies, such as changing dose intensity, should be the way forward to improve the efficacy of combinations.
One of the reasons for the poor results of anti-VEGF therapies appears to be drug resistance. This was not seen as a major problem at the outset because of the genetic stability of vascular endothelial cells. Tumours also seem to develop escape mechanisms.
There is optimism that new combinations with targeted therapies could be useful in combatting both resistance and escape mechanisms to anti-angiogenesis agents. A number of possibilities are under investigation aimed at improving effectiveness and avoiding too much toxicity. One is olaparib, a first-in-class poly(ADP-ribose) polymerase (PARP) inhibitor which was recently approved by the FDA in the US.
In a Phase II trial, olaparib is being combined with an VEGF inhibitor the TKI cedinarib. It significantly improved PFS in patients with recurrent platinum-sensitive high-grade serious or endometrial ovarian cancer. However, there is concern oplaparib in combination with cediranib may cause toxicity. Using olaparib with bevacizumab may be a better option which will soon be investigated in a Phase III trial.
Immunotherapy, the cutting edge of research into new cancer treatments, is another area being explored. The aim is to counteract a tumor’s ability to suppress the immune systems so that it fails to recognise and destroy cancer cells.
Immune checkpoint inhibitors are being used to maintain the physiological immune response. Regulating the tumor vasculature could be pivotal to the development of more effective anti-cancer immunotherapies and VEGF is an important part of this.
Combining antiangiogenic agents with immune checkpoint inhibitors is being tested in a number of areas. Efficacy was reported in a trial where patients with metastatic melanoma were treated with bevacizumab in combination with ipilimumab. Ovarian cancer is said to have some of the criteria for which combining immunotherapy with antiangiogenic therapies could be useful.
Giavazzi concluded her talk by saying that angiogenesis inhibitors have shown benefit for certain tumor types but resistance and escape to treatment are a problem. She suggested that combining angiogenesis inhibitors with chemotherapy, new target drugs or with immune checkpoint inhibitors may provide the most promising use of these types of therapies.
However, she also said that more research needs to be done to understand the better response of combination strategies. The need for predictive biomarkers to select the patients who will benefit most from the use of angiogenesis inhibitors was also highlighted.