Time to stop using PFS outcomes for antiangiogenesis therapies: oncologist


By Michael Woodhead

28 Nov 2019

An Australian oncologist has questioned whether further trials of the antiangiogenesis therapy bevacizumab in metastatic cancers are justified in the absence of an overall survival benefit.

Associate Professor Ian Haines of Monash University says the results from numerous trials of the anti-VEGF inhibitor in nine different cancer indications have only shown benefit in the ‘inferior’ endpoint of progression free survival (PFS) but not in OS.

In a letter in the Journal of Clinical Oncology, co-authored with Dr George Miklos (PhD), Professor Haines says that recently published results from a nine year follow up of ovarian cancer patients add to three other trials showing that bevacizumab-based targeting of VEGF in stage III or IV ovarian cancer fails to increase median lifespan compared to chemotherapy.

The authors say the results highlight concerns about the validity of PFS as an endpoint in trials of the VEGF inhibitor in more common cancers.

They note that in metastatic breast cancer, five major randomised controlled phase III trials found no significant increase in OS with bevacizumab-based treatment.

The discrepancy between positive PFS and negative OS outcomes might be due to radiologists disagreeing about 50% of the time as to whether tumour progression had occurred, “starkly exposing the severe limitations of PFS as a proxy for OS, where ambiguity is absent”, according to Professor Haines.

“The additional clinical concern is that bevacizumab contributes to many adverse events, including thromboembolism, GI perforation, hypertension, and proteinuria,” he writes.

And no benefit on OS has been in RCTs of bevacizumab-based VEGF therapy in nine out of 11 cancer indications, with the only  OS benefit being seen in trials for metastatic cervical cancer and unresectable pleural mesothelioma.

“On the basis of the OS gold standard, the angiogenesis-based VEGF hypothesis is on life support,” the letter authors say.

“This is hardly unexpected, because extrapolating the basic molecular and cellular foundations of ligand interactions with normal endothelial cells to the outputs from tumours is hazardous. Perturbation of the multiple isoforms of VEGF will rarely disturb the interactions from heterogeneous tumour outputs and their endothelial targets, especially because tumours themselves adapt by constructing abnormal tumour-derived endothelial cells and hence bypass most molecular roadblocks.”

They say additional large randomised trials in these nine metastatic cancers are not justified, given the lack of OS benefit with bevacizumab.

Instead, they advise the exploration of novel approaches in immunotherapy and personalised radiation treatment based on metallomics.

And with the costs of bevacizumab now exceeding U$50 billion they suggest the oncology profession now try to disregard the inferior PFS end point and rely solely on OS whenever possible.

However in a response to Professor Haines, the authors of the latest trial maintained that PFS was an important clinical endpoint in ovarian cancer where sensitivity to chemotherapy is retained.

“The length of postprogression survival is so long that OS is an unrealistic end point,” said Dr Krishnansu Tewari, director of the gynaecological oncology program at the University of California, Irvine.

He added that bevacizumab may exhibit enhanced activity in ovarian cancer because HPV-mediated carcinogenesis produces a homogeneous entity, and there is a wide spectrum of responses due to it being a heterogenous disease.

“These biologic phenomena have informed the decision by the FDA to recognise the value of PFS in ovarian cancer,” he said.

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