Anti–Vascular Endothelial Growth Factor Therapy in Breast Cancer: Game Over?

In the article that accompanies this editorial, Mackey et al present the results of ROSE/TRIO-12, a randomized phase III trial comparing single agent docetaxel to the combination of docetaxel and ramucirumab in front-line metastatic breast cancer. This large, wellpowered, placebo-controlled international trial replaced bevacizumab (a vascular endothelial growth factor [VEGF] –A ligand blocking antibody used in numerous phase III trials) with ramucirumab (a human immunoglobulin G1 VEGF receptor [VEGFR] –2–binding monoclonal antibody recently approved for gastric cancer) as the anti-VEGF agent to be studied. The results are disappointing but familiar to those who have followed the story of anti-VEGF therapy in breast cancer—yet another failure. Bevacizumab, the first anti-VEGF therapy to enter the breast cancer arena, electrified the field in 2005 with the E2100 trial, which showed a doubling in progression-free survival (PFS) when combined with weekly paclitaxel. Two subsequent trials (AVADO [Phase III Trial of Avastin and Docetaxel] and RIBBON-1 [Regimens in Bevacizumab for Breast Oncology]) combined bevacizumab with docetaxel, and while neither demonstrated the same degree of PFS benefit as the initial trial, all three demonstrated statistically significant improvements in PFS. These trials were based on a substantial body of preclinical and clinical evidence suggesting the centrality of angiogenesis in general, and VEGF in particular, to breast cancer growth, invasion, and metastasis. Increased tumor VEGF was associated with impaired outcome in numerous clinical studies, and inhibition of VEGF in preclinical models (alone or in combination with other chemotherapeutics and biologics) was associated with improved outcome. Taxanes are imbued with their own antiangiogenic activity, and the combination of taxanes with bevacizumab in particular appeared to provide synergistic antitumor activity in preclinical models of breast cancer. Things went downhill from the initial presentation of the first three randomized trials. After the approval of bevacizumab for metastatic breast cancer by the US Food and Drug Administration (following a contentious ODAC meeting), mature survival results demonstrated that the three trials (individually and collectively) failed to demonstrate an overall survival advantage. Bevacizumab, the beneficiary of an accelerated approval based on initial results, lost its breast cancer label in the United States. Other failures followed. An ambitious adjuvant program was launched, based on the original disease-free survival results. The main results of these large adjuvant trials are now in, and like the metastatic trials, they disappoint. Whether the anti-VEGF hypothesis was tested in a general population (E5103), a human epidermal growth factor receptor 2 (HER2) –positive population (BETH [Treatment of HER2 Positive Breast Cancer With Chemotherapy Plus Trastuzumab vs Chemotherapy Plus Trastuzumab Plus Bevacizumab]) or in triplenegative breast cancer (BEATRICE [A Study of Avastin (Bevacizumab) Adjuvant Therapy in Triple Negative Breast Cancer]) the results were the same: no statistically significant improvement in disease-free survival was seen. Was this failure a failure of bevacizumab, or of the underlying anti-VEGF hypothesis for breast cancer? This is a reasonable question to ask: we do not always get it right with the first drug to target a malignant process. Sunitinib, a small molecule receptor tyrosine kinase inhibitor of VEGFR2 (and many, many other kinases) struck out in multiple phase III trials in metastatic breast cancer, despite interesting phase II monotherapy results. And now ramucirumab joins the list of failed attempts to use anti-VEGF therapy in metastatic breast cancer. Ramucirumab is a human immunoglobulin G1 monoclonal antibody that binds the extracellular domain of VEGFR-2, as opposed to bevacizumab’s ligand-binding qualities. While there was a numerically increased PFS resulting from the addition of ramucirumab to docetaxel (from 8.2 to 9.5 months), this did not reach statistical significance (P .077), and failed to prolong overall survival (27.3 v 27.3 months). The drug, in addition, added significantly more toxicity, in the form of increased rates of fatigue, hypertension, febrile neutropenia, hand-foot syndrome, and stomatitis. The US Food and Drug Administration approved ramucirumab for use in gastric cancer, where it (albeit modestly) improves both PFS and overall survival. So once again (as with bevacizumab and sunitunib) this seems a breast cancer failure rather than a general failure for the anti-VEGF hypothesis. Since ramucirumab, like bevacizumab and sunitunib, target essentially the same process (VEGF-driven angiogenesis) in the same disease, its failure is perhaps unsurprising. But why has VEGF-based therapy for breast cancer, which began with such promise, failed so completely? In particular, why has the improvement seen in PFS seen with bevacizumab (and at least hinted at with ramucirumab) not translated to an improvement in overall survival in the metastatic setting, or in disease-free survival in the adjuvant setting? JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 2 JANUARY 1