Researchers Remain in Pursuit of Angiogenesis Inhibition

Hope Rugo, MD

Although the FDA revoked the indication for bevacizumab (Avastin) in metastatic breast cancer late last year, many researchers and oncologists anticipate a role for antiangiogenic strategies in future treatment paradigms. Yet just what that role will be remains elusive, said Hope S. Rugo, MD, clinical professor and director of the Breast Oncology Clinical Trials Program at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco.

“We had very high hopes and were very excited about the role of bevacizumab, as well as other antiangiogenic agents, and here we are today really in a gray area, where we’re not quite sure what the direction is (going) forward,” Rugo said during a presentation at the 11th International Congress on the Future of Breast Cancer. “We do know that antiangiogenic therapy does have activity in breast cancer, we just don’t know exactly how to use it, and where the activity is best seen or where the agents are best used.”

Rugo called for a change in approach when investigating antiangiogenic agents, which she defined as those specifically targeted to a pathway involved with the vascular endothelial growth factor (VEGF) receptor. She said researchers must focus on defining the subsets of patients most likely to benefit from angiogenesis inhibitors, adding that it will be worthwhile to try combining “new agents with angiogenesis agents, maybe looking at vascular disrupting or angiopoietin inhibitors in combination with antiangiogenesis agents like bevacizumab.”

“There are many different ways to activate PI3-kinase, and Raf, Ras, MEK, etc,” Rugo said. “If you block downstream, you can still get activation of VEGF, and if you block VEGF, you can get activation of the downstream pathways, so it’s very complicated, and it suggests that in the future we need combinations of agents to be most effective.”

Potential Bevacizumab Biomarkers Explored

Bevacizumab, a humanized monoclonal antibody that binds to and inhibits the activity of VEGF, has demonstrated in clinical trials an improvement in progression-free survival (PFS) but not overall survival (OS) in patients with metastatic breast cancer when combined with chemotherapy.

Last year, the FDA revoked bevacizumab’s approval for use in combination with paclitaxel in HER2-negative metastatic breast cancer on the basis that the drug did not offer enough benefit to outweigh its health risks, including high blood pressure, bleeding, and heart failure. (Avastin retains its label indications in four other tumor types.)

Rugo maintained that many of the bevacizumab trials could have provided more and better information if they had been designed differently. She said a pooled safety analysis of bevacizumab plus chemotherapy versus chemotherapy alone showed that the main increased risk in the experimental groups was hypertension, although the number of deaths did not increase with the addition of bevacizumab.

“We need to go back to the drawing board because we know patients benefit,” Rugo said. “All of these studies showed a PFS benefit, and there are a few patients out there who’ve continued to have disease control many years after starting bevacizumab—we just weren’t smart enough to figure out who was going to benefit.”

Investigators have, for some time, been seeking to identify biomarkers to help predict which patients would benefit from bevacizumab, Rugo said. She said there’s some evidence that a “VEGF signature” might exist and correlate with bevacizumab benefit, possibly in patients with triple-negative breast cancer (TNBC). The RIBBON 2 trial supported that idea, she said, by demonstrating a median PFS of six months in patients with TNBC who took bevacizumab, compared with a median PFS of 2.7 months for the study’s overall population (J Clin Oncol. Published online ahead of print October 11, 2011, doi: 10.1200/ JCO.2010.34.1255).

In two neoadjuvant trials whose results were published earlier this year, bevacizumab was added to standard chemotherapy in subgroups of breast cancer patients, with a primary endpoint of improved pathologic complete response (pCR). In the GeparQuinto study (Lancet Oncol. 2012;13(2):135-44), patients with TNBC demonstrated the most benefit, while the NSABP B-40 study (N Engl J Med. 2012; 366(4):310-320) showed a greater response in hormone receptor-positive patients, Rugo explained.

While both trials “showed an increase in pCR in tumors with high-grade histology,” there was vast disagreement in the study designs regarding what constituted TNBC and pCR, which makes it difficult to compare and apply their results, Rugo said.

Some encouragement about bevacizumab’s applicability in patient subgroups came out of the AVEREL trial in HER2-positive breast cancer, which compared trastuzumab with and without bevacizumab, Rugo said (Cancer Res. 2011;71[24 suppl]: abstr S4-8]).

“The most important data came in trying to understand the plasma VEGF levels, which correlated with PFS,” she said. For a subset of patients with higher levels of plasma VEGF-A, “adding bevacizumab seemed to counteract the poor prognostic impact of the high VEGF-A level.”

More Inhibitors Under Study

While bevacizumab targets the ligand to the VEGF receptor, pharmaceutical companies are exploring a number of other agents that employ different strategies (Table Below).

Ramucirumab, which also is an antibody, targets the receptor itself, Rugo said. A phase III trial of doceatxel with or without ramucirumab as first-line therapy in HER2-negative, unresectable, locally advanced or metastatic breast cancer has completed accrual, with results due in June 2013.

Meanwhile, aflibercept, a soluble receptor, releases “a receptor into circulation, trapping the ligand so it can’t bind to the receptor.” Unfortunately, Rugo said, aflibercept “hasn’t moved forward quite as much as they had originally hoped. There are so many redundant pathways that the soluble receptor idea hasn’t really taken off.”

Other mechanisms on the table include vascular disrupting agents and immune modulation, Rugo said.

Finally, in the arena of small-molecule inhibitors, she said, sorafenib demonstrated a modest improvement in PFS when it was tested in a phase II trial with capecitabine, versus capecitabine alone, as first- or second-line therapy for locally advanced or metastatic breast cancer. However, patients in the phase III RESILIENCE trial, now accruing, will get a reduced dose of sorafenib due to significant toxicity, Rugo said.

Such toxicities are typical for drugs on a “huge list” of small-molecule inhibitors that block VEGF and other tyrosine kinases, Rugo said. “The problem is that offtarget toxicity is making us unable to give enough dose to get an antitumor effect,” she said.

The researcher recalled a phase I study in which she gave the small-molecule inhibitor axitinib to a patient with TNBC. “Her tumor melted away from her chest wall until she became hypertensive two weeks later and seized,” Rugo recalled. “Once we reduced the dose so there was no uncontrollable hypertension, the tumor immediately came back.”

“Maybe, by looking at other ways of blocking angiogenic pathways in the future, we can overcome that,” she said.

Table. Selected Agents Targeting the VEGF Pathway

Class

Examples

Targets

Stage of

Development

Company

Agents targeting the VEGF ligand

Antibodies

Bevacizumab

Ramucirumab

VEGF

VEGFR2

Phase III

Phase III

Genentech

ImClone

Soluble receptors

VEGF-Trap (aflibercept)

VEGF and PIGF

Phase III

Regeneron/Sanofi

Agents targeting the VEGF Receptors

Small-molecule

inhibitors

Sunitinib

Axitinib

SU014813

Pazopanib

Sorafenib

VEGFR2, PDGFR, c-Kit

VEGFR2

VEGFR1/2; c-Kit

VEGFR1/2; (PDGFR, c-Kit)

Raf, VEGFR1/2; c-Kit

Phase III

Phase II/III

Phase II

Phase II/III

Phase III

Pfizer

Pfizer

Pfizer

GlaxoSmithKline

Bayer/Onyx

Vatalanib

AEE788

VEGFR1/2 PDGFR, c-Kit

VEGFR1/2; ErbB1/2

Phase II/III

Phase I/II

Novartis

Novartis

Vandetinib

Cediranib

Motesanib

ABT 869

Brivanib

TKI258

VEGFR2/EGFR

VEGFR, c-Kit

VEGFR1/2; PDGFR, c-Kit

VEGFR1/2

VEGFR2, FGFR

VEGFR, FGFR, PDGFR

Phase II/III

Phase II/III

Phase II/III

Phase I/II

Phase II

Phase II

AstraZeneca

AstraZeneca

Amgen

Abbott

Bristol-Myers Squibb

Novartis

Rugo H. Role of angiogenesis inhibition in breast cancer today. Presented at: 11th International Congress on the Future of Breast Cancer; July 26-28, 2012; Coronado, CA.