Recent data from adjuvant trials of antiangiogenic therapy have left many in the field scratching their heads. For an approach seemingly brimming with promise, what went wrong? Is there a place for antiangiogenic therapy in early-stage tumors?

The topic is "hot" enough that it was debated before a filled auditorium by leaders in the field at the ESMO/ASCO Joint Symposium, presented October 11 at the 35th ESMO Congress in Milan, Italy. ASCO President George Sledge, MD, and ESMO President David Kerr, MD, emphasized the importance of the issue.

"This is a fantastic opportunity to discuss an issue that is very topical, incredibly timely, and of huge interest to clinicians," Dr. Kerr said in an interview.

"We have proof of concept that antiangiogenesis therapy is beneficial for patients with a wide spectrum of cancers," Dr. Sledge added. Clinical success has been shown in renal cell and hepatocellular cancers, non-small cell lung cancer (NSCLC), colorectal cancer, breast cancer, and gliomas. "But there are challenges."

Although in the metastatic setting studies of bevacizumab (Avastin), usually when combined with chemotherapy, have been positive, findings from adjuvant trials have been clearly negative. The unanticipated findings have "led to clinical and financial turmoil," he said. "After a decade in the clinic, we have a number of questions" (Table 1).

A Look at the Clinical Scenario

Lee M. Ellis, MD, of the Departments of Cancer Biology and Surgical Oncology at The University of Texas MD Anderson Cancer Center, Houston, said it was a predictable next step to take bevacizumab into the adjuvant setting. "It's just what we do in oncology," he said. "We take a drug that is efficacious on the metastastic setting and test it in adjuvant studies."

But two phase III adjuvant trials in colorectal cancer-NSABP C-O8 and AVANT-found no additional benefit for bevacizumab (plus maintenance) vs chemotherapy alone, nixing the notion that what is good for metastatic disease is also good for early-stage cancer.

"These are examples that more is not better, and there is no reason to think that tweaking the regimen will provide any benefit," Dr. Ellis suggested.

Dr. Sledge commented, "The old paradigm that what works in metastasis will work in the adjuvant setting is no longer necessarily the case, and not just for bevacizumab. These findings tell us that we have to totally revisit how we look at adjuvant therapy in cancer."

Furthermore, Dr. Ellis noted that the additional risk of toxicities with bevacizumab is important "when 65% to 70% of patients will be cured by surgery alone."

Meanwhile, based on C-O8 and AVANT, the future of the ongoing adjuvant trials is uncertain. This includes Eastern Cooperative Oncology Group (ECOG) 5202, which has been suspended after enrolling 3,125 patients, and QUASAR-2, with 2,240 patients. ECOG 5202 was designed to study patients with stage II colorectal cancer stratified by risk; high-risk patients were randomly assigned to modified FOLFOX6 (oxaliplatin, leucovorin, fluorouracil [5-FU]) with or without bevacizumab, and low-risk patients were observed. In QUASAR-2, patients receive capecitabine with or without bevacizumab for 6 months, plus 6 months of bevacizumab.

Dr. Kerr, the principal investigator of QUASAR-2, told The ASCO Post, "Of course we have concerns and are having ongoing discussions. Our Data Safety and Monitoring Committee will advise us as to whether we should stop bevacizumab."

Other adjuvant trials with vascular endothelial growth factor (VEGF)-targeted agents include two in renal cell carcinoma, one in NSCLC, and three in breast cancer.

Is Further Study Warranted?

Meanwhile, is there a way to improve upon the FOLFOX/bevacizumab-based regimen in the adjuvant setting? "This is doubtful," Dr. Ellis said. "Adding a monoclonal antibody to the epidermal growth factor receptor (EGFR) was detrimental in two trials in the metastatic setting."

Nor is longer duration of bevacizumab treatment the answer. Since most responses in patients with metastatic colorectal cancer occurred within the first 4 months, "there is no reason to believe that longer-term combination therapy or single-agent bevacizumab will lead to more cures," he maintained. "After 12 months of bevacizumab, including 6 months of chemotherapy, I think we can declare tumor cells resistant. Also, giving bevacizumab 'forever,' as a cytostatic agent, is simply not feasible."

Dr. Ellis called for interim analyses of all ongoing studies in the various tumor types, noting that some cancers may respond differently to the drugs. "As I stated at the plenary session at the 2009 ASCO Annual Meeting, if AVANT is not 'outright positive,' no further study of long-term adjuvant anti-VEGF treatment in colorectal cancer is warranted. Lacking a biomarker, we should not administer a potent drug like bevacizumab forever in a population where up to 95% of patients will not benefit." ■