The expanded use of Avastin (bevacizumab) into the first-line setting, adjuvant therapy, as well as into additional advanced cancers is a high-stakes proposition for Roche. The drug is currently used to treat advanced colon, breast, lung, and kidney cancers. In the past year, however, Phase III trials have failed to show its potential in late-stage prostate, advanced stomach, or early-stage colon cancers.
A test to identify potential responders to Avastin and/or to monitor therapy results and disease progression would prove extremely valuable for Roche’s development plans. It would also spare those patients who would not see a response to the drug from the side effects associated with it. The therapy has been linked to arterial clots, heart attacks, stroke, and bowel perforations.
On March 12, Roche reported that a Phase III trial investigating the use of Avastin in combination with docetaxel and prednisone in men with hormone-refractory prostate cancer (HRPC) did not extend overall survival compared to chemotherapy and prednisone alone. In February another late-stage study of Avastin with Xeloda did not extend survival among individuals with inoperable or advanced stomach cancer when compared to chemotherapy alone. And in April 2009, Roche reported that a Phase III study (NSABPC-08) of Avastin plus chemotherapy following surgery in patients with early-stage colon cancer did not meet its primary endpoint of reducing the risk of cancer recurrence.
The 2,710-person NSABPC-08 study was the first of many testing Avastin in the adjuvant setting, the most profitable piece of the oncology market. After 35.6 months of follow up, the Avastin arm yielded a disease-free survival (DFS) rate of 77.4% compared to 75.5% for the control group, a nonsignificant difference. But at one year, there was reportedly a 40% reduction in favor of Avastin. Over time, however, the effect diminished and lost statistical significance.
The lead author of the study report, Norman Wolmark, M.D., chairman of the National Surgical Adjuvant Breast and Bowel Project (NSABP), which ran the study, suggested that based on study results, Avastin might produce lasting benefits if patients received it for a longer time. But in an analysis of the trial results published in HemOnc Today, David Ilson, M.D., Ph.D., an attending physician at Memorial Sloan-Kettering Cancer Center and a member of the HemOnc Today editorial board, commented, “The negative results indicate that bevacizumab should not be incorporated into adjuvant treatment and should be reserved only for use in metastatic disease.”
The early trend toward improved DFS is not sufficient to treat all patients with Avastin when there may be no overall survival difference, he noted. “To propose to look at another trial in all patients extending the use of bevacizumab is not justifiable. If we can identify a subset of patients that may benefit, then that group could be targeted in another trial.”
Tests to predict who will benefit have emerged for other drugs, among them Eli Lilly's mAb Erbitux and AstraZeneca’s small molecule drug Iressa, which both target the EGFR receptor. Only patients with tumors expressing a mutant form of the molecule respond to Iressa.
Scientists are currently working to identify patients who have responded to Avastin and to characterize those responses on a molecular level. For example, researchers from Genentech, which developed Avastin and is now part of Roche, and the NCI sought to find gene-expression profile signatures to distinguish patients with partial response (PR) from those with stable disease (SD) and progressive disease (PD) among women treated for breast cancer with Avastin as a neoadjuvant followed by Avastin plus chemotherapy.
Twenty patients with inflammatory breast cancer and one with locally advanced breast cancer were treated with one cycle of Avastin followed by six cycles of Avastin plus docetaxel/doxorubicin prior to surgery. Baseline angiogenic tumor markers and gene-expression profiles were measured.
The investigators found that angiogenic markers, 26 GO categories, and five functional molecular pathways were differentially expressed between the responders and nonresponders. Key markers in the angiogenesis process that were associated with response to therapy were VEGF-A, the molecular target of Avastin; PDGFRs, the receptors of VEGF-A; and CD31, an endothelial cell-adhesion molecule whose expression may be modulated by VEGF-A. Patients with higher tumor VEGF-A, CD31, and PDGFR-β expression in the tumor vasculature tended to be more likely to benefit from Avastin treatment plus chemotherapy.
The findings indicate, according to the researchers, that Avastin may be specifically given as a targeted agent, although their data requires confirmation by larger cohorts. In a statement to GEN, Genentech said that it is committed to determining whom may benefit the most from its medicine. The firm said that the majority of its clinical trials include tissue collection for biomarker analysis.
“Research to date has shown that the benefits of Avastin-based treatment are not influenced by common cancer biomarkers. More than 150 potential Avastin biomarkers have been studied, but so far none have been found that consistently and accurately predict which patients may benefit most from Avastin-based treatment.
“Expression profiling methods like those described in the paper by Yang et al. are one of the many approaches we are using in our biomarker research program. Their results are consistent with our prior published research that suggests the expression of certain genes in the angiogenesis pathway should be fully evaluated as potential biomarkers for Avastin-based treatment.”
It is possible that response profiles may be different in different patients and shift over time. The aim of efforts to find consistent biomarkers for patient responsiveness is to improve treatment options and enable informed patient inclusion in clinical trials.