Adding bevacizumab to standard first-line carboplatin and paclitaxel chemotherapy didn’t improve survival in a large retrospective cohort study of patients aged 65 and older who had advanced non–small cell lung cancer, according to a report in the April 18 issue of JAMA.
This finding is consistent with subgroup analyses of older lung cancer patients in efficacy studies of bevacizumab (Avastin), as well as with the results of a recent meta-analysis of four randomized clinical trials. Taken together, the findings demonstrate that bevacizumab should only be used "judiciously," and should not be considered the standard of care in this age group, said Junya Zhu of the Center for Patient Safety, Dana-Farber Cancer Institute, Boston, and her associates.
Approximately two-thirds of patients with lung cancer are diagnosed at age 65 or older, they noted.
Bevacizumab, a monoclonal antibody that inhibits tumor angiogenesis, was approved by the Food and Drug Administration (FDA) in 2006 as a combination therapy with carboplatin and paclitaxel for advanced nonsquamous non–small cell lung cancer (NSCLC). The pivotal Eastern Cooperative Oncology Group (ECOG 4599) trial demonstrated a statistically significant 2-month survival advantage with the addition of bevacizumab, but subset analyses did not find significant survival differences in older patients.
Ms. Zhu and her colleagues assessed the treatment in a Medicare population of 4,168 patients diagnosed with stage IIIB or IV nonsquamous NSCLC in 2002-2007, linking data from their medical records with data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) cancer registry.
The investigators compared outcomes in patients diagnosed in 2006-2007 who received bevacizumab plus carboplatin-paclitaxel (318 subjects) with outcomes in patients who received first-line carboplatin and paclitaxel alone (1,184 subjects). To mitigate any selection bias that might confound the results of the first comparison, they also compared survival outcomes with a second control group, 2,664 patients treated in 2002-2005 before bevacizumab was commercially available.
All study subjects were followed for a minimum of 2 years after diagnosis, at which point 83% were deceased.
The median unadjusted survival was 9.7 months for patients receiving the bevacizumab combination, compared with 8.9 months for those receiving carboplatin-paclitaxel only and 8.0 months for the historical controls. When the data were adjusted to control for demographic and clinical characteristics, there was no significant difference in survival among the three study groups, the investigators said (JAMA 2012;307:1593-1601).
In four further data analyses that adjusted for propensity scores, there also was no evidence to support the superiority of adding bevacizumab to standard chemotherapy in these patients. Sensitivity analyses did not change these results. And analyses of subgroups of patients such as those with the most advanced disease or those with a high burden of comorbidity also showed no benefit from adding bevacizumab to the standard chemotherapy regimen.
Perhaps as important as the clinical results was the finding that following FDA approval of bevacizumab, only 20%-22% of the subjects in this study received the drug as a component of their first-line chemotherapy. This suggests that "the medical oncology community requires therapeutic evidence specific to a particular disease prior to adoption," Ms. Zhu and her associates said.
"Medical oncologists, particularly those in private practice, may have financial incentives to administer new, expensive treatment agents if they can purchase them for less money than [Medicare] reimburses. Because bevacizumab is expensive and was covered by [Medicare], if oncologists were subject to powerful treatment incentives as some have suggested, we would have expected to observe them in this context.
"That we did not observe rapid or complete uptake of bevacizumab provides some measure of reassurance that oncologists are circumspect and judicious in their use of new agents with uncertain benefit in the Medicare population," the researchers noted.
The study also points to the need for greater representation of the elderly in relevant clinical trials, according to the authors. Less than half of patients in the pivotal ECOG trial – 44% of those given standard treatment and 42% of those given bevacizumab with standard treatment – were diagnosed at 65 years or older, compared with 100% of the population in the current analysis.
"In the future, for malignancies like NSCLC that disproportionately affect elderly patients or where [Medicare] covers a large proportion of treatment costs, negotiations with pharmaceutical sponsors of pivotal trials might mandate adequate representation of elderly patients and/or preplanned subgroup analyses relevant to the Medicare population," they added.
This study was supported by the National Cancer Institute, the U.S. Agency for Healthcare Research and Quality, the California Department of Public Health, and the Centers for Disease Control and Prevention. No relevant financial conflicts of interest were reported.