April 17, 2012 — The addition of the targeted therapy bevacizumab (Avastin, Genentech) to standard chemotherapy for advanced nonsmall cell lung cancer (NSCLC) did not significantly increase survival rates for patients 65 years and older, according to a new retrospective study, which appears in the April 18 issue of JAMA.
Bevacizumab should not be considered part of the "backbone" of treatment or the standard of care for older patients with advanced disease, said lead author Deborah Schrag, MD, MPH, from the Dana-Farber Cancer Institute in Boston, Massachusetts. She spoke at a press conference, held in Washington, DC, on the journal's new issue, which centers on comparative effectiveness research.
Older patients with advanced disease make up the majority of NSCLC patients. Around 80% of NSCLC is diagnosed when it is already advanced (stage IIIB or IV); overall, about two thirds of all lung cancers are diagnosed at 65 years and older, the researchers note.
This study is important because the addition of bevacizumab to standard chemotherapy for the treatment of advanced NSCLC has shown efficacy; this indication was approved by the US Food and Drug Administration (FDA) in 2006, on the basis of the Eastern Cooperative Oncology Group (ECOG) 4599 trial.
However, this is not the same as showing effectiveness.
Dr. Schrag explained that efficacy studies such as ECOG 4599, which are restricted to controlled settings and usually feature younger healthier patients, ask: "Can this intervention work?" In contrast, effectiveness studies such as this one, which are set in the "real world," ask: "Does this intervention work?"
In the ECOG 4599 efficacy study, a "minority" of patients were 65 years or older, said Dr. Schrag. It did not demonstrate a survival advantage with the expensive drug in that minority — the subgroup of 366 patients who were 65 years and older, she said.
To examine the effectiveness of bevacizumab in older patients, Dr. Schrag and colleagues used population-based data from the Surveillance, Epidemiology, and End Results (SEER) program, which are linked to Medicare claims.
They found that median overall survival was 9.7 months for patients receiving the 3-drug combination of bevacizumab, carboplatin, plus paclitaxel, compared with 8.9 months for those receiving the 2-drug standard-therapy combination of carboplatin plus paclitaxel in 2006 and 2007 (after bevacizumab approval), and 8.0 months for those receiving standard therapy from 2002 to 2005 (before bevacizumab approval).
Despite the longer survival with the 3-drug combination therapy, the differences were not statistically significant when the researchers adjusted the data to "minimize confounding and selection bias," said Dr. Schrag.
No matter what we did, our finding held.
Five different statistical analyses failed to produce a finding indicating significance. "No matter what we did, our finding held," she said.
For instance, in models stratified by propensity score, the hazard ratio for overall survival for bevacizumab, carboplatin, plus paclitaxel, compared with postapproval standard therapy, was 1.01 (95% confidence interval [CI], 0.89 to 1.16; P = .85). Compared with preapproval standard therapy, it was 0.93 (95% CI, 0.83 to 1.06; P = .28).
The probability of surviving for 1 year was 39.6% for those who received the 3-drug combination, compared with 40.1% for postapproval standard therapy, and 35.6% for preapproval standard therapy, the researchers report.
These studies are just a little bit tricky.
The statistical rigor of this study was applauded by Phil Fontanarosa, MD, executive editor of JAMA, who moderated the press conference. "These studies are just a little bit tricky," he said. Dr. Schrag and colleagues did a commendable job evening out the differences between the treatment groups that existed in the study, he explained.
The study was partly funded by the Agency for Healthcare Research and Quality, as part of its DEcIDE (Developing Evidence to Inform Decisions About Effectiveness) program, which conducts studies on the outcomes of medical treatments and services.
In a press statement, Genentech responded to the new study by saying that only a 7.6% (318 of the 4168) of the records used in the study were from patients who received bevacizumab.
The company also pointed to another observational study that indicated that clinical outcomes in older patients (70 years and older) with advanced disease are consistent with the drug's efficacy in all patients with advanced disease. In that study, known as ARIES (Avastin in Combination With Chemotherapy for Treatment of Colorectal Cancer and Non-Small Cell Lung Cancer), 1970 lung cancer patients received bevacizumab and first-line chemotherapy. The median survival for all patients was 13.6 months. For the subset of participants 70 years and older (n = 650), the median survival was 12.6 months.
This effectiveness study is important because it provides evidence that bevacizumab was not rapidly and completely adopted by oncologists in the treatment of these older patients, said Dr. Schrag.
Instead, in the wake of the 2006 FDA approval decision, the adoption of bevacizumab was "judicious" and "by no means universal," she said.
In 2007, only 22% of older patients with advanced NSCLC received bevacizumab as a component of their first-line carboplatin plus paclitaxel chemotherapy regimen, she reported.
In contrast, bevacizumab was "more rapidly adopted" by oncologists for its use in the treatment of colorectal cancer, Dr. Schrag said.
The researchers report that oncologists in private practice might have had "financial incentives" to prescribe bevacizumab, because they can purchase it for less than the Center for Medicare & Medicaid (CMS) reimburses. But there was no stampede in lung cancer prescribing in 2007, the year after approval.
The data show some of the differences between efficacy and effectiveness, the researchers note.
In this effectiveness study, the magnitude of the survival benefit — both for standard chemotherapy and for combination therapy with bevacizumab — was lower than that observed in clinical trial participants, the researchers report.
The median survival for patients treated with the bevacizumab combination in this effectiveness study was 9.7 months; in the ECOG 4599 efficacy trial, it was 12.3 months.
For patients treated with standard therapy in this effectiveness study, median survival was 8.9 months in the postapproval group and 8.0 months in the preapproval group; in the ECOG 4599 efficacy trial, it was 10.3 months.
The favorable results seen in the clinical trials are "not entirely surprising," the researchers write, because less than 50% of those participants were 65 years or older, compared with 100% of the patients in this effectiveness study, they observe.
These patients should be included in future pivotal trials of cancer drugs that affect older patients, say the authors.
"In the future, for malignancies like NSCLC that disproportionately affect elderly patients or where the CMS 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 write.
Funding for this effectiveness study was provided by the Agency for Healthcare Research and Quality and the National Cancer Institute. Dr. Schrag reports receiving payment for American Society of Clinical Oncology educational talks.
JAMA. 2012;307:1593-1601. Abstract
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