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Continuation of bevacizumab with second-line chemotherapy extends survival in patients with metastatic colorectal cancer
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CHICAGO — The addition of bevacizumab to standard chemotherapy during second-line treatment extended OS for patients with metastatic colorectal cancer who also received the combination during first-line treatment, according to results of a phase 3 study.
The trial was the first to evaluate the impact of continued VEGF inhibition with the addition of bevacizumab (Avastin, Genentech) to standard chemotherapy in second-line treatment for patients who also underwent the combination treatment in a first-line setting, researchers said.
Many US oncologists already provide the combination regimen in both first- and second-line settings, suspecting that extended treatment results in meaningful benefits for patients with advanced colorectal cancer.
The findings will validate that approach, and they likely will alter the standard of care in other parts of the world — including Europe — where bevacizumab often is used only in first- or second-line treatment, the researchers said.
Dirk Arnold, MD, director of the Hubertus Wald Tumor Center at the University Cancer Center of University Clinic Eppendorf in Hamburg, Germany, and colleagues enrolled 820 patients between February 2006 and June 2010. All patients had metastatic, inoperable colorectal cancer.
All patients had received either oxiliplatin- or irinotecan-based chemotherapy plus bevacizumab as first-line therapy and progressed within 3 months after discontinuation. After disease progression, the patients were randomized to a second round of treatment, this time with the opposite chemotherapy regimen, plus either bevacizumab (n=409) or placebo (n=411).
The primary endpoint was OS. Secondary endpoints included PFS, response rate and safety.
The patients assigned to bevacizumab in second-line treatment experienced statistically significant improvements in OS and PFS compared with the patients who received chemotherapy alone.
Median OS was 11.2 months in the bevacizumab arm vs. 9.8 months in the chemotherapy-alone arm (HR=0.81; 95% CI, 0.69-0.94; P=.0062). Median PFS was 5.7 months in the bevacizumab arm vs. 4.1 months in the chemotherapy-alone arm (HR=0.68; 95% CI, 0.59-0.78; P<.0001).
“The study confirms that the continuation of bevacizumab beyond progression while changing chemotherapy is beneficial for patients,” Arnold said during a press conference. “This clearly provides a new treatment option [in the second-line setting] for patients who have been pre-treated with a bevacizumab-combination regimen.”
The response rate was 5.4% in the bevacizumab group and 3.9% among the placebo group (P=.3113).
Patients in both arms tolerated the treatments well, the researchers said. Adverse events reported by patients assigned to the bevacizumab arm were consistent with those reported in prior studies, and bevacizumab-related adverse events did not increase when continuing its use beyond progression, the researchers said.
“[The findings] provide an important new insight about the biology of advanced colorectal cancer, showing us that if the disease develops resistance to chemotherapy, it does not necessarily mean that tumors become resistant to anti-angiogenic therapy,” Arnold said in a press release. “By simply switching chemotherapy drugs when the cancer progresses and continuing with bevacizumab, we can make second-line treatment even more powerful. This finding will likely spur research into other cancer types that are sensitive to both bevacizumab and chemotherapy.”
For more information:
Arnold D. Abstract #CRA3503. Presented at: the 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago.
Disclosure: The researchers report serving as a consult or adviser for, as well as receiving research funding and honoraria from, Amgen, Baxter International, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Merck, Novartis, Pfizer, Roche and Sanofi.
Perspective
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Richard Goldberg, MD
This Roche-funded study is long overdue. For years, clinicians have relied on data from the retrospective Genentech-funded BRITE registry reported in the Journal of Clinical Oncology by Grothey and colleagues in 2008 to make a decision about whether to continue bevacizumab with subsequent lines of chemotherapy after progression on initial chemotherapy administered with bevacizumab. That report suggested a major survival benefit to continuing bevacizumab, and the Arnold data show us that the BRITE data were misleading. Interpretation of the TML study is complicated by the design, which permitted enrolling physicians to use any of three initial irinotecan or oxaliplatin and 5-FU therapies and then crossed patients over to the reciprocal chemotherapy. It is likely that the interactions between bevacizumab and irinotecan are not the same as the those with oxaliplatin.
In any case, the median OS benefit for continuing bevacizumab in the heterogeneously treated study population is a modest 5 weeks. The good news is that additive toxicity was also modest. It is likely that this study’s outcome will not change oncologists’ behaviors much. Many US oncologists already use bevacizumab upon progression, although a substantial number do not. In many countries outside the United States, the cost/benefit ratio will exceed the threshold for what nationalized health care systems consider for coverage and its use will not be supported. Whether to continue the agent across lines of therapy remains a matter of perceived value and societal values, as well as the patient’s, payer’s and physician’s opinions about the modest median survival benefit. The positive spin put on the pre-ASCO press releases from Roche leading up to this meeting suggest that the results will be used enthusiastically to market the continuation strategy. My own degree of enthusiasm about these data remains tepid.
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