Metastatic Colorectal Cancer: Prolonged Bevacizumab Improves Outcomes, New Targeted Therapies on the Horizon

August 2012 Vol 5, No 5, Special Issue ASCO 2012 Payers' Perspective

Chicago, IL—The addition of new targeted agents, as well as prolonged use of bevacizumab even beyond disease progression, extend overall survival (OS) and improve progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC), according to several studies presented at ASCO 2012.

The More Bevacizumab, the Better
In the phase 3 clinical trial TML 18147, which was highlighted at a press briefing, the administration of the anti-VEGF (vascular endothelial growth factor) bevacizumab beyond the point of disease progression in­creased survival.

“This is the first randomized trial to prospectively evaluate bevacizumab beyond first progression. The study confirms that continuing bevacizu­mab beyond progression when changing chemotherapy is beneficial for patients, and this finding has translated into a significant improvement in OS in metastatic colorectal cancer patients, as well as progression-free survival,” said Dirk Arnold, MD, of the University Clinic Eppendorf in Hamburg, Germany.

The TML 18147 trial enrolled 820 patients with mCRC whose disease had progressed after first-line chemo­therapy. The patients received an irinotecan-based or oxaliplatin-based regimen plus bevacizumab. Upon disease progression, the patients were randomized to second-line therapy with the regimen they did not receive first, with or without concomitant bevacizumab.

The median OS was 11.2 months with maintenance bevacizumab compared with 9.8 months with chemo­therapy alone, for a 19% reduction in mortality risk (P = .062). Median PFS was 5.7 months and 4.1 months, respectively (P <.001).

This study tested an important biologic concept for antiangiogenic drugs, showing that duration of treatment does matter. In addition, although the current evidence comes from research in mCRC, this principle could hold true for lung and breast cancer as well, some believe.

Dr Arnold said that although bevacizumab produced mixed results in other cancers, it plays a significantly favorable role in mCRC. “These findings indicate that this might serve as a new model for a treatment approach by multiple treatment lines in metastatic colorectal cancer and across other tumor types,” he said.

Axel Grothey, MD, a CRC specialist at the Mayo Clinic, Rochester, MN, agreed that using bevacizumab be­yond progression represents a new treatment approach that is currently being tested in other tumor types.

Press briefing moderator Bruce J. Roth, MD, of Washington University in St. Louis, commented that oncologists have been trained to discontinue cytotoxic chemotherapy at the time of progression, “but the issue is more complicated for anti-VEGF therapies like bevacizumab, and this issue has been raised in other tumor types.” He said that the mechanism of resistance to anti-VEGF agents may be different, which may explain the benefit.

Potential New mCRC Therapies
Two additional studies presented at the meeting showed benefits from adding kinase inhibitors or an epidermal growth factor receptor (EGFR) to mCRC regimens.

In the phase 3 clinical trial CORRECT, the investigational oral multi­kinase inhibitor regorafenib was compared with placebo in 760 patients with mCRC whose disease was refractory to chemotherapy.

The use of regorafenib significantly extended OS from 5.5 months with placebo to 6.6 months, hazard ratio 0.77 (95% confidence interval, 0.64-0.94; P = .052). Although the absolute difference in OS was only 1 month, Dr Grothey emphasized that these results are best viewed in terms of the hazard ratio. He noted that many patients with mCRC are still fit and able to undergo further treatment after they become resistant to chemotherapy, and regorafenib addresses that unmet need.

A New Drug Application was submitted to the US Food and Drug Ad­ministration for regorafenib on May 23, 2012, for the treatment of patients with mCRC.

In the phase 3 GERCOR DREAM trial, patients with previously untreated mCRC received chemotherapy plus bevacizumab, and those without disease progression were randomized to maintenance therapy with bevacizu­mab alone or with bevacizumab plus the EGFR erlotinib.

Median PFS was improved with the addition of erlotinib from 4.6 months to 5.8 months (P = .005). There was, however, an increase in diarrhea and skin toxicity with erlotinib. Neverthe­less, the study suggests that there may be a role for dual targeting of VEGF and EGFR in CRC, according to Dr Grothey.

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