Second-Line and Salvage Treatment of mCRC

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Both VEGF and EGFR inhibitors have demonstrated efficacy as first- and second-line treatments for patients with metastatic colorectal cancer (mCRC). To attempt to find an optimal approach, the phase II SPIRITT trial examined FOLFIRI plus bevacizumab or panitumumab following treatment with bevacizumab plus an oxaliplatin-based chemotherapy regimen for patients with wild-type KRAS metastatic mCRC.

In the study, 182 patients were randomized in a 1:1 ratio to receive FOLFIRI plus panitumumab (n = 91) or bevacizumab (n = 91). The median progression-free survival (PFS) with panitumumab was 7.7 months compared with 9.2 months with bevacizumab. However, the findings were not statistically different, with a hazard ratio (HR) of 1.01. The median overall survival (OS) with panitumumab was 18.0 months versus 21.4 months with bevacizumab (HR = 1.06).

Interestingly, Tanios Bekaii-Saab, MD, points out, the objective response rate (ORR) was higher with panitumumab at 28% compared to 16% with bevacizumab. Another intriguing aspect of this trial, Bekaii-Saab believes, is that the response to these treatments in the second-line setting closely resembled the responses experienced with frontline treatment.

The SPIRITT study was initiated in 2007, at the time KRAS mutations were only defined by alterations in codons 12 and 13, Bekaii-Saab notes. Recent research has demonstrated that expanding the definition to all RAS mutations is more predictive in mCRC. An analysis looking more specifically at RAS mutations in the SPIRITT trial may reveal a subset that benefits more with one agent, Bekaii-Saab speculates.

Adding to this, Fadi Braiteh, MD, cautions that not all biologic agents function through the same mechanisms. As a result, Braiteh cautions, ziv-aflibercept should not be blindly swapped for bevacizumab and panitumumab may not be equivalent to cetuximab.

Switching gears to the third-line or salvage setting, Axel Grothey, MD, describes the phase III CORRECT trial, which led to the FDA approval of the multikinase inhibitor regorafenib. Initially, Grothey notes, the study hoped to enroll 690 patients in 26 months; however, the trial quickly enrolled 760 patients in only 10 months.

The 760 patients in the trial were randomized in a 2:1 ratio to receive regorafenib or placebo plus best supportive care. For the primary endpoint of OS, the trial was positive with a HR of 0.77. Trends in the PFS data suggest that further analysis is needed to find specific subgroups of patients who do and do not respond, Grothey explains.

The overall success of this trial demonstrates that it is possible to conduct clinical trials in the last-line setting, Grothey believes. However, now that an agent is available in this space, it may be difficult to conduct new drug development, Alan P. Venook, MD, believes. To address this concern, Grothey believes it would be possible to conduct trials in a third-line setting before administering regorafenib; however, he cautions, patients with very aggressive tumors may be unlikely to respond to treatment with regorafenib.

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