The VELOUR trial was presented at ECCO-ESMO 2012 and randomized 1,200 patients after initial FOLFOX therapy to receive FOLFIRI plus placebo or FOLFIRI plus ziv-aflibercept.Approximately 30% of patients received bevacizumab with initial chemotherapy. Results were very similar to the TML trial, with a modest improvement in both progression free (median 6.9 months vs. 4.67 months, P<0.0001) and overall survival (13.5 months. vs. 12.06 months, P=0.0032) with the addition of ziv-aflibercept.  Improvement in outcome was consistent regardless of prior bevacizumab. However, the addition of ziv-aflibercept increased grade 3/4 toxicities, particularly with respect to diarrhea, hypertension, and stomatitis, with more than twice as many patients discontinuing study treatment in the ziv-aflibercept arm due to adverse events. Based on these results, the FDA approved ziv-aflibercept in combination with FOLFIRI for the treatment of mCRC patients after progression on FOLFOX.

Taken in sum, the TML and VELOUR trials support the addition (or continuation) of an anti-angiogenic agent with second-line chemotherapy. Both bevacizumab and ziv-aflibercept result in modest improvements in survival. There is no head-to-head comparison between the two agents (and it is unlikely there will ever be such a trial).  Thus, both are options with second-line therapy. Oncologists have more experience with bevacizumab and its mild toxicity profile, and thus it is likely to be the most commonly used agent. However, experience with ziv-aflibercept will grow. If it is well tolerated in the clinic, it will be a legitimate second-line option, potentially for patients with rapid progression on front-line chemotherapy plus bevacizumab (who were not eligible for the TML trial).


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Beyond Second-Line Therapy

Assuming the most common treatment algorithm of initial FOLFOX plus bevacizumab and second-line FOLFIRI plus bevacizumab (and based on VELOUR, perhaps FOLFIRI plus ziv-aflibercept), patients whose tumors have KRAS wild-type will frequently receive irinotecan-based therapy plus cetuximab or panitumumab. Patients with KRAS mutated tumors do not benefit from anti-EGFR therapy. In either event, after progression on or inability to receive anti-EGFR therapy, treatment options have been limited.

The recent FDA approval of regorafenib will likely change that. The CORRECT study randomized patients who had progressed on or within 3 months of receiving all standard agents to receive either regorafenib or placebo in a 2:1 randomization. Patients receiving regorafenib had modestly improved median survival compared to placebo (6.4 months. vs. 5.0 months, P=0.0052). The disease control rate (responses plus stable disease) was improved with regorafenib compared to placebo (41% vs. 15%), although objective responses were rare (1%). Benefit appeared to be similar in the KRAS wild-type and KRAS mutant patient populations. Side effects were not trivial, however, including grade 3/4 hand-foot syndrome in ~16% and fatigue in nearly 10%.

Regorafenib is thus a reasonable treatment option for patients with mCRC who have received all standard therapy and maintain adequate performance status. Given the modest benefit, oncologists should resist the urge to treat patients whose performance status is inappropriate for additional therapy.

Summary

New treatment options may be confusing, but this is a good problem to have. Increased clinical experience will ultimately tell the story of the acceptance of ziv-aflibercept (compared to bevacizumab) in second-line therapy, and regorafenib dictating the frequency of their incorporation into clinical practice.  Availability of KRAS results before initial treatment discussions with patients and willingness of oncologists to consider FOLFIRI as initial therapy will dictate the frequency of first-line use of cetuximab.