The last few months have seen a flurry of activity in the development and refinement of treatments for metastatic colorectal cancer (mCRC). At ASCO 2012, the TML trial was presented, demonstrating that continuing the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab with second-line chemotherapy modestly improves survival compared to second-line chemotherapy alone. Shortly after the ASCO meeting, the FDA expanded the indication for the anti-epidermal growth factor receptor (EGFR) antibody cetuximab for first-line treatment with FOLFIRI for patients with KRAS wild-type mCRC. This approval was based on data from the Crystal trial.
In August, the FDA approved ziv-aflibercept, a recombinant fusion protein which binds to VEGF-A, VEGF-B, and placental growth factor, for second-line treatment of mCRC with FOLFIRI after progression on FOLFOX. This approval was based on results from the VELOUR trial. Finally, just 2 weeks ago, the FDA approved regorafenib, a small molecule inhibitor of multiple tyrosine kinases including VEGF receptors as monotherapy for the treatment of mCRC, which has progressed on all other agents. With all these advances, how should we integrate these new options into our clinical practice?
Although FOLFOX plus bevacizumab is the most common initial therapy utilized nationally in the clinic for mCRC, the expanded indication for cetuximab with FOLFIRI based on the Crystal trial presents this combination as a reasonable initial treatment option for patients with KRAS wild-type mCRC. In the real world, there are a few challenges to overcome for more routine cetuximab integration into frontline therapy. For one, KRAS testing is increasingly ordered during the course of mCRC therapy, but results are usually unavailable at the time of the initial treatment discussion with a patient. However, the expanded utilization of nurse navigators to assist in patient care may facilitate the ordering of KRAS testing prior to the medical oncologist’s initial visit with a patient. Test results will need to be available quickly for more widespread initial use of cetuximab.
A second barrier to increased frontline cetuximab utilization is the clear choice of FOLFOX as the initial chemotherapy of choice for U.S. oncologists, despite FOLFIRI having similar efficacy. As cetuximab appears to be less effective with FOLFOX, chemotherapy preference will have to change for more widespread adoption of front-line cetuximab. Although cetuximab may increase response rate more than bevacizumab with initial chemotherapy (and thus have particular utility in patients with potentially resectable liver metastases), this is only a theoretical consideration and remains unproven in the clinic. Two large trials testing chemotherapy plus bevacizumab vs. chemotherapy plus cetuximab as initial therapy for mCRC recently completed accrual, and their results are eagerly awaited.
For patients progressing after initial FOLFOX plus bevacizumab, FOLFIRI with bevacizumab or FOLFIRI with ziv-aflibercept are both reasonable options. The TML trial randomized 820 patients after progression on chemotherapy plus bevacizumab to receive either chemotherapy alone or chemotherapy with continued bevacizumab. Patients receiving irinotecan-based first-line therapy (~60%) received oxaliplatin-based therapy with bevacizumab second-line, and those receiving oxaliplatin-based first-line therapy received irinotecan-based therapy with bevacizumab second-line. Of note, patients with rapid progression (within 3 months) of starting first-line chemotherapy plus bevacizumab were not included in this trial. The results demonstrated a modest median progression-free survival (5.7 months vs. 4.1 months, P<0.0001) and overall survival benefit for the continuation of bevacizumab (11.2 months vs. 9.8 months, P=0.0062). No unexpected added toxicity was noted with the continuation of bevacizumab.