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Recognizing Patient Subtypes in Late-line Colorectal Cancer for Selection of Targeted Therapy
Hyunjee Song, 2018 PharmD Candidate, and Michael R. Page, PharmD, RPh
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Recognizing Available Therapies and Treatment Differences Within Classes in Colorectal Cancer
David Bai, 2018 PharmD Candidate, and Michael R. Page, PharmD, RPh
Perspectives in Targeted Therapy for Colon Cancer with Scott Paulson, MD
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Recognizing Available Therapies and Treatment Differences Within Classes in Colorectal Cancer

David Bai, 2018 PharmD Candidate, and Michael R. Page, PharmD, RPh
Targeted Therapy
Targeted therapies work against cancer by blocking or interfering with certain receptors or molecules that are involved in the growth, progression, or spread of cancer. Because of their specificity, targeted therapies may be less toxic than traditional chemotherapeutic treatments. Additionally, targeted therapies are generally used only in patients with specific genetic markers, a distinct subset. 
Below, we summarize available targeted therapies for colon cancer (see also  Table 2).21-26
 
Anti-EGFR Targeted Therapy
EGFR, a cellular-signaling receptor, has an important role in cell development, proliferation, and differentiation.27 Two EGFR-targeted therapies effectively used for colon cancer treatment are cetuximab and panitumumab, but only after a patient has been genetically tested for the KRAS mutation. These anti-EGFR treatments are generally used only in patients with wild-type KRAS; they should be avoided by patients with KRAS-mutated cancers.28

Cetuximab is a chimeric product with both murine and human portions of its sequence.28 In a trial that compared the resection rates of chemotherapy alone versus the combination of cetuximab and chemotherapy in patients with metastatic colorectal cancer with unresectable liver metastases, cetuximab was shown to significantly improve rates of complete resection (25.7% with cetuximab/chemotherapy vs 7.4% with chemotherapy alone; P <.01). Not only was the resection rate in this trial improved, but a meta-analysis of 4 separate trials revealed that the addition of cetuximab or panitumumab to chemotherapy improved rates of complete resection by 11% to 18% (P = .04).27

Two other trials, CRYSTAL and OPUS, have also demonstrated the benefits of cetuximab in the treatment of patients with metastatic colorectal cancer. In CRYSTAL, patients assigned to FOLFIRI and cetuximab compared with FOLFIRI alone demonstrated greater PFS (9.9 months vs 8.7 months; P = .02) and OS (23.5 months vs 20.0 months; P = .0093). In OPUS, response rates were higher in patients who received FOLFOX and cetuximab in combination compared with patients receiving FOLFOX alone (61% vs 37%; P = .011).27

Panitumumab differs from cetuximab in that it is a fully human antibody.28 PRIME was the major trial involved in the approval of panitumumab, and in the panitumumab and FOLFOX combination group versus the FOLFOX-only group, the addition of panitumumab resulted in both better PFS (10 months vs 8.6 months; P = .01) and OS (23.9 months vs 19.7 months; P = .17).29
 
Anti-VEGF Targeted Therapy
VEGF, an angiogenic factor, is another target for treatment of colorectal cancer. Signaling of VEGF stimulates the proliferation of endothelial cells and blood vessel growth.9 One of these treatments is bevacizumab, a humanized anti-VEGF monoclonal antibody that inhibits VEGF-A from binding to its receptors, thereby inhibiting angiogenesis. In patients with metastatic colorectal cancer, the addition of bevacizumab to an oxaliplatin-based regimen significantly improved PFS (9.4 months vs 8.0 months; P = .0023), but no improvement in OS was detected. In another trial, the addition of bevacizumab to a FOLFOX regimen was associated with an improvement in OS (12.9 months vs 10.8 months; P = .0011).27

Other anti-VEGF drugs include ziv-aflibercept, ramucirumab, and regorafenib. Ziv-aflibercept is a humanized recombinant fusion protein. Instead of binding to the VEGF receptor directly, this medication binds to VEGF itself, preventing VEGF from attaching to the receptor and initiating angiogenesis. In the VELOUR trial, OS improved for patients receiving ziv-aflibercept in combination with FOLFIRI versus those receiving FOLFIRI alone (13.5 months vs 12.1 months; P = .003).27

Ramucirumab, too, prevents VEGF from binding to its associated receptors and promoting angiogenesis. In the phase III trial RAISE, improvement of OS was seen in patients who received ramucirumab in combination with FOLFIRI versus patients receiving FOLFIRI alone (13.3 months vs 11.7 months; P = .02).27

Another medication, regorafenib, targets VEGF, but as a multi-kinase inhibitor, it has other modes of action as well, targeting a multitude of other receptors including BRAF. Two trials, CORRECT and CONCUR, demonstrated regorafenib’s efficacy and safety of regorafenib. In the CORRECT trial, patients assigned to the treatment with regorafenib plus best supportive care had an OS of 6.4 months compared with 5.0 months for supportive care alone (P = .005). In another trial, CONCUR, conducted in Asian patients, use of regorafenib also significantly improved OS versus supportive care (8.8 months vs 6.3 months; P = .00016).27
 


 
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