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The Evolution of Biomarkers to Guide the Treatment of Metastatic Colorectal Cancer
Lisa E. Davis, PharmD, FCCP, BCPS, BCOP
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The Evolution of Biomarkers to Guide the Treatment of Metastatic Colorectal Cancer

Lisa E. Davis, PharmD, FCCP, BCPS, BCOP
Considerations for the choice of therapy are based on the goals of therapy, prior therapy(ies), the mutational profile of the tumor, and the toxicity profiles of individual agents. The NCCN does not consider one regimen (ie, oxaliplatin, 5-FU/LV [FOLFOX]; capecitabine plus oxaliplatin [CAPEOX]; irinotecan, 5-FU/LV [FOLFIRI]; infusional 5-FU/LV, capecitabine or oxaliplatin, irinotecan [FOLFOXIRI]) to be preferable over the others as initial therapy, but does recommend one of these regimens, with or without an added targeted therapy, for patients for whom initial therapy with an intensive therapy is appropriate.6 No biologic agent (ie, bevacizumab, cetuximab, panitumumab, or none) as part of initial therapy is preferred.6 Targeted therapies can be included in the second-line or third-line treatment of mCRC, depending on prior therapy.3,6 In patients with advanced or metastatic disease who are not appropriate for intensive therapy, targeted therapies, such as cetuximab or panitumumab (category 2B) are indicated as first-line single-agent treatment by the NCCN guidelines for KRAS/NRAS wild-type and left-sided tumors only.6 The NCCN guidelines for initial systemic therapy for advanced or metastatic CRC treatment are shown in Table 4.6

Selection of Subsequent Therapy

Patients with wild-type KRAS/NRAS tumors who experience progression on therapy that did not contain an EGFR inhibitor should receive cetuximab or panitumumab plus irinotecan, cetuximab, or panitumumab plus FOLFIRI, or single-agent cetuximab or panitumumab. For patients whose therapy did contain an EGFR inhibitor, use of another EGFR inhibitor is not recommended.6 The NCCN guidelines for subsequent therapy for advanced or metastatic CRC are summarized in Table 5.6

The NCCN discourages switching to either cetuximab or panitumumab after failure of the other drug.3 Anti-VEGF therapies are frequently used in cytotoxic drug combinations for the treatment of mCRC. The NCCN panel recommends bevacizumab over ziv-aflibercept and ramucirumab, both of which also block VEGF signaling, for mCRC after progression due to concerns about toxicity, low activity, and costs.6 Regorafenib, a small-molecule inhibitor of VEGF receptor (VEGFR), is recommended for patients with disease that is refractory to chemotherapy.6 Trifluridine-tipiracil, a recently approved cytotoxic agent, may be given before or after regorafenib.6 Pembrolizumab and nivolumab block immune checkpoint proteins and may help in reestablishing immune response against tumors.31 Either agent may be used in the second or third line, but if tumor progression occurs, then the other agent should not be offered.6 Pembrolizumab and nivolumab are recommended for patients whose tumors are dMMR or MSI-H.6 This information should be routinely obtained during the workup of the patient. Pembrolizumab and nivolumab are also indicated as first line for only dMMR/MSI-H patients with advanced or metastatic disease who are not appropriate for intensive therapy.6

Patients with better performance status and fewer comorbidities generally have better outcomes. Surgical resection is considered standard of care for patients with resectable metastatic disease.6 Many patients who present with mCRC have unresectable metastases. Some patients with metastatic disease may be candidates for neoadjuvant (preoperative) combination chemotherapy in an effort to reduce the size of metastases, thereby converting the patient to having resectable disease. Any active therapy may be used to convert the patient to having resectable disease, although it is important to keep in mind that irinotecan- and oxaliplatin-based chemotherapeutic regimens can cause liver damage.6 The addition of a targeted biologic agent (eg, cetuximab or panitumumab for KRAS/NRAS wild-type tumors or bevacizumab) to chemotherapy can increase tumor response and complete resection rates, and is considered acceptable.6 Surgery is recommended as soon as possible after the patient is deemed resectable to avoid chemotherapy-induced hepatic injury.6 Adjuvant therapy after metastasectomy is recommended.6 

New and Emerging Agents for mCRC

In the United States, several novel agents have been approved for mCRC since 2015. These agents include the antiangiogenic agent ramucirumab, cytotoxic therapies such as trifluridine-tipiracil (TAS-102), and the immune checkpoint inhibitors pembrolizumab and nivolumab.31-34 

Ramucirumab

Ramucirumab is a vascular endothelial growth factor receptor 2 (VEGFR2) antagonist that is administered as an intravenous infusion.31 In contrast to bevacizumab and ziv-aflibercept, which bind to soluble VEGF-A, ramucirumab binds to the extracellular domain of VEGFR2, thereby inhibiting the binding of several VEGF ligands and interrupting the VEGF-VEGFR signaling pathway at the receptor level.35 Ramucirumab has been approved in combination with FOLFIRI for patients with mCRC who have disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.31 The efficacy and safety of ramucirumab versus placebo was assessed in the RAISE phase 3 clinical trial with a combination with second-line FOLFIRI in patients experiencing mCRC progression during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.35 A total of 1072 patients were enrolled. Median overall survival (OS) was 13.3 months versus 11.7 months for patients in the ramucirumab group versus the placebo group, respectively (P = .022). Grade 3 or higher AEs were seen in greater than 5% of patients and included neutropenia (38% vs 23% in the ramucirumab vs placebo groups, respectively), with incidence of febrile neutropenia (3% vs 2%), hypertension (11% vs 3%), diarrhea (11% vs 10%), and fatigue (12% vs 8%). A subgroup analysis of the phase 3 RAISE clinical trial demonstrated a statistically significant improvement in OS, regardless of time to disease progression or KRAS status.31,36

Ramucirumab is FDA approved in combination with FOLFIRI for the treatment of mCRC with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.31 Ramucirumab is indicated as one of the options in the NCCN clinical guidelines for the primary treatment of unresectable metachronous metastases in patients who have had prior adjuvant FOLFOX/CAPEOX within the past 12 months, or as subsequent systemic therapy for patients who received adjuvant FOLFOX/CAPEOX more than 12 months prior or received previous 5-FU/leucovorin or capecitabine.6 The ESMO guidelines recommend ramucirumab as a second-line agent in combination with FOLFIRI in patients with disease progression during or after first-line therapy with oxaliplatin, bevacizumab, and a fluoropyrimidine.3 Although ramucirumab has no contraindications, it does have a boxed warning for increased risk of hemorrhage, gastrointestinal (GI) perforation, and impaired wound healing.31 Patients should permanently discontinue ramucirumab if they experience severe bleeding or GI perforation. Patients who experience impaired wound healing should discontinue ramucirumab until the wound is fully healed.31

Trifluridine-tipiracil (TAS-102)

Trifluridine-tipiracil is an oral drug combination of trifluridine, a cytotoxic thymidine analog, and tipiracil hydrochloride, a thymidine phosphorylase inhibitor.6 Trifluridine is incorporated into DNA, thereby interfering with DNA synthesis and inhibiting cell proliferation. Tipiracil prevents the rapid degradation of trifluridine via thymidine phosphorylase. Results from the RECOURSE phase 3 clinical trial were critical for FDA approval of this novel cytotoxic drug. The trial enrolled 800 patients with mCRC who had progressed beyond 2 prior regimens. Patients were randomized 2:1 to receive trifluridine-tipiracil or placebo. The median OS improved from 5.3 months with placebo to 7.1 months with TAS-102 (hazard ratio [HR] .68; 95% CI, 0.58-0.81; P < .001).29 Trifluridine-tipiracil is FDA approved for the treatment of mCRC in patients who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF mAb, and if RAS wild-type, an anti-EGFR therapy.3 The NCCN recommendations include trifluridine-tipiracil as a third-line treatment option for patients with disease progression through standard therapies.6 Trifluridine-tipiracil can be given prior to or following treatment with regorafenib as there are no data to suggest the best order for these agents.6 The most frequently reported adverse reactions with trifluridine and tipiracil include asthenia/fatigue (52%), nausea (48%), decreased appetite (39%), diarrhea (32%), vomiting (28%), and infections (27%). Dose delays and reduced doses may be necessary to reduce incidence and severity of neutropenia and thrombocytopenia.32,37

Immunotherapies: Anti–PD-1/PD-L1 Monoclonal Antibodies

The immune system includes multiple checkpoints that turn off or prevent inappropriate immune activity.38 Tumor cells manipulate these mechanisms, thereby reducing T cell activity within tumors and escaping immunosurveillance. The PD-1/PD-L1 system is often used by tumors to block T cell activity. PD-1 is a protein on T cells which, when bound to PD-L1, a protein present on normal and malignant cells, inhibits T cell activity. Increased PD-1/PD-L1 expression is increased in a subset of mCRC and in association with MSI.39 Coupled with the very high mutation prevalence in, and high antigenic potential of CRC, the therapeutic efficacy of immune checkpoint inhibitors has been investigated. Five anti–PD-1/PD-L1 mAbs have received FDA approval and are currently under study: pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab.40

 
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