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Salvage Therapy and Emerging Agents in Colorectal Cancer

Jennifer Wu, MD
Published: Thursday, Feb 25, 2016

Jennifer Wu, MD

Jennifer Wu, MD


The treatment of refractory colorectal cancer includes 2 new FDA-approved oral agents, each producing modest improvement in overall survival. This article reviews the mechanism of action, efficacy, and differences in side-effect profiles of the new agents. The potential exists for each of the 2 agents to exert synergy when combined with other treatments in colorectal cancer. This article also reviews biomarker-directed emerging therapies in refractory colorectal cancer, with a focus on immunotherapy in mismatched repair-deficient patients, BRAF and EGFR inhibitors in BRAF-mutated patients, and agents such as stem cell inhibitors and heat shock protein 90 inhibitors in EGFR inhibitor–refractory patients.


The treatment options for both first-line and second-line metastatic colorectal cancer in the modern era include combination chemotherapy and/or biologics. However, researchers have made incremental progress with the addition of new therapies such as angiogenesis inhibitors on the foundation of fluoropyrimidines. In addition, in RAS wild-type tumors, EGFR inhibitors and fluoropyrimidine-based therapies provide other treatment options in both first-line and second-line settings.

Regorafenib: The First Single Agent Mechanism of Action and Efficacy

In 2012, regorafenib, an oral tyrosine kinase inhibitor (TKI) with activity against multiple pathways showed single-agent activity in patients with refractory colorectal cancer. The CORRECT study used regorafenib, a TKI that inhibits angiogenesis, including vascular endothelial growth factor receptors 1,2,3, Tie-2 receptor and fibroblast growth factor receptors, platelet-derived growth factor beta, in addition to RAF, RET, and KIT receptors.1 In patients who progressed after standard of care that included fluoropyrimidine, oxaliplatin and/or irinotecan, angiogenesis inhibitors, and EGFR inhibitors if the tumors were KRAS wild-type, regorafenib increased overall survival (OS) from 5.0 months to 6.4 months compared with placebo.2 This phase III study reached its primary endpoint of OS that was statistically significant (HR, 0.77; 95% CI, 0.64-0.94; P <.0052). Moreover, the difference persists regardless of prespecified subgroups such as patient age, number of prior lines of therapy, Eastern Cooperative Oncology Group (ECOG) performance status, and KRAS status.

Adverse Effects of Regorafenib

The most common adverse effects (AEs) of regorafenib were fatigue, hand and foot syndrome, diarrhea, anorexia, and voice changes; up to 93% of patients experienced AEs, and as many as 54% were grade 3 or 4, most of which were manageable. The potential of liver toxicity, hemorrhage, dermatologic side effects, and hypertension led to frequent dose reduction (38% vs 3%) and dose interruptions (61% vs 22%) of regorafenib compared with placebo, respectively. Because of the rare but potentially fatal toxicity of liver failure, it is important to check liver function tests in patients taking regorafenib every 2 weeks for the first 2 months and then monthly or as frequently as indicated after 2 months.

Although most AEs are not life threatening, dose modifications were required in most patients. In treatment trials, the full dose of regorafenib (160 mg orally daily for 21 days of a 28-day cycle) has been very difficult to tolerate, and most oncologists start at a lower dose, such as 80 mg or 120 mg. In general, patients can rarely be titrated to the full dose. The CORRECT study established regorafenib as a new treatment for refractory colorectal cancer; in fact, it has emerged as an option for standard of care. However; because of its tolerability issues, there is an urgent need to refine the optimal dosing for this drug.

Potential Synergy With Chemotherapy

One way of lowering the active dose of regorafenib is through combination therapy. Because of its synergy with irinotecan in vitro, a phase II study using regorafenib in combination with FOLFIRI (irinotecan, 5-fluorouracil [5-FU], and folinic acid) demonstrated an acceptable safety profile.3 This led to a phase II randomized study to test progression-free survival (PFS), comparing FOLFIRI + regorafenib versus FOLFIRI + placebo in second-line patients with colorectal cancer. This study has finished accrual; investigators are eagerly awaiting its results.

Trifluridine/Tipiracil: A Second New Agent Mechanism of Action and Efficacy

In 2015, trifluridine/tipiracil (TAS-102) was also approved as a single agent in patients with refractory colorectal cancer. There are both similarities and differences between trifluridine/ tipiracil and 5-FU, a form of fluoropyrimidine.

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