A frequent quandary for oncologists is the selection of chemotherapy and biologic therapy for patients with metastatic colorectal cancer in second-line and higher treatment settings. While not approved by the US Food and Drug Administration (FDA) in the first-line setting, the vascular endothelial growth factor (VEGF)-targeting agents ziv-aflibercept and ramucirumab are appropriate treatment options in the second-line setting, as is continuation of first-line bevacizumab. Tumor RAS mutational status is helpful to determine which patients may benefit from epidermal growth factor receptor (EGFR)-directed therapies, and other novel biomarkers (BRAF, HER2, and mismatch repair deficiency) allow us to select patients who may benefit from biologic therapies that are FDA-approved for other malignancies. Maintenance therapy for patients with stable disease following first-line therapy is a unique clinical situation that warrants special attention. Immunotherapy has thus far been ineffective for patients with mismatch repair–proficient tumors, but novel combination strategies are being studied to break through this treatment barrier. Finally, several new biologic therapies with novel targets are under development and will likely contribute to the growing arsenal of treatment options for patients with metastatic colorectal cancer.
Novel Biologic Therapies Under Development
Ensituximab is a chimeric immunoglobulin (Ig)G1 monoclonal antibody against the polypeptide MUC5AC, a member of the mucin gene family that is aberrantly glycosylated in colorectal and pancreatic tumors and absent in the normal adult colon and pancreas. Ensituximab functions via antibody-dependent cellular cytotoxicity and spares noncancerous colon and pancreas tissues. In a phase I study of treatment-refractory patients who had received third-line and higher chemotherapy, Beg and colleagues found the maximum tolerated dose to be 3 mg/kg IV every 2 weeks (dose-limiting toxicities at 4 mg/kg were grade 3/4 anemia and hyperbilirubinemia). Of 11 evaluable patients, 5 had stable disease (4 with colorectal cancer and 1 with pancreatic cancer), and 6 had progressive disease. The phase II portion of this study (QUILT-3.019) is ongoing (ClinicalTrials.gov identifier: NCT01040000).
- Bevacizumab in second-line therapy (even if used in the first line) is supported due to its potential to improve overall survival. Ziv-aflibercept and ramucirumab in the second-line setting are also supported.
- In the third line, if patients have not been previously treated with epidermal growth factor receptor (EGFR)-directed therapies, then panitumumab or cetuximab may be used. If obtaining an objective response is important, then one of these anti-EGFR therapies should be favored over treatment with regorafenib or trifluridine/tipiracil.
- Checkpoint inhibitors, currently limited to treatment of patients with mismatch repair–deficient tumors, hold promise for the treatment of patients with metastatic colorectal cancer.
Nimotuzumab, a humanized IgG1 monoclonal antibody against EGFR, is a potent radiosensitizer lacking the dermatologic and gastrointestinal toxicities associated with cetuximab and panitumumab. In a single-arm phase II study, nimotuzumab at 400 mg IV weekly was safely combined with capecitabine-based chemoradiation in the treatment of 21 patients with locally advanced rectal cancer. Four patients (19%) had a pathologic CR. This approach has not been evaluated in a randomized controlled trial.
Urelumab is a fully humanized IgG4 monoclonal antibody agonist of CD137 (4-1BB); the latter is an immune costimulatory molecule that induces cytokine production and cytotoxic T-cell activation. The maximum tolerated dose was 0.1 mg/kg IV, administered every 3 weeks; transaminitis was the main dose-limiting toxicity, and no immune-mediated adverse events were observed. A phase I study of cetuximab and urelumab in advanced colon cancer and head and neck squamous cell cancers (ClinicalTrials.gov identifier: NCT02110082), and a phase I/II study of urelumab administered in combination with the anti–PD-1 antibody nivolumab for the treatment of solid tumors and non-Hodgkin lymphoma (ClinicalTrials.gov identifier: NCT02253992) are ongoing.
Varlilumab is a fully humanized IgG1 monoclonal antibody that behaves as a CD27 agonist. CD27, an immune costimulatory molecule found on the T-cell surface, binds to CD70 on antigen-presenting cells and promotes T-cell proliferation and survival. A phase I trial of varlilumab in select cancer types is ongoing (ClinicalTrials.gov identifier: NCT01460134).
Imalumab is a first-in-human fully humanized monoclonal antibody against anti-oxidized migration inhibitory factor, which is implicated in tumor angiogenesis, proliferation, and stromal inflammation. In a phase I study, imalumab administered at a dose of 10 mg/kg IV weekly was determined to be the recommended phase II dose and schedule (the only dose-limiting toxicity was hypersensitivity pneumonitis, observed in 1 patient). A phase II trial of imalumab in combination with 5-FU/leucovorin and panitumumab (if RAS wild-type) is ongoing (ClinicalTrials.gov identifier: NCT02448810).
Atezolizumab and cobimetinib
There is an important ongoing effort to identify therapies that can render MMRp colorectal tumors sensitive to immune checkpoint inhibition. Combination therapy with the anti–programmed death ligand 1 monoclonal antibody atezolizumab and the oral MEK inhibitor cobimetinib leads to upregulation of major histocompatibility complex class I on tumor cells and T-cell infiltration into the tumor. A phase IB study of the combination included 23 patients (22 KRAS-mutant patients and 1 KRAS wild-type patient) with metastatic colorectal cancer. Dose expansion occurred at the dosages of atezolizumab, 800 mg IV every 2 weeks, and cobimetinib, 60 mg by mouth daily. The ORR of 17% was considerably higher than that reported in the medical literature, which showed a 0% ORR following pembrolizumab monotherapy in patients with MMRp colorectal cancer. Combination therapy with atezolizumab and cobimetinib is under investigation in a phase III trial (ClinicalTrials.gov identifier: NCT02788279) in which patients with refractory metastatic colorectal cancer are randomized 1:1:1 to the combination, to atezolizumab monotherapy, or to regorafenib (with the last being the standard of care).
The standard of care for patients with previously treated metastatic colorectal cancer involves sequencing combinations of chemotherapy backbones with biologic therapies. Maintenance therapy often consists of low-dose chemotherapy in combination with a biologic agent. Beyond RAS mutational status, novel biomarkers are playing important roles, especially in later lines of therapy. Broader use of genomic tumor profiling has elucidated rare but actionable mutations suitable for off-label use. Checkpoint inhibitors, currently limited to treatment of MMRd tumors, hold promise for use in metastatic colorectal cancer. Much research is ongoing to bring this treatment option to patients with MMRp tumors. It is hoped that, in the near future, biologic agents now under development may yield meaningful clinical outcomes for patients with metastatic colorectal cancer.
Financial Disclosure: Dr. Salem serves as a speaker for, and consultant to, Genentech. The other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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