The concept of using a chemical that is specific to a pathogenic target dates back to the early 1900s but did not become a reality for colorectal cancer (CRC) until decades later with the approval of the EGFR inhibitor cetuximab (Erbitux) and the VEGF/VEGFR inhibitor bevacizumab (Avastin) in 2004.
Over the subsequent 15 years, the FDA approved the anti-EGFR agent panitumumab (Vectibix) for CRC, followed by the VEGF/VEGFR inhibitors ziv-aflibercept (Zaltrap), regorafenib (Stivarga), and ramucirumab (Cyramza), and immune checkpoint inhibitors pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab (Yervoy). Though not FDA-approved for CRC, BRAF- and HER2-targeted agents have demonstrated activity in selected patients with mutation-positive disease, and the National Comprehensive Cancer Network (NCCN) has included the agents in CRC clinical guidelines.
Numerous other potential targets for therapeutic development have already been identified. As additional molecular abnormalities become potential targets for therapy, CRC clinicians should keep in mind that currently available options have substantially extended survival in the metastatic setting and that conventional chemotherapy remains effective in many patients.
“Frontline chemotherapy for colon cancer works pretty well, which is different from melanoma, for example, and some other cancers,” said Michael Overman, MD, of the University of Texas MD Anderson Cancer Center in Houston. “With our current frontline chemotherapy for colon cancer, you have a progression-free survival of almost a year. When you’re looking at other therapies, particularly with the idea of earlier use of the therapies, you have a stronger competitor, so you need stronger data to make a case.”
For stages I-III, surgery continues to offer the best hope for cure, and surgery followed by adjuvant chemotherapy remains standard of care for most patients. Various chemotherapy regimens have demonstrated comparable efficacy, so the choice of regimen rests with the treating physician and is influenced by local and regional standards of care.
In the metastatic setting, chemotherapy alone remained the standard until fairly recently. Identification of specific mutations has led to regimens that combine chemotherapy with a targeted drug.
“It’s the targeted agent that you add to the chemotherapy backbone that depends on the mutation status,” said Ryan Nipp, MD, of Massachusetts General Hospital Cancer Center in Boston. “We know that if you have RAS-mutant or RAS wild type, it’s always safe to start with bevacizumab, because the data are out there to show that it’s effective regardless of RAS status. If you know that a patient has a RAS wild-type tumor, there is also evidence to support use of an EGFR-targeting agent. If someone has a RAS or RAF mutation, you would want to avoid an EGFR-targeting agent.”
“There are other nuances in the metastatic setting,” he continued. “For example, if someone has a HER2 cancer, then you might get a little more excited about adding in a HER2-targeted agent. There are also situation where you might want to refer a patient to a clinical trial. If you know a patient has a certain mutation and you know of a clinical trial of a drug targeting that mutation, even if it’s experimental, not FDA approved, you might consider referring the patient because some interesting results have come from those trials.”
With one possible exception, a positive result for a specific mutation does not necessarily represent a mandate to use a drug targeting the mutation, said Suneel Kamath, MD, of the Cleveland Clinic. The exception arose from results of the BEACON trial, which evaluated encorafenib (Braftovi) and cetuximab with or without binimetinib (Mektovi) versus cetuximab and chemotherapy in patients with BRAF-mutated CRC. The initial results showed significantly better overall survival with the three-drug combination versus standard of care. A subsequent analysis showed the encorafenib-cetuximab doublet worked just as well.
“Those are really compelling data,” said Kamath. “Also, routine therapy for those patients is quite ineffective, as we’re talking about a survival of just a few months. Patients tend to progress very rapidly after FOLFOX or FOLFOXIRI chemotherapy. I think that’s a case where we can recommended targeted therapy a lot sooner.”
For patients without any biomarkers to sway clinical decision making, chemotherapy remains standard of care.
“Unfortunately, probably 80%-85% of our patients end up in that boat,” Kamath. “We test patients and find the usual pattern of tp53 and ACP mutations, which are not particularly actionable.”
Mounting evidence of immune checkpoint inhibitors’ activity in mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) CRC could sway decision-making regarding treatment options. NCCN recommends testing all patients for dMMR/MSI-H status. Pembrolizumab, nivolumab, and ipilimumab have tumor-agnostic indications for those malignancies. Additionally, tumors that test positive for TRK gene fusions open the possibility of tumor-agnostic therapy with an NTRK inhibitor.
Source: MedicalNewsToday.com
