Expert Discusses Treatment Options in Advanced CRC

Cathy Eng, MD

There has been an ongoing conversation surrounding the use of TAS-102 as opposed to the multikinase inhibitor regorafenib (Stivarga) in patients with colorectal cancer (CRC) who have progressed on prior therapies.

Both options are associated with their own set of toxicities, explains Cathy Eng, MD. Some physicians have avoided regorafenib, as its designated dose is often too high for patients, resulting in hand-foot skin reactions. Additionally, Eng adds, both are oral agents, so physicians must be diligent in keeping up with patient compliance.

OncLive: Please provide an overview of your lecture on CRC.

During an interview at the 35th Annual CFS^® Meeting, Eng, professor of gastrointestinal medical oncology at The University of Texas MD Anderson Cancer Center, discussed optimizing sequencing beyond disease progression in CRC. She also shed light on available treatments in CRC, encouraged physicians to dose adjust therapy for their patients, and highlighted studies further exploring immunotherapy in the field.Eng: I discussed what therapies are available to patients following first-line treatment, especially in the setting of progression of disease. I focused not only on the continuation of antiangiogenic agents in the second-line setting, but also the role of anti-EGFR therapy in the second- or third-line setting. Of course, there are the recent oral drugs that have been approved—regorafenib and TAS-102—in the refractory setting. I wanted to highlight some of the more recent trials that are more focused on rare subsets—specifically patients with a BRAF-mutated tumor—which is present in less than 10% of patients. It’s a very poor prognostic indicator.

What factors do you consider when deciding between regorafenib and TAS-102 for a patient?

There are also some interesting data that are not necessarily new, but there is a new clinical trial focusing on the presence of HER2/neu amplification, and its association with anti-EGFR resistance. That is a great question. This is something that comes up all the time—whether you should use regorafenib or TAS-102. The reality is that they have different side effects; regorafenib may be associated with increased liver function studies. Therefore, if I have a patient with significant tumor burden in the liver, [regorafenib] may not be my first choice necessarily for them. It is also an antiangiogenic agent, so if you have a patient who is at risk, you have concerns about either blood pressure issues, a recent stroke, potential risk of bowel obstruction, or putting them at risk for perforation, then that would sway me away from regorafenib.

Are there any next steps we can take with regorafenib?

Whereas, TAS-102 results in increased myelosuppression. However, then you can kind of work around that either by adjusting the dose and the schedule or by providing filgrastim (Neupogen) or pegfilgrastim (Neulasta). However, I do want to highlight that they are both oral agents, so you have to follow patients and make sure that they are compliant with your recommendation. The myelosuppression from TAS-102 can result in a very dangerous situation. It was just approved recently for use in the second-line setting in the treatment of hepatocellular carcinoma. [Investigators] have obviously tried to look at it in combination with chemotherapy, but I am not exactly sure what the next steps are. It [involves] just trying to engage more physicians to utilize it.

Therefore, it is more so just figuring out the optimal dose—which might vary from patient to patient?

What are some data from studies that have looked at the BRAF-mutant CRC population?

I have to say: a lot of people have shied away from it because they started patients with the full dose [of regorafenib] and it resulted in significant hand-foot skin reactions—even though that is the dose in the FDA insert. In all fairness, I normally start my patients off at a lower dose of 120 mg daily.Correct. It is very much like in the old days when we utilized capecitabine; no one actually used the full dose. Everyone gave patients a lower dose and, as time goes by, you adjusted accordingly based on their hand-foot syndrome. A recent study that was presented at the 2017 Gastrointestinal Cancers Symposium and 2017 ASCO Annual Meeting by my colleague Dr Scott Kopetz was SWOG 1406, which looked at a control arm of irinotecan and cetuximab (Erbitux) plus or minus vemurafenib (Zelboraf) with a primary endpoint of progression-free survival (PFS). The study was positive for PFS, and there was crossover allowed, so it was not positive for overall survival.

However, it was an eye-opening study in terms of you should consider providing a BRAF inhibitor to patients as part of a clinical trial. Also, testing for BRAF mutations encouraged individuals to test their patients’ tumors for the presence of BRAF mutations. Keep in mind, this is not the BRAF mutation that is associated with hypermethylation for microsatellite instability (MSI).

The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) has been tried in various solid tumors. Is MEK also expressed in CRC where this treatment might be an option?

Are we looking at any specific targeted therapies for patients with HER2 amplification?

What does the next 5 years in this landscape look like to you?

There are other trials; there have been a lot of phase I and phase II trials. There is an ongoing phase III trial regarding the BRAF mutation that is a pharmaceutical-sponsored study.MEK by itself is not effective, but we are looking at MEK inhibitors in combination with a lot of PD-1/PD-L1 inhibitors in several ongoing trials. Dr Johanna Bendell is the primary investigator in one of the studies, and I am an investigator in a study as well that is looking at the role of immunotherapy and MEK inhibitors in combination.There were some data from the Fondazione del Piemonte per l'Oncologia, looking at lapatinib (Tykerb) specifically in that setting, and we saw a response rate greater than 30%. The SWOG study is basically looking at pertuzumab (Perjeta) in combination, with the hope that they find some promising results, as well. I would definitely say that, for the refractory setting, we are going to continue to swing away from cytotoxic chemotherapy, and, hopefully, move forward to more immune-modulated agents. [This will not be] necessarily as single agents, but in combinations, especially in the RAS-mutant and MSI patient populations.