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Kim Highlights Growing Treatment Options for GI Cancers Based on 2 Case Scenarios

Samantha Hitchcock
Published Online:7:15 PM, Mon July 16, 2018

Richard Kim, MD

Richard Kim, MD, recently shared his treatment considerations and decisions he makes when treating patients with hepatocellular carcinoma and colorectal cancer. Kim, associate professor of oncology, University of South Florida College of Medicine, and medical oncologist in the Gastrointestinal Oncology Department, Moffitt Cancer Center, explained his treatment decisions based on 2 gastrointestinal case scenarios during a Targeted Oncology live case-based peer perspectives program.

Case 1

February 2016

A 53-year-old Caucasian man without a previous colonoscopy presented to his primary care physician complaining of rectal bleeding and abdominal tenderness. His past medical history revealed hypertension, which was well-controlled on a beta-blocker. Family history indicated that his mother died from breast cancer.

A colonoscopy done with biopsy showed an ulcerated non-obstructive mass in the right colon. Pathology results confirmed poorly differentiated adenocarcinoma. Molecular testing showed that he was BRAF mutated and microsatellite stable. A CT of the abdomen, pelvis, and chest showed multiple liver lesions and a large nodule in the right lower pulmonary lobe. He was diagnosed with metastatic adenocarcinoma of the right colon; T4N0M1.

What factors do you consider when determining systemic therapy for this patient?

When we treat a patient with stage IV colon cancer we look at multiple factors, including the mutational profiling, the side of the tumor, meaning left versus right, and the goal of treatment. The goal of treatment for this patient is palliative intent and not curative. We also look at the patient's performance status to see if the patient can tolerate a more aggressive form of chemotherapy if needed.

Should the patient have additional genetic testing?

As standard practice now, we test for KRAS, NRAS, and BRAF. We also test for the status of mismatch repair (MMR). More and more, we are testing for HER2 mutations, for 2 reasons. First, patients who are HER2-positive tend to be resistant to epidermal growth factor receptor (EGFR) drugs in therapy later on. Now, there are trials in colon cancer for patients who are HER2-positive.

Recently, there have been more data that about 1% of [patents with] colon cancer will also have a tropomyosin receptor kinase (TRK) fusion. Therefore, we oftentimes do send the tissue out to foundation testing to do a profiling of multiple genes in hoping that we may catch that 1% of patients with a TRK fusion.

What is the significance of the BRAF mutation in this patient?

If someone is BRAF mutated, it tells us a couple of things. First, those patients tend to have a much worse prognosis. Secondly, they tend to be more resistant to the EGFR drugs. Thirdly, now there are trials that have been done in patients with BRAF mutations combining a BRAF inhibitor with an EGFR inhibitor, showing that the combination may have efficacy.

Because patients with BRAF mutation have worse prognosis, we tend to give more aggressive therapy. This rationale is based on the TRIBE study with folinic acid, fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) with bevacizumab (Avastin). As long as the patient has a very good performance status, that is what we are inclined to do.

What is the significance of his right-sided tumor (versus a left-sided tumor) in terms of response to biologic therapy?

I think that the sidedness is prognostic. A patient with a right-sided tumor tends to do worse than a patient with a left-sided tumor. Now, based on multiple phase III studies, the FIRE-3 study and the CALGB/SWOG 80405 study, we know that patients with right-sided tumors, even if they are RAS wild-type, do not respond to EGFR drugs. Therefore, for the right-sided tumor, bevacizumab should likely be used.

On the other side, the left-sided tumor, it is sort of more controversial. There are studies showing an overall survival (OS) benefit for use of an EGFR drug in left-sided tumors versus a vascular endothelial growth factor (VEGF) drug, such as bevacizumab. However, the CALGB/SWOG 8045 study showed that although there was a slight improvement of OS if you used an EGFR drug versus a VEGF drug, but the maximum benefit of OS was only 1 to 2 months.1

If you look at the National Comprehensive Cancer Network (NCCN) guidelines for a left-sided tumor, they give you a choice of using an EGFR inhibitor or a VEGF inhibitor. But if you look at the European Society for Medical Oncology (ESMO) guidelines, for left-sided tumors, which are all RAS wild-type, they recommend giving chemotherapy plus an EGFR inhibitor and not a VEGF inhibitor.

Should surgical or liver-directed modalities be considered?

At this time, there are phase III studies going on randomizing surgery plus or minus chemotherapy to see if taking out the primary makes a difference. Until the data is out, I think surgery should not be done unless the patient is symptomatic.

In terms of liver-directed modalities, there are a couple of phase III studies looking at radioembolization (yttrium-90; Y-90) plus chemotherapy versus chemotherapy alone. Unfortunately, these studies show that adding Y-90 to chemotherapy had no benefit in terms of OS. Actually, there was more toxicity associated with the combination. Therefore, at least in the first-line setting, liver-directed therapy should be avoided.

The patient was started on FOLFOXIRI and bevacizumab; therapy was well tolerated after management of grade 2 neutropenia. Three months later, his second follow-up scan showed a 35% decrease in 2 of the liver lesions and stability in the lung lesion. He continued on FOLFOXIRI plus bevacizumab for 6 months and then developed grade 1 neuropathy, so he was switched to folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus bevacizumab.

January 2017

The patient did well radiologically and biochemically. But 11 months later, he developed intermittent shortness of breath; he continued his normal activities. Imaging later showed a new 3-mm lung lesion with increased size of the pleural lesion and stability in the liver lesions. He had an ECOG performance status of 1.

What are the choices for therapy after the patient progresses on FOLFOXIRI plus bevacizumab?

As I said before, patients with BRAF mutations most likely do not respond to an EGFR drug. So, that is a drug that I probably wouldn't use at this moment. There is a SWOG trial using a BRAF inhibitor plus an EGFR inhibitor and that is the route that I would take. That study also added chemotherapy with irinotecan, as well.

Additionally, there are 2 oral pills available in the refractory setting that is approved by the FDA. The first one is regorafenib (Stivarga), which is a tyrosine kinase inhibitor (TKI) that blocks the molecular pathway. There is another oral pill called trifluridine/tipiracil (TAS-102; Lonsurf), which is a cytotoxic chemotherapy that is also approved in the refractory setting. There is no head-to-head study, so it is difficult [to determine] if regorafenib is better than TAS-102; however, we clearly know that the toxicity profile is very different.

How do the toxicity profiles differ between regorafenib and TAS-102?

With regorafenib, there is more hand-foot/skin reaction, fatigue, and diarrhea. On the other hand, the main toxicities associated with TAS-102 are hematologic. After discussing the profile difference with the patient, I think one can choose regorafenib or TAS-102 depending on their preference.

What is your preference for this patient?

It all depends on how the patient tolerated their prior chemotherapy. For example, if the patient got FOLFOXIRI plus bevacizumab and experienced a lot of hematologic toxicity from the chemotherapy, I would probably avoid TAS-102 and go with regorafenib. However, if the patient had a lot of hand-foot/skin reaction or maybe more fatigue with the prior chemotherapy, then I would probably go with TAS-102.

What dose would you start with regorafenib?

The main issue with regorafenib in the past was the toxicity issue. We were starting at a 160-mg dose, and many patients couldn't tolerate that dose. The ReDOS trial randomized patients to dose escalations starting at 80 mg to 120 mg, and then to 160 mg if tolerated.2 The primary endpoint of the study was trying to see how many patients got to cycle 3, where they got a restaging CT scan.

The trial showed that it was feasible to start at 80 mg and dose escalate. The toxicity profile was better and, interestingly, it did not compromise the overall outcome in terms of OS. Based on this study, I start my patients on 80 mg daily for a week, and dose escalate as tolerated up to the maximum dose of 160 mg.

The patient was started on regorafenib.

What are the choices for therapy when this patient develops further disease progression?

You could try the TAS-102 or, if you are able to get a BRAF inhibitor, you could combine a BRAF inhibitor such as vemurafenib (Zelboraf), which was the drug used in the SWOG study, plus irinotecan. These are the 2 options that the patient would benefit from aside from a clinical trial.

What are the factors that go into this decision?

If vemurafenib was readily available, I think that is the next step that should be chosen. I would use that plus irinotecan, plus rituximab. However, if the BRAF inhibitor was not available, unfortunately the only FDA-approved drug that is still left would be TAS-102.

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