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

Richard Kim, MD

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 aTargeted Oncologylive 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 wasBRAFmutated 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 forKRAS,NRAS, andBRAF. We also test for the status of mismatch repair (MMR). More and more, we are testing forHER2mutations, for 2 reasons. First, patients who areHER2-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 areHER2-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 theBRAFmutation in this patient?

If someone isBRAFmutated, 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 withBRAFmutations combining a BRAF inhibitor with an EGFR inhibitor, showing that the combination may have efficacy.

Because patients withBRAFmutation 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 areRASwild-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 allRASwild-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 withBRAFmutations 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.²The 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.

Case 2

February 2014

A 63-year-old Asian man with chronic hepatitis B virus (HBV) was referred for further imaging studies after suspicious findings on routine ultrasound surveillance for hepatocellular carcinoma (HCC). His alpha-fetoprotein (AFP) levels were 5400 IU/mL. Laboratory findings showed platelets, 230,000 cells/mcL; bilirubin, 1.0 mg/dL; albumin: 3.5 g/dL; hepatic encephalopathy, none; and ascites, not present. He had a Child-Pugh score of A.

A CT scan revealed 2 lesions in the right hepatic lobe measuring 2 cm and 5 cm; no extrahepatic disease. Biopsy findings showed grade 2 HCC with moderate fibrosis and both lesions were resected with R0 margins.

What is the prognosis of this patient?

Based on the size of the tumor, I would say that this is a [patient with a] moderate risk for recurrence.

Is there any evidence for use of adjuvant therapy in patients with HCC?

Unfortunately, there is no evidence that getting adjuvant therapy makes any difference in HCC. Therefore, if the patient can't be seen in the clinic, there is nothing for me to offer the patient and we would do a close surveillance.

There was a trial using the TKI sorafenib (Nexavar) in the adjuvant setting in patients with intermediate- or high-risk liver cancer after resection. That trial randomized patients to sorafenib versus surveillance. Unfortunately, that trial was negative. The only adjuvant trial that I am aware of is with nivolumab (Opdivo) as adjuvant immunotherapy versus surveillance in patients with intermediate- or high-risk tumor (NCT03383458).

August 2016

Routine follow-up imaging showed a new lesion in the liver measuring 2.3 cm. A chest CT showed 3 small lesions (<1 cm) in the left upper lobe of the lung. The patient was started on sorafenib 200 mg twice daily and tolerated therapy well after management of grade 1 diarrhea.

What factors do you consider when deciding when to initiate therapy with sorafenib?

The patient is a good candidate [for sorafenib] because he has a very good synthetic liver function with Child Pugh A liver cirrhosis. Additionally, he has a good performance status and [no] contradiction to sorafenib.

How may the availability of lenvatinib (Lenvima) change your approach?

The recent REFLECT study, which is a noninferiority study comparing lenvatinib versus sorafenib, met its endpoint.³The conclusion was that lenvatinib was noninferior to sorafenib. Lenvatinib is not approved yet, but it has been submitted to the FDA and hopefully within the next 1 to 2 months we will hear if it gets approved in the first-line setting.

It is interesting to look at the REFLECT study, which is a first-line study, even though there was no difference in OS, there were improvements in response rates and progression-free survival (PFS), favoring the lenvatinib arm compared to sorafenib. However, it did not lead to an improvement in OS. The reason for that is unclear.

How do the toxicity profiles differ between lenvatinib and sorafenib?

Lenvatinib tends to have more toxicity with high blood pressure compared to patients who are on sorafenib, who have more issues with hand-foot/skin reactions.

What are practical strategies to manage these toxicities?

With lenvatinib, it is something we would monitor weekly or every 2 weeks. We would see the patient back and start them on anti-hypertension medication, or go up on the medication that the patient is already on. From our experience with other VEGF drugs, we know how to handle this.

With sorafenib, most of the evidence are anecdotal. We could use cream to moisturize the skin. If the patient develops grade 3 hand/foot/skin reaction, we hold the drug and modify it accordingly. But, the key point is that we need to be proactive with managing patients on sorafenib. I tend to see the patient back once a week or every 2 weeks, at least for the first 6 weeks, just to make sure that the toxicity does not get out of hand.

April 2017

The patient complained of increasing fatigue. A CT scan showed new lesions in the lung nodules. He had an ECOG performance status of 1 and his aspartate transaminase increased to >10,000 U/L.

What are the options for therapy after the patient progresses?

A few years ago, there would be nothing to offer the patient aside from a clinical trial. Now, we have 2 drugs that are FDA approved [in this setting]. One is regorafenib, which is a TKI that is very similar to sorafenib. This drug was approved based on the large phase III RESORCE study. The second is the checkpoint inhibitor nivolumab, which was approved based on the CheckMate 040 study. This was a single phase II arm study, where it showed a response rate of 15% to 20%, but those responses seemed to be very durable.⁴Based on that, the FDA approved it in the second-line setting.

Which of the 2 drugs do you use?

The toxicity profiles [for these 2 drugs] are totally different. Patients that were eligible for the RESORCE study must have tolerated sorafenib 400 mg daily to go on the study. Nivolumab, on the other hand, is a checkpoint inhibitor and as a single agent it is very well tolerated. Even though there are immune-related adverse events that we do hear about.

If the patient had stable disease with sorafenib, and tolerated it well, I think going with regorafenib makes perfect sense. However, if the patient progressed very rapidly on sorafenib or could not tolerate it, nivolumab is a good answer as well. The key point here is that nivolumab does not work on everybody. But if it works, it works for a very long time.

How may the availability of cabozantinib (Cabometyx) impact your practice?

Cabozantinib is another TKI. There was a trial that was presented at the 2018 Gastrointestinal Cancers Symposium that showed that there was a benefit in OS and PFS [with cabozantinib]. In that trial, they included second-line and third-line patients. So, cabozantinib may be something we can use third line.

The benefit in the second line seems much greater than the third line. But how you distinguish cabozantinib versus regorafenib is a question mark. At least from the data that was presented, cabozantinib seems to be a little more toxic compared to regorafenib. The patients that were included in those 2 studies were a little bit different, so I don't want to compare apples and oranges. But, it is good to have more options for the patient. As the data matures on cabozantinib, hopefully we will see long-term responses.

The patient was started on regorafenib 160 mg. He later complained of intermittent diarrhea.

How do you manage toxicity with regorafenib in a patient with advanced HCC?

The key point here is that most of the adverse events occur within 6 weeks. Therefore, we must see the patient once a week or every 2 weeks to manage the toxicity—including diarrhea, hand-foot/skin reaction, rash, and fatigue&mdash;and manage it accordingly. Unfortunately, we don't have data like the ReDOS study in colon cancer, where we dose escalate. I cannot recommend [dose escalation] for a patient with HCC.

What if the patient had poor tolerance to sorafenib?

I think the answer to this question is 2-fold: nivolumab or cabozantinib. In the cabozantinib study, patients who were intolerant to sorafenib were also allowed in the study. I think if the patient had poor tolerance to sorafenib, those are the options that you have.

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

I think that the key here is the sequencing. The key point is that if the patient is healthy enough, they should be able to get all of the drugs. But what is the right sequencing for managing this patient? That will be a key question that should be answered in future trials.

References:

1. Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1&ordm;) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance).J Clin Oncol.2016;34(suppl; abstr 3504).
2. Bekaii-Saab TS, Ou FS, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)—an ACCRU Network study.J Clin Oncol. 2018;36(suppl 4S; abstr 611).
3. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomized phase III non-inferiority trial.Lancet. 2018;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.
4. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with locally advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase I/II dose escalation and expansion trial.Lancet. 2017;389(10088):2492-2502. doi: 10.1016/S0140-6736(17)31046-2.