Marshall Details Treatment Options for Patients With GI Cancers in 2 Case Studies

John Marshall, MD

John Marshall, MD

John Marshall, MD, recently shared the treatment considerations and decisions he makes when treating patients with gastrointestinal (GI) cancers. Marshal, chief of the Division of Hematology/Oncology, director of the Otto J. Ruesch Center for the Cure of GI Cancer, Medstar Georgetown University Hospital, in Washington, DC, explained his treatment decisions based on a case scenario during aTargeted Oncologylive case-based peer perspectives presentation.

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 showed hypertension, which was well-controlled on a beta-blocker. His mother died from breast cancer.

A colonoscopy with biopsy showed an ulcerated non-obstructive mass noted in the right colon and pathology results confirmed poorly-differentiated adenocarcinoma. Molecular testing showed he wasBRAF-mutated and microsatellite stable. A CT of abdomen, pelvis, and chest showed multiple liver lesions and a large nodule in the right lower pulmonary lobe. He was later diagnosis with metastatic adenocarcinoma of the right colon, stage T4N0M1.

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

Marshall:The first thing that you want to do when you’re considering the treatment of metastatic colon cancer is to figure out whether or not the patient has the option of resectability for potential cure. That is really a judgement call. Not everybody worries about how many metastases there are or where they are, and whether or not they are deemed resectable. In this case, we know that the patient has multiple liver and chest lesions. So, the patient is almost certainly unresectable. Although, the beauty is in the eye of the beholder. It depends on where the liver lesions and lung lesions were.

If we're assuming that we are going to go forward with systemic therapy, regardless of respectability, the next thing you need to know is the patient's molecular profile through genetic testing. First, we want to know whether the patient is microsatellite stable. This helps us to understand if immune therapy is in play. The next thing we would want to know is whether the patient is right-sided or left-sided. We now know that right-sided colon cancers do not respond well to EGFR-targeted therapies. In this case, the patient is right-sided, so that means that [those therapy options] are out.

What is the significance of hisBRAFmutation?

We then learn that the patient has aBRAFmutation, which is a prediction for a bad prognosis and a rarer tumor. However, we now have some newer data using combination targeted therapy, which suggests we might have some benefit there. I don't think that we would use [this therapy] frontline. Instead, this patient might consider it in later lines of therapy. TheBRAFmutation matters a lot. Traditionally, we have not used aBRAFmutation as a frontline molecular target, but I think newer evidence suggests that we probably should.

The patient was started on fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) and bevacizumab (Avastin). The 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 folinic acid, fluorouracil, oxaliplatin (FOLFOX) for 6 months and then switched to capecitabine (Xeloda) and bevacizumab due to grade 1 neuropathy.

January 2017

The patient did well radiologically and biochemically. Eleven months later, he developed intermittent shortness of breath; he continued his normal activities.

Imaging showed 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 is the rationale for FOLFOXIRI plus bevacizumab as initial therapy for this patient?

[With this patient], we are going to start with chemotherapy and take into account that he is right-sided, which means we should not use an EGFR-targeted therapy. We also know that if you have aBRAFmutation, it is the worst prognosis. There is some evidence to suggest that there is a better response to the multidrug regimen FOLFOXIRI. In this case, the patient was given the more aggressive regimen of FOLFOXIRI and bevacizumab as initial therapy. This is based on several studies that look at right- and left-sided tumors in colon cancer, and the TRIBE study, which enabled the FOLFOXIRI regimen to demonstrate an overall survival (OS) and overall response rate benefit.¹If you put all of those combinations and trials together, you get a very reasonable frontline choice for this patient of FOLFOXIRI plus bevacizumab.

The patient has an initial response, he responds well, and then we need to proceed with maintenance therapy. Typically, we cannot keep giving people aggressive chemotherapy week in and week out, particularly with the best regimen of FOLFOXIRI plus bevacizumab. Almost certainly, a patient like this would move on to maintenance therapy. This would typically be gemcitabine and bevacizumab.

What are the choices if the patient then progresses on maintenance therapy?

Subsequently, almost a year later, the patient begins to develop progression of disease. The question then becomes: what would you do next with this patient? I think there are multiple options for this patient. We have already had fluorouracil, oxaliplatin, and irinotecan, and bevacizumab. Certainly, regorafenib (Stivarga) or TAS-102 (Lonsurf) would be reasonable choices next. There is a mention in the fact that the patient has aBRAFmutation, which might also predict his response to a newer combination of EGFR-targeted therapy and the BRAF inhibitor vemurafenib (Zelboraf). I think the standard of care would be regorafenib in this patient.

The patient was started on regorafenib.

What is the rationale for regorafenib in this patient?

Patients with refractory chemotherapy are traditional for second-line therapy. Regorafenib has an OS benefit. We now know, with the ReDOS clinical trial, that you can start at a lower dose of 80 mg and escalate up, depending on tolerance.²In fact, counter to our typical thinking, starting lower and then escalating patients had a better survival than starting higher and deescalating for toxicity. This phase II randomized trial, although small, has given us a new standard on how to correctly dose the medicine. That is why the patient received this therapy.

[To be mindful], the toxicities associated with regorafenib are hand and foot syndrome, which is probably the biggest deal, and fatigue and liver function abnormalities. Those are the toxicities we should watch out for.

What are the options for therapy after further disease progression for this patient?

After regorafenib, I would either consider TAS-102 or, if the patient is interested, the combination of an EGFR-targeted therapy and vemurafenib, which would make a lot of sense. There is a phase II, randomized SWOG S1406study that was done [looking at irinotecan and cetuximab with or without vemurafenib inBRAF-mutant colorectal cancer].³It was positive enough that it changed the guideline. InBRAFmutations, there was evidence of a response rate and progression-free survival (PFS) benefit.

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 levels were 5,400 IU/mL. Laboratory findings showed: platelets, 230,000 cells/mcL; bilirubin, 1.0 mg/dL; albumin, 3.5 g/dL; hepatic encephalopathy, non; ascites were not present.

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

Targeted Oncology: What is the prognosis of this patient?

Marshall:Liver cancer remains a very serious and life-threatening disease, even when the case is potentially surgically resectable and controllable. Some patients have very bad liver disease and cirrhosis, and therefore get sicker. For this case, the patient has a pretty normal liver function with an HBV infection. So, I would quote a little bit better prognosis on average, but still a very high-risk issue.

This patient undergoes surgery, with an R0 resection, meaning they got [the tumor] completely out.

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

Currently, despite progress in therapy for HCC, there is no role for adjuvant chemotherapy. About a year later, the patient unfortunately presented with relapse. Now it is considered unresectable metastatic disease in the liver with lung lesions. The patient was started on standard-of-care frontline therapy with sorafenib (Nexavar) at 400 mg twice daily.

August 2016

Routine follow-up imaging showed a new lesion in the liver measuring 2.3 cm. Chest CT showed 3 small lesions (<1 cm) in the left upper lobe of the lung.

The patient was started on sorafenib 400 mg 2 times per day and tolerated therapy well after management of grade 1 diarrhea.

What is the rationale for the use of sorafenib in this patient?

The rational with sorafenib is pretty straight forward. It has been the standard of care for frontline metastatic disease for some time now. This is the ideal candidate for this type of treatment, mainly because of his performance status and his liver function, which is in pretty good shape.

How will this rationale change with the availability of lenvatinib (Lenvima)?

Regarding lenvatinib, studies suggest a better response rate and PFS in these patients. The toxicity profile is very similar [between the 2 drugs]. I believe that once this drug becomes available and approved, it will likely get increased usage.

What are practical strategies to manage toxicities?

To manage the toxicities with sorafenib or lenvatinib, the primary thing is to continue to follow patients and doses accordingly. There is clear evidence that many patients will need dose modifications from the 400 mg twice daily dosing of sorafenib. Similar adverse effects include high blood pressure, hand and foot syndrome, fatigue, and laboratory abnormalities.

April 2017

The patient complained of increasing fatigue and CT scans later showed new lesions in the lung nodules.

He still had an ECOG performance status of 1, but his aspartate aminotransferase increased to >10,000 IU/L.

What are the treatment options after the patient shows pression of disease?

The patient was on treatment for a while, and shows progression of disease. Unbelievably, we now have a lot of choices for refractory metastatic HCC. We have 2 main therapy options, regorafenib and nivolumab (Opdivo).

I think that we are on a magic ride with immunotherapy, and a lot of us are trying these drugs very early. But, we have to remember the RESORCE clinical trial actually shows very impressive results in the refractory second line with regorafenib after sorafenib in the frontline.⁴The trial clearly shows a significant benefit and nice PFS in its refractory setting. This is a large phase III randomized study. The CheckMate 040 study is a much smaller phase I/II study with a dose-expansion cohort.⁵The trial noted only a 20% response rate in that patient population.

We also have to remember with immunotherapy that there will be adverse effects. Immunotherapy is as if we are swinging for the fences. Only 1 in 5 patients benefit, but when they do benefit they can benefit to a large degree. On the other hand, if you look at a drug like regorafenib, probably more people benefit but not to as large of a degree. The way I think about it is that you will probably want to end up trying both of the medicines when all is said and done in this patient. It would be appropriate to initiate treatment with regorafenib in this patient, but I also would not be against anyone who decided to use immunotherapy in this patient as well.

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

How would you manage toxicities with regorafenib in a patient with advanced HCC?

If the patient has toxicity on 160 mg, I would stop, let the patient quiet down, and then resume dosing at some lower dose level. What we are not sure of is the new data in colon cancer that says that you can start lower, at 80 mg—would that also apply to liver cancer? For the moment, I think the default is to start higher. If you develop these side effects, then hold the drug, let it quiet down, and then resume treatment at a lower dose. After the patient progresses on regorafenib, he is a still a candidate for immunotherapy, such as nivolumab, if the patient hasn't had it yet.

References:

1. Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study.Lancet Oncol.2015;16(13):1306-1315. doi: 10.1016/S1470-2045(15)00122-9.
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).doi: 10.1200/JCO. 2018.36.4_suppl.611.
3. Kopetz S, MdDonough SL, Lenz HJ, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406).J Clin Oncol. 2017;35(suppl 15; abstr 3505).doi: 10.1200/JCO.2017.35.15_suppl.3505.
4. Bruix J, Qin S, Merle P, et al; RESORCE Investigators. Regorafenib for patients with hepatocellular car- cinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-con- trolled, phase 3 trial.Lancet. 2017;389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9.
5. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase I/II dose escalation and expansion trial.Lancet Oncol. 2017;389(10088):2492-2502. doi: 10.1016/S0140-6736(17)31046.