Richard Kim, MD, recently discussed the treatment considerations and decisions he makes when treating patients with hepatocellular carcinoma. Kim, an associate professor oncology, University of South Florida College of Medicine, and medical oncologist, Gastrointestinal Oncology Department, Moffitt Cancer Center, explained his treatment decisions based on 2 case scenarios during a <em>Targeted Oncology</em> live case-based peer perspectives program.
Richard Kim, MD
Richard Kim, MD, recently discussed the treatment considerations and decisions he makes when treating patients with hepatocellular carcinoma. Kim, an associate professor oncology, University of South Florida College of Medicine, and medical oncologist, Gastrointestinal Oncology Department, Moffitt Cancer Center, explained his treatment decisions based on 2 case scenarios during aTargeted Oncologylive case-based peer perspectives program.
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 included hypertension, well controlled on a beta-blocker, and it was noted in his family history that his mother had died from breast cancer.
He underwent colonoscopy with a biopsy and an ulcerated nonobstructive mass was noted in the right colon. His pathology results confirmed poorly differentiated adenocarcinoma. Molecular testing revealedBRAF-mutated, microsatellite stable disease.
A CT of abdomen, pelvis, and chest showed multiple liver lesions and a large nodule in the right lower pulmonary lobe. He was later diagnosed with metastatic adenocarcinoma of the right colon, TIVN0M1.
TARGETED ONCOLOGY: What factors do you consider when determining systemic therapy for this patient?
With any patient that we see that has metastatic disease, there are many things that we look at, including comorbidity, PS, age, and the burden of disease. Now, every patient will get molecular profiling done. This includes theRASstatus, checking for mismatch repair for possible use of immunotherapy, and, as of recently, checking forHER2to see if they areKRASwild-type. Patients who areHER2mutationpositive or who express aHER2mutation, will be resistant to epidermal growth factor receptor (EGFR) therapies. This is the type of molecular profiling that we do on all patients, which determines the kind of chemotherapy we will offer those patients.
What is the significance of theBRAFmutation?
We know that theBRAFmutation is prognostic, in that patients who areBRAF-mutant tend to have a poorer outcome. Most patients with aBRAFmutation tend to have right-sided tumors. The median overall survival (OS) in those patients is anywhere from 12 to 18 months. It is much shorter than patients who haveBRAFwild-type, where the median OS is greater than 2 years. Therefore, these types of patients tend to have a more aggressive disease and the disease tends to be resistant to certain therapies. Typically, at least in my practice, for patients who have aBRAFmutation, due to their poorer prognostic study we tend to use more aggressive therapies, such as leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRNOX) plus bevacizumab.
What is the significance of his right-sided tumor in terms of response to biologic therapy?
Recently, there have been a lot of data presented with regards to comparing right-sided tumors versus left-sided tumors. We know that colon tumor sidedness is an independent prognostic factor. The fact is that patients with right-sided tumors tend to do worse than the left-sided tumors irrespective of theRASstatus. You could haveBRAF-mutant orBRAFwild-type, but if you have a right-sided tumor, you will tend to do worse.
Data from CALGB/SWOG 80405, a phase III trial, clearly dictate that the right-sided tumors, irrespective of theRASstatus, do not respond to EGFR-targeted therapies.1On the other hand, on the left-sided tumor, there is a trend toward benefit of EGFR drugs compared with VEGF drugs. In the left-sided tumor, it is reasonable to use an EGFR drug up front because of the possible OS benefit. However, some of the oncologists in the United States, due to the toxicity of the EGFR drugs, will use bevacizumab on the left-sided tumors. With regards to the right-sided tumor, at least in the first-line setting, EGFR drugs do not have any efficacy. So, even if they areRASwild-type and have a right-sided tumor, the EGFR drug should not be used and [you should] instead use bevacizumab with chemotherapy.
Should surgical or liver-directed modalities be considered?
Surgery should only be considered in the curative setting or in a palliative setting. Obviously, this patient that presented with multiple liver lesions and lung nodules, most likely is not resectable. The liver-directed therapies, such as yttrium-90 (Y-90) or chemoembolization, have been studied at least in the first-line setting. There is a trial that was presented last year known as the FOXFIRE study, which compared chemotherapy plus selective internal radiation therapy (SIRT) versus chemotherapy alone.2Unfortunately, although there was an improvement in progression-free survival (PFS) in the liver, there was no improvement in OS or overall PFS. Also, due to considerable possible liver toxicities with Y-90 or SIRT, liver-directed therapy in the first line is generally not recommended.
The patient was started on 5-fluorouracil, folinic acid, and oxaliplatin (FOLFOX) and bevacizumab (Avastin). His 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 FOLFOX for 6 months and then switched to capecitabine (Xeloda) and bevacizumab due to grade 1 neuropathy.
The patient did well radiologically and biochemically; however, 11 months later, he developed intermittent shortness of breath, although he continued his normal activities and had an ECOG performance status of 1. Imaging showed a new 3-mm lung lesion, increased size of the pleural lesion, and stability in the liver lesions.
The patient was treated withirinotecan plus vemurafenib (Zelboraf) and cetuximab (Erbitux) and did well for 4 months, but then progressed andwas started on regorafenib (Stivarga).
What are the choices for therapy at this point?
The patient received FOLFOX series plus bevacizumab and progressed. The question then [became]: Now that the patient has failed, what do you do? There are a couple of options available in the refractory setting. Since the patient isKRASwild-type andBRAF-mutant, one could argue that an EGFR drug would be a good option in this setting. However, there are data that continue to come out suggesting that if you areBRAF-mutant, most likely you will not respond to an EGFR drug. Therefore, unless I am out of options, I will hold off using an EGFR therapy in this setting. We are left with a clinical study, if it is available.
I would not continue bevacizumab at this point, where the patient has progressed with FOLFOX series plus bevacizumab and is now on a maintenance therapy. Therefore, you are left with 2 oral pill options: regorafenib and TAS-102 (trifluridine/tipiracil; Lonsurf). Unfortunately, there is no head-to-head study, so it is difficult to say which one should be used in this second-line setting. Having said that, the patient who has a good PS will hopefully get both of the drugs, in the hopes that one of them may show some activity. Typically, we select patients based on phenotype. For example, if you thought the patient had a very good benefit from bevacizumab, which is a vascular endothelial growth factor (VEGFR) drug, then I would also consider going with regorafenib. However, if the patient had a lot of fatigue, or a lot of hand-foot skin reaction, then I would choose TAS-102, which is more of a cytotoxic chemotherapy.
What is the rationale of treating this patient with regorafenib?
One of the issues when regorafenib first got approved a few years ago was the toxicity at the full dose. The FDA label for regorafenib is to start at 160 mg daily, with 3 weeks on and 1 week off. However, as clinicians, we started to discover that 160 mg daily is tough to tolerate, as patients would suffer from rash, fatigue, hand-foot skin reaction, and diarrhea.
Recently at the 2018 Gastrointestinal Cancers Symposium, Tanios Bekaii-Saab, MD, and colleagues presented a trial called the ReDOS study.3ReDOS is a phase II study that randomized a standard arm of 160 mg daily of regorafenib for 3 weeks on and 1 week off (arm B) and compared that to an arm of dose escalation starting at 80 mg per day (arm A). The primary endpoint was to try to see what portion of the patients completed 2 cycles of regorafenib and started a third cycle. This is very important, because if you look at the CORRECT study, which is the original study, most of the patients progressed within 2 months.4Therefore, we want to get the patient to 2 months to see who will benefit and who will not.
Until this data came out, as clinicians we were sort of fearful of at starting at a lower dose, in fear of compromising the efficacy. However, the ReDOS study met its primary endpoint and more patients in the dose-escalation arm received more chemotherapy compared with the standard arm, at 33% vs 25%. Not only that, but efficacy as well was shown to be even slightly better than the standard arm. The OS with the 80-mg daily dose escalation was 9 months compared with 5.9 months with the standard-arm dose. The PFS was also better, with 2.5 months in arm A compared with 2 months in arm B. From this, we cannot conclude that dose escalation is better than the standard dose; however, we can conclude that by starting at a lower dose, we are not compromising the efficacy of the drug. Based on this data, I am now more comfortable starting patients at a lower dose.
A 63-year-old Asian man with chronic hepatitis B virus infection was referred for further imaging studies after suspicious findings on routine ultrasound surveillance for hepatocellular carcinoma (HCC).
Laboratory findings showed: alpha-fetoprotein, 5400 IU/mL; platelets, 230,000 cells/mcL; bilirubin, 1.0 mg/dL; albumin, 3.5 g/dL. There was no hepatic encephalopathy and ascites were not present. His Child-Pugh class was A.
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. Both lesions were resected with R0 margins.
What is the prognosis of the patient?
The patient had what we call a multifocal disease, with 2 lesions at 2 cm and 5 cm. Even though this patient was resected, I would call this patient a moderate risk of reoccurrence. At this time, there are no data supporting adjuvant therapy benefiting the patient. There was a trial called the STORM study, which randomized patients to sorafenib versus a placebo in the adjuvant setting.5Unfortunately, in that trial, it did not show any benefit using sorafenib in the adjuvant setting after a liver resection, similar to in this patient. Therefore, there was no evidence [supporting the use of] adjuvant therapy in this patient, [so we continued] to monitor this patient with surveillance.
Routine follow-up imaging showed a new lesion in the liver measuring 2.3 cm and a chest CT showed 3 small lesions (<1 cm) in the left upper lobe of the lung. The patient was started on sorafenib (Nexavar) 400 mg twice a day and tolerated therapy well after management of grade 1 diarrhea.
What factors do you consider when deciding when to initiate therapy with sorafenib? Would this patient be a good candidate?
After liver resection, this patient now has metastatic disease in the lung. Therefore, the patient is now stage IV with advanced HCC, and the only FDA-approved drug at this time for advanced disease is sorafenib, which is indicated for patients with unresectable HCC. This patient seems to be a very good candidate, as the patient has very good liver function with Child-Pugh A liver cirrhosis and, at least in the beginning, has labs within the label of using the drug.
How will your decision change with availability of lenvatinib (Lenvima)?
Recently, there was a trial called REFLECT that compared lenvatinib against sorafenib in the first-line setting in patients with unresectable HCC.6This was a noninferiority study, so it was not trying to prove that it was better than sorafenib, but merely show that it was not inferior. One thing you want to distinguish between the REFLECT study and the SHARP study is that in SHARP study they excluded patients with main portal invasions and patients who had a tumor burden greater than 50% in the liver. This was a selective study, which weeded out some of the bad actors.
In this study, when they presented the data at ASCO last year, they met the noninferiority goal. By giving lenvatinib, they proved it to be not inferior compared with sorafenib. However, it did not show that it was superior to sorafenib. Interestingly, all of the secondary endpoints, including the PFS, the time until progression, and the objective response rate (ORR), were much higher in the lenvatinib arm. It did not, however, translate into an OS benefit. The grade 3/4 adverse events (AEs) were similar in both arms, but there was more hypertension and diarrhea in the lenvatinib arm. This compared to sorafenib, where there was more hand-foot skin reaction.
We hope to hear from the FDA regarding the drug's approval sometime in May. But with its availability, we will have more options for the patient to use. It is unclear, at this time, which patient should get which. But based on the inclusion criteria, some of the patients were excluded from this trial to receive lenvatinib. In those patients, you would definitely want to consider sorafenib. However, in other cases of metastatic disease, there is some benefit of lenvatinib, which may be meaningful to some patients. Without the OS, it will be up to the treating physician to decide which drugs to use.
What are the practical strategies to managing toxicities?
At least with sorafenib, due to the several AEs that occur, including fatigue and hand-foot skin reaction, we sometimes see the patient every 2 weeks to check labs and also to be proactive in terms of the hand-foot skin reaction. We tend to prescribe topical creams for the reaction.
In terms of lenvatinib, the most common AEs are hypertension and diarrhea. Similar to sorafenib, in this case we would watch the patient and would see them back at least every 2 weeks to monitor the hypertension and add any medications that may be needed. Also, to try to help the diarrhea with anti-diarrhea medication. The key is that in both drugs you want to be proactive in terms of the AEs.
The patient complains of increasing fatigue and CT scans show widely scattered lung nodules. He had an ECOG performance status of 1.
The patient was started on 160 mg of regorafenib, but he later complained of intermittent diarrhea.
What are the options for therapy?
Once the patient progresses on frontline therapy with sorafenib, there are currently 2 options: regorafenib, a tyrosine kinase inhibitor (TKI) that blocks multiple pathways similar to sorafenib, and nivolumab (Opdivo), a new immunotherapy checkpoint inhibitor approved by the FDA. Of note, regorafenib was approved based on the RESORCE trial [results].7In that trial, the patients must have tolerated sorafenib at least 400 mg daily for greater than 20 days [before receiving regorafenib]. So in this trial these are patients who have tolerated sorafenib well and who benefited from regorafenib compared with placebo. Based on the phase III study, clearly there is evidence that patients who tolerate sorafenib could go on regorafenib and you will hopefully see an improvement in PFS and OS.
Nivolumab was approved based on [findings from] a single-arm study, the phase I/II CHECKMATE-040 study.8These were patients who failed or were intolerant to sorafenib. What they found was that the ORR in the refractory setting was about 20%. Interestingly, the difference between this drug, immunotherapies, and other cytotoxic drugs is that the 20% that responded had a very durable response rate. Therefore, based on this impressive duration of response to nivolumab, the drug was approved in the second-line setting. This was a conditional approval. In the first-line setting, there is a trial comparing nivolumab versus sorafenib, and we are eagerly anticipating the results.
In the second-line setting, the choice of agent depends on what the patient's characteristics are; for example, if the patient had a difficult time tolerating sorafenib. The easy answer is to go with a checkpoint inhibitor, because those patients were included in the CHECKMATE study. However, if the patient did well with sorafenib, you may consider changing to regorafenib in the second-line setting, then using nivolumab in the third-line setting.
Generally speaking, nivolumab is very well tolerated, and therefore, for the patients who had a tough time with sorafenib, it is something that we would consider. But once again, not everyone who gets nivolumab will respond. About 20% will respond. Unfortunately, at this time we do not have a biomarker that will predict who will better respond to regorafenib or nivolumab. It is a decision that would have to be made by a treating physician, depending on the patient's characteristics.
How do you manage disease progression in this patient?
If the patient is healthy enough to get both of the drugsfor example, if they get regorafenib and progress on it—we would probably then go to nivolumab. If the patient progresses on nivolumab and tolerated sorafenib, you may want to consider trying regorafenib. However, if the patient progresses on nivolumab and did not tolerate sorafenib well, then you are left with possibly a clinical study or cabozantinib (Cabometyx), which was presented at ASCO this year and will hopefully get an indication in the refractory setting as well sometime this year.
How do you manage toxicity with regorafenib in a patient with advanced HCC?
The management of toxicity with regorafenib is very similar to how we manage toxicity in colon cancer. We are very proactive with this, and I tend to see the patient once a week or every 2 weeks to manage not only the liver function tests, but also fatigue, hand-foot skin rash, and diarrhea. If there are any signs or symptoms of this disease, you may want to dose reduce the patient's drug from 160 mg to 120 mg daily.
Having said that, the main difference between using regorafenib in the colon cancer study versus the liver study is that in the colon cancer study, the patients who received regorafenib were all TKI naive. However, the patients in the HCC study tolerated sorafenib to a certain degree. We expect that regorafenib in this setting would be less toxic compared to colon cancer. Despite that, we still want to see the patient every week or every 2 weeks to manage the toxicity and be proactive.