Decisions in the Clinic: Treating Patients With Hepatocellular Carcinoma
E. Gabriela Chiorean, MD
Hospital and Institutional Affiliations
Professor of Medicine University of Washington
Director, Gastrointestinal Oncology Program University of Washington/Fred Hutchinson Cancer Research Center
Associate Member Fred Hutchinson Cancer Research Center, Clinical Research Division
After a patient is diagnosed with hepatocellular carcinoma (HCC), what are the first treatment options you consider? What are the key patient factors that influence your decision making?
As of today, we have two US Food and Drug Administration (FDA) approved first-line options: sorafenib and lenvatinib. Nevertheless, if I had an opportunity to enroll a patient in a clinical trial using an immunotherapy, possibly in combination with a tyrosine kinase inhibitor, then I do think that would be my first choice.
In the absence of a clinical trial, today my preference would be to treat the patient with lenvatinib. There was a noninferiority randomized phase 3 study, REFLECT, comparing lenvatinib to sorafenib that showed equivalent efficacy and potentially better tolerability with lenvatinib.1 Based on that, the FDA just approved lenvatinib for HCC patients.
But practice could change very soon, after the European Society of Medical Oncology 2018 meeting when we will hear results of the CHECKMATE-459 study that compared sorafenib with nivolumab for first-line HCC treatment.
What is the role of molecular profiling in HCC management? In what ways can it be useful to have a tissue diagnosis for patients?
First of all, right now, when safe and feasible we recommend biopsy for liver tumors especially if eligibility for a clinical trial involves a certain biomarker being checked. But in general, patients with HCC do not undergo standard biopsies due to typical radiographic appearance on imaging scans.
Outside of clinical trials requirements, biopsies can be helpful in several situations: (1) we can identify mixed hepatocellular plus cholangiocarcinoma mixed tumors, which can change treatment; (2) it can help to identify fibrolamellar subtypes, which requires genomic testing for DNAJB1-PRKACA fusion; (3) in addition, less than 1% of HCC patients may have microsatellite instability (MSI-High status), which pertains high responses to immune checkpoint inhibitors; (4) we can perform genomic tumor profiling and identify novel targetable alterations and offer patients new treatment options.
What research from the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting did you find to be most relevant to treating patients with hepatocellular carcinoma?
The CELESTIAL trial was one of the important studies of the year to date. It was presented at the 2018 Gastrointestinal Cancers Symposium and subsequently at the 2018 ASCO annual meeting.2
In the CELESTIAL study, which compared cabozantinib to placebo for HCC patients previously treated with sorafenib, the median survival was 10.2 months compared with 8 months, with an overall 24% improvement in survival. Looking strictly at second-line treated patients (about 70% of all enrolled), overall survival was 11.3 months — a very promising and encouraging result in second-line setting. These results demonstrate the highest overall survival with antiangiogenic therapies in second-line setting vis a vis to other agents.
On the other side, we had the VEGFR2 antibody ramucirumab in the randomized phase 3 REACH-2 study for patients with alpha-fetoprotein levels more than 400 ng/mL.3 Overall survival was 8.5 months vs 7.3 months with placebo, with an absolute overall survival and progression-free survival benefit compared with best supportive care of only 1.2 months.
While in general we should avoid cross-trial comparison, these results may not seem as favorable in comparison to cabozantinib, which had an absolute benefit of 4.1 months in survival and approximately 3.6 months in progression-free survival in the second-line setting. The patient population in CELESTIAL vs REACH-2 were similar and included about 40% of patients with hepatitis B and 30% hepatitis C patients, and all patients in REACH 2 and 40% in CELESTIAL had AFP levels greater than or equal to 400 ng/mL.
Even though it was not a phase 3 large randomized study, one of the most exciting results from the 2018 ASCO Annual Meeting was probably Stein and colleagues’ phase 1b study that used the PD-L1 inhibitor atezolizumab in combination with the anti-VEGF antibody bevacizumab in previously untreated patients with HCC.4 Preliminary results showed a response rate of 62%, but survival data is immature. Based on these results, the FDA assigned fast track research designation for this combination.
How might the data on agents like cabozantinib (eg, from the CELESTIAL trial), lenvatinib (REFLECT trial), and ramucirumab (REACH-2) change your decision making for patients?
When we make treatment decisions we need to balance efficacy and toxicities. Cabozantinib, like other VEGFR tyrosine kinase inhibitors, confers higher rates of hand/foot reaction (grade 3/4 incidence was 17%) and this toxicity does not happen with ramucirumab. Rates of grade 3/4 hypertension with cabozantinib and ramucirumab are similar.
As I mentioned earlier, in the first-line setting we now have two medications that are FDA-approved: sorafenib and lenvatinib. Lenvatinib is a multireceptor tyrosine kinase inhibitor. The phase 3 REFLECT study was obviously a very large study; it enrolled about 1000 patients. What struck me about the study is that even if overall survival was similar — 13.6 with lenvatinib vs 12.6 months with sorafenib — we do see a doubling in progression-free survival [PFS] benefit with lenvatinib (7.4 vs 3.7 months with sorafenib). That was a secondary endpoint. Looking across patient populations, whether alpha-fetoprotein levels or hepatitis B versus hepatitis C-induced cancer, all of the patients seemed to have slightly more benefit from lenvatinib than from sorafenib.
In terms of toxicities, the lenvatinib-treated patients developed higher rates of hypertension. When you look at the grade 3/4 hypertension of lenvatinib versus sorafenib, it’s worse with lenvatinib — 23% versus 14%.
On the other hand, hand/foot reaction is often the adverse event patients treated with sorafenib cannot tolerate, and it was twice as bad with sorafenib vs lenvatinib — 50% versus 27%. That is very important.
Both medications caused liver enzyme elevations and sometimes myelosuppression. Overall, the main differences were more hypertension with lenvatinib and more hand/foot skin reaction with sorafenib. More patients stop treatment due to hand/foot reaction, which is important for clinical practice.
Are there any ongoing clinical trials you would recommend for patients with advanced, unresectable HCC?
The research field is moving forward with development of combinations of antiangiogenic and immunotherapies, combinations of radiotherapy and immunotherapy, and doublet immunotherapies. Things are moving fast in the first-line setting, so options for second-line are going to shift too.
There are several clinical trials in the first-line setting that combine immunotherapy with VEGF-inhibiting tyrosine kinase inhibitors like lenvatinib, sorafenib, and regorafenib. Examples are the phase 3 trial (ClinicalTrials.gov Identifier: NCT03006926) combining pembrolizumab and lenvatinib vs lenvatinib, that is very exciting, as is the phase 3 study (ClinicalTrials.gov Identifier: NCT03434379) of atezolizumab plus bevacizumab vs sorafenib (IMbrave 150).
Several clinical trials are combining radiation therapy modalities (including radioembolization and stereotactic radiation) and immunotherapy. We believe radiotherapy can enhance immunotherapy effects.
There are also doublet immunotherapy combinations of CTLA-4 and PD-1/PD-L1 immune checkpoint inhibitors with the goal of enhancing the activity over just one immunotherapeutic.
These are very exciting times for hepatocellular cancer clinical practice and research. I see new treatment options being instituted as soon as 6 months from now, and the research field will be pushing new horizons with many novel clinical trials.