Ghassan Abou-Alfa, MD
While the hepatocellular carcinoma (HCC) field shifted in 2018 with the addition of newly available treatment options, more pivotal research is on the way, said Ghassan K. Abou-Alfa, MD.
For a 10-year span, there was only 1 approved drug for the treatment of patients with advanced HCC. In the decade that followed, the chain of negative trials was broken with the August 2018 FDA approval of lenvatinib (Lenvima) for the frontline treatment of patients with unresectable disease.
The approval was based on data from the phase III REFLECT trial, which demonstrated the noninferiority of lenvatinib to the standard sorafenib (Nexavar). Median overall survival (OS) was 13.6 months for those who received lenvatinib compared with 12.3 months for those who received sorafenib. The toxicity profile was also comparable between the 2 arms.1
Beyond the frontline setting, nivolumab (Opdivo) has been approved as a second-line treatment, while its potential as a frontline agent is anticipated in the CheckMate-459 trial. In November 2018, the FDA granted an accelerated approval to pembrolizumab (Keytruda), based on data from the phase II KEYNOTE-224 trial in which the single-agent induced a modest overall response rate of 17% in patients with advanced HCC who progressed on a first-line TKI.2
Most recently, the FDA approved cabozantinib (Cabometyx) as a treatment for patients with HCC who previously received sorafenib. The decision was based on findings from the phase III CELESTIAL trial, in which the median OS with cabozantinib was 10.2 months versus 8.0 months for placebo, representing a 24% reduction in the risk of death (HR, 0.76; 95% CI, 0.63-0.92; P
Additionally, ramucirumab (Cyramza) has also been assessed as a potential second-line treatment for those who progress on sorafenib in the phase III REACH-2 trial. Among patients with elevated alpha-fetoprotein, results showed a median OS of 8.5 months in the ramucirumab arm compared with 7.3 months for placebo.4
Median progression-free survival was significantly improved in patients treated with ramucirumab (2.8 months) versus placebo (1.6 months). Also available in the second-line space is regorafenib (Stivarga).
In an interview with OncLive
, Abou-Alfa, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed the rapidly evolving treatment options in HCC and other developments in GI cancers.
OncLive: What have been the biggest advancements made in the field of HCC?
: It has been a great year with regard to many malignancies. Specifically, in the hepatobiliary domain, we have seen many positive changes. We are going to continue hearing a lot about the advances [being made] in HCC.
As we all know, we started back in 2007 with only 1 [FDA-approved] drug: sorafenib. Now, we are really flooded, to say the least, with different [therapeutic] options. If anything, this is great news for patients before anyone else. In the frontline setting, the FDA approved lenvatinib as an excellent second option for patients. In addition to that, we have regorafenib (Stivarga) in the second-line setting for patients who progress on sorafenib.
There is potential for use with nivolumab, which is still in conditional approval for second-line treatment [for these patients]; advent data for cabozantinib in the second- and third-line setting; and there are also data for ramucirumab.
Other than TKIs, there has been great interest in exploring the role of checkpoint inhibitors. As I mentioned, nivolumab is the first one so far with a conditional approval. We are all eager to hear the results of the CheckMate-459 trial; this is of nivolumab versus sorafenib. This will help guide us for what is coming in the first-line setting. Will it be TKIs or checkpoint inhibitors?
What is the treatment approach for patients with biliary cancers?
The second biggest discussion [in the space] has focused on biliary cancers and the adjuvant approach. Is it chemotherapy alone, as we gather data from the BILCAP study with capecitabine? Or, is it going to be a regimen of chemotherapy plus radiation? It will be nice to see the 2 different approaches.
Are there other recent data in the space that you are excited about?
Something else we are seeing some data with is fibrolamellar carcinoma; this is a very rare cancer that, unfortunately, affects people in their 20s and 30s. Sadly, it still does not have a standard of care. One of our fellows [at Memorial Sloan Kettering Cancer Center recently] presented a very educational case in terms of this disease. He gave a prelude to some of the ongoing clinical trials in this space. There is, specifically, a study evaluating the use of neratinib (Nerlynx) for these patients. We can at least be excited that there is ongoing [research] for these patients.
- Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi:10.1016/S0140-6736(18)30207-1.
- Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial [published online June 1, 2018]. Lancet Oncol. doi: 10.1016/S1470-2045(18)30351-6.
- Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC) who have received prior sorafenib: Results from the randomized phase III CELESTIAL trial. J Clin Oncol. 2018;36(suppl 4S; abstr 208).
- Zhu A, Kang YK, Yen CJ, et al. REACH-2: a randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib. REACH-2 investigators. J Clin Oncol. 2018;36(suppl; abstr 4003). ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.4003.