Richard D. Kim, MD
Although pembrolizumab (Keytruda) failed to demonstrate a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) in patients with previously treated advanced hepatocellular carcinoma (HCC), the treatment armamentarium remains strong, with the use of TKIs, monoclonal antibodies, and another checkpoint inhibitor, said Richard Kim, MD.
“The treatment of HCC is evolving. The study with pembrolizumab was negative. That's the reason why we do these studies––[to prove their benefit or lack thereof],” said Kim. “The era of immunotherapy is evolving. It's unclear exactly what's going to happen. Having said that, we have many kinase inhibitors and other drugs to fight HCC.”
In terms of frontline therapies, in August 2018, lenvatinib (Lenvima) became the second TKI to receive regulatory approval from the FDA for the treatment of patients with unresectable HCC after demonstrating noninferiority to sorafenib (Nexavar) in the phase III REFLECT trial.
For second-line treatment, physicians can choose between regorafenib (Stivarga), cabozantinib (Cabometyx), nivolumab (Opdivo), or pembrolizumab.
The negative news about pembrolizumab came in February 2019 when Merck, the manufacturer of the drug, announced that although the PD-1 inhibitor showed an improvement in PFS (HR, 0.78; 95% CI, 0.61-0.99; P
= .0219) and OS (HR, 0.78; 95% CI, 0.611-0.998; P
= .0238) in previously treated patients enrolled in the phase III KEYNOTE-240 trial, the benefit was not determined to be statistically significant.
The news follows the November 2018 FDA approval of the PD-1 inhibitor based on positive results from the phase II KEYNOTE-224 trial. According to Kim, the label was contingent on expectedly positive results from KEYNOTE-240; therefore, whether the label will be pulled remains to be seen.
Although this has cast somewhat of a shadow over immunotherapy in HCC, nivolumab remains an appropriate choice in the second-line setting, said Kim, who added that the agent is also being compared with sorafenib in the frontline setting (NCT02576509).
In an interview during the 2019 OncLive®
State of the Science Summit™ on Gastrointestinal Malignancies, Kim, an assistant professor of oncology at University of South Florida College of Medicine and a medical oncologist in the Department of Gastrointestinal Oncology at Moffitt Cancer Center, discussed the therapeutic landscape of advanced HCC in light of recent findings and highlighted anticipated research in the field.
OncLive: How has the field of HCC evolved in recent years?
: There has been a tremendous evolution in the treatment of HCC. Since 2007, the only drug that was FDA approved for the treatment of patients with advanced HCC was sorafenib. Recently, there have been many advances in the treatment of patients with HCC, including TKIs along with immunotherapy.
What targeted therapies have been introduced into the field?
Until last year, sorafenib was the only drug that was approved in the first-line setting. Now, we have another TKI called lenvatinib; it's a dirty TKI that blocks the VEGF/EGFR/FGFR pathways. That was approved by the FDA last year based on findings from the REFLECT trial, which was a phase III noninferiority trial against sorafenib. The trial showed that lenvatinib was noninferior to sorafenib. If you look at the secondary endpoints of time to progression, PFS, and response rate, it seems like lenvatinib was superior in those regards. However, the OS was very similar between treatments. Sorafenib tends to have more hand–foot skin reaction. Lenvatinib tends to have a higher rate of hypertension. There are subtle differences between the 2 drugs, but now we have another option for patients in the frontline setting.
We have a couple of FDA-approved drugs in the second-line setting as well. The first one is regorafenib, which is another dirty TKI that blocks multiple pathways. In the RESORCE trial, patients were randomized to receive either regorafenib or placebo. However, patients must have been able to tolerate 400 mg of daily sorafenib to be eligible for participation. The trial showed an OS benefit with regorafenib. Based on the positive results, the drug was approved for patients with advanced HCC who failed sorafenib.
Cabozantinib is the second FDA-approved drug, and it’s a dirty TKI that blocks VEGF, c-MET, and other pathways. [The trial that led to its approval] was similar in design in that patients who failed sorafenib or who were intolerant to sorafenib were randomized to receive either cabozantinib or placebo. In this study, patients were allowed up to 2 prior lines of therapy. The primary endpoint was OS, and the trial met its endpoint; cabozantinib was found to be superior to best supportive care.