Experts Remain Hopeful About Immunotherapy in HCC

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).

OncLive: How has the field of HCC evolved in recent years?

What targeted therapies have been introduced into the field?

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.Kim: 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.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.

Beyond TKIs, there are also immunotherapies that are available. Nivolumab was approved based on a single-arm phase II trial that showed a durable response rate with the agent. The same thing was true of pembrolizumab. However, on February 20, 2019, a press release came out on the KEYNOTE-240 trial. Here, patients were randomized to receive either pembrolizumab or placebo, but the press release stated that the PD-1 inhibitor did not meet the coprimary endpoints of PFS and OS. Now, we're not sure what to do with immunotherapy because a trial that we all thought would be positive was negative.

Could you discuss the toxicity concerns with TKIs?

Based on the negative results of KEYNOTE-240, could the FDA pull the label for second-line pembrolizumab?

Pending the data from the frontline trial with nivolumab, could immunotherapy will replace TKIs in the frontline setting?

However, one trial we're eager to see [results from] is a first-line study of nivolumab compared with sorafenib—that’s the CheckMate-459 trial. That trial will hopefully read out sometime this year. We're hoping that will be a positive study.The toxicity of TKIs is an issue. The problem with TKIs is that they’re not pure kinase inhibitors; they block multiple pathways. Therefore, you see multiple symptoms. One of the biggest issues with sorafenib is that around 10% to 15% of patients will not be able to tolerate it for various reasons. Toxicity is an individual issue, and we have to see how it plays out.Pembrolizumab was conditionally approved by the FDA based on results from the single-arm study with the understanding that there will be a pivotal study showing a benefit. The pivotal study was negative. The trial has not been presented yet. I don't have the exact numbers but based on the deal they had with the FDA, I would think that pembrolizumab will be pulled from the indication.We all think that the single-arm study with nivolumab is going to be positive. If it is positive, it will change the treatment landscape of HCC. Nivolumab will become the first-line choice because it's better tolerated than the kinase inhibitor and its grade 3/4 toxicity is very low. However, our optimism is not as great as it was before the press release came out on the KEYNOTE-240 trial. We thought pembrolizumab would be better than best supportive care, and it wasn’t. Now, nivolumab is going up against an active agent. We’re cautiously optimistic that it will be positive.

Where does this leave ramucirumab?

If it's negative, however, we'll have to start from scratch to see what else we can do with immunotherapy. That may be combining immunotherapy with kinase inhibitors or with other agents. Right now, we're eagerly anticipating the results of the trial and hoping it will be positive so that we have more options available.Ramucirumab is a monoclonal antibody against VEGFR-2. This agent was studied in 2 large phase III trials called REACH and REACH-2. REACH was a negative second-line study. In that trial, ramucirumab was compared with placebo.

However, when they looked at a subset group, they found that patients who had alpha-fetoprotein (AFP) greater than 400 ng/mL benefitted from ramucirumab. That's why they conducted the REACH-2 study in patients with AFP greater than 400. That trial was positive; there was an observed improvement in OS [with the agent]. Investigators also did a pooled analysis which showed the same benefit in patients treated with ramucirumab and an AFP greater than 400 ng/mL.

We're waiting for an FDA approval for that drug and we think it will get approved soon. The nice thing is that it's a monoclonal antibody—not a kinase inhibitor—so it seems like there are fewer associated adverse events as well. There will be some portion of patients who will fail first-line therapy, have AFP greater than 400 ng/mL, and who are not candidates for immunotherapy who may benefit from this VEGFR-2 inhibitor.

Right now, we're trying to figure out how to sequence these agents so that patients receive everything. The main question is: what is the role of immunotherapy now? With the negative second-line study [with pembrolizumab], we're hoping the first-line study [with nivolumab] will be positive. We're anticipating those results sometime at the end of this year.

Merck Provides Update on KEYNOTE-240, a Phase 3 Study of KEYTRUDA® (pembrolizumab) in Previously Treated Patients with Advanced Hepatocellular Carcinoma. Merck. Published February 20, 2019. https://bit.ly/2SQ6J45. Accessed February 20, 2019.