Research Shifting to Explore Combinations for Treatment of Advanced HCC, Expert Says

In an interview with <em>Targeted Oncology</em>, Llovet discussed the positive results from the REACH-2 trial and how its results are shaping future combinations therapies for the treatment of patients with advanced HCC.

Josep M. Llovet, MD

Now that several single-agent tyrosine kinase inhibitors (TKIs) have been ingrained as standards of care treat patients with hepatocellular carcinoma (HCC) in the first- and second-line settings, the next wave of research is shifting and single agents will become a thing of the past, according to Josep M. Llovet, MD.

“Now, we're finishing a period of single-agent [therapies] and moving to the next phase, which is combination therapies…. I think we're moving to the next 5 years where we will see combinations of agents in frontline and second line,” said Llovet, professor of medicine at the Mount Sinai School of Medicine, New York University.

One such TKI that Llovet expects to be explored in combination therapies in the future is ramucirumab (Cyramza), which wasapproved by the FDA for the treatment of patients with HCC who have an alpha-fetoprotein (AFP) &ge;400 ng/mLin May 2019.

The approval was based on the results of the phase III REACH-2 trial (NCT02435433), a follow-up study to the unsuccessful REACH trial (NCT01140347),1which showed a significant survival benefit with ramucirumab versus placebo for the second-line treatment of patients with (HCC) and elevated AFP in the second line, meeting the primary endpoint of the study.2

In 2015, the double-blind, multicenter phase III trial of ramucirumab plus placebo as second-line treatment for patients with HCC (REACH) did not show a significant improvement in overall survival in the ramucirumab cohort compared to the placebo group. In REACH-2, researchers followed the REACH methodology having patients aged 18 years older with HCC Barcelona Clinic Liver Cancer (BCLC) stage B or C randomized to receive either ramucirumab (8 mg) or placebo plus the best supportive therapy (8 mg), every 2 weeks. The primary endpoint for REACH-2 was overall survival (OS); however, unlike in the REACH trial, the researcher set secondary endpoints which included progression-free survival (PFS) and objective response rate (ORR).

The findings showed a median OS of 8.5 months in the ramucirumab arm versus 7.3 months for placebo (HR, 0.710; 95%, CI 0.531-0.949;P= .0199).

Patients who received ramucirumab also had a better PFS rate compared with placebo (2.8 vs 1.6 months; HR, 0.452; 95% CI, 0.339-0.603;P<.0001). The final secondary endpoint, ORR, was 4.6% in the ramucirumab group versus 1.1% in the placebo group.

With data showing that ramucirumab is beneficial for patients with advanced HCC, Llovet believes that the drug will now be explored in combinations with another TKI, a checkpoint inhibitor, or with a TGF-beta inhibitor in future clinical trials.

In an interview withTargeted Oncology, Llovet discussed the positive results from the REACH-2 trial and how its results are shaping future combinations therapies for the treatment of patients with advanced HCC.

TARGETED ONCOLOGY: Can you discuss the 2 studies on ramucirumab versus placebo in patients with advanced HCC?

Llovet: Nowadays, for the management of advanced-stage HCC, we have 5 drugs. In the frontline, we have sorafenib (Nexavar) and lenvatinib (Lenvima), and in second-line we have regorafenib (Stivarga), cabozantinib (Cabometyx), and ramucirumab.

Ramucirumab is [FDA-approved] as a result of 2 randomized controlled trials. The first randomized controlled trial is REACH, and the trial was negative comparing ramucirumab versus placebo in all patients. Then, in a subgroup analysis of patients with high AFP, that means patients with aggressive tumors, it seems that ramucirumab showed a signal of efficacy. As a result of that, the company designed a second trial that is called REACH-2.

REACH-2 was positive, suggesting that ramucirumab has significantly better survival compared with placebo. Then there was a meta-analysis of the 2 studies, [it included] the subgroup analysis of AFP-high and the full trial. The overall results are as follows: The median survival for [patients who received] ramucirumab was 8 months. For placebo, it is was 5 months. The hazard ratio was 0.71. As a result of that, ramucirumab is now one of the standards of care of second-line therapies in advanced HCC, only for patients with aggressive tumors with an AFP more than 400.

TARGETED ONCOLOGY: How would you characterize the impact of these studies on the paradigm?

Llovet: The 3 drugs we have in the second-line [each] have different characteristics. We have regorafenib, which is only indicated for patients who can tolerate sorafenib in the frontline. It's an important drug but it can also cause some adverse events. Then, we have cabozantinib, which works better in [certain] subgroup analyses, and is a MET inhibitor and VEGF inhibitor. Then, we have ramucirumab that only works for patients with AFP more than 400 and has a specific adverse events profile. The other TKIs have the classic adverse effects [such as]; fatigue, diarrhea, hand-foot skin reaction, and hypertension. Ramucirumab mostly has hypertension as the most important adverse event. So, it has a specific adverse event profile that may, in some patients, be critical to select which is the second-line option.

TARGETED ONCOLOGY: Will any other studies explore ramucirumab in other settings?

Llovet: In HCC, at this point, the plan is to explore combinations with checkpoint inhibitors, or eventually as a triplet combination. As you know, we now have the frontline populated with several trials in combination.

[For example], we have pembrolizumab (Keytruda) plus lenvatinib, cabozantinib and pembrolizumab. We also have atezolizumab (Tecentriq) plus bevacizumab also in the frontline. We have the HIMALAYA trial (NCT03298451), and a lot of other trials.

Ramucirumab will probably move ahead with a different strategy, not only in a combination with a checkpoint inhibitor, [but also with] another TKI or with a TGF-beta inhibitor.

TARGETED ONCOLOGY: Can you discuss the phase II trial with namodenoson as second-line treatment in patients with Child-Pugh B advanced HCC?

Llovet: The beauty of this study is that the mechanism of action with the drug is still unknown. [It’s focused on] patients with Child-Pugh B (CPB)—Child-Pugh is a classification that describes the process of liver failure. HCC develops in cirrhotic patients in 90% of cases, and some of the patients may have very advanced liver failure. So, Child-Pugh A (CPA) means good liver function, CPB means bad, and Child-Pugh C means the liver function is very bad and the patient needs a transplant right away.

All the drugs have been tested in CPA patients, or patients with good liver function. Now, what we are seeing is that patients who have CPB and also have HCC don't even have a frontline therapy. Most of the TKIs are toxic in these patients. [Namodenoson] has a good safety profile first of all. Secondly, the suggestion is targeted only among CPB patients with more persevered liver function. [The drug] also has a signal of efficacy in this group of patients with CPB 7. The median survival is 6.8 months compared to 4.3 months [with placebo]. We're talking about second-line and very bad liver function and in this scenario, [the results] may be a signal to move ahead in a phase III trial.

TARGETED ONCOLOGY: What does all the new research tell you about the future of HCC?

Llovet: We cover several different stages. The first stage was when we had no systemic therapy, Then, in 2007, I presented at ASCO an abstract of sorafenib, [which] was the first drug and it has been, [around] for 10 years. Now in the last 2 years, we got these 5 new drugs. Now, we're finishing a period of single-agent [therapies] and moving to the next phase, which is combination therapies. Forget about single-agents. It will be very weird to have single agents, at least for the conventional frontline and second-line therapies. Now the bar has been [raised], you have to heed good outcomes to beat the drugs that are currently approved.

I think we're moving to the next 5 years where we will see combinations of agents in frontline and second-line.

TARGETED ONCOLOGY: Is there any recent research on HCC that shows we&rsquo;re heading in this new direction?

Llovet: There are 2 abstracts that are very interesting. One is the trial with pembrolizumab versus placebo in the second-line. This abstract is interesting because it is the first time that we have a clinically positive study that has been negative because of the trial design—statistically the trial is negative, but in terms of clinical results it is positive. In second-line, you have 10.8 months for placebo and 13.6 months for pembrolizumab—a 3-month difference. This speaks to how we should design trials. We should be conservative in terms of not having so many co-primary endpoints or slashing the alpha with interim analysis. This is what happened with this trial. Still, the FDA is holding this approval, so it's approved in the second-line in the United States, but not in Europe. We'll have to see what happens with pembrolizumab.

The second abstract is a poster [looking at] the combination of 2 checkpoint inhibitors, nivolumab (Opdivo) and ipilimumab (Yervoy). It's a small study and the cohort that shows exciting results included 50 patients. The objective response rate was 32% and the median survival was 23 months. So, it's [great] data and I think we need to follow-up on this.


  1. 1) Zhu AK, Park JO, Ryoo B, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial.Lancet Oncol. 2015;16(7):859-870. doi: 10.1016/S1470-2045(15)00050-9.
  2. 2) Zhu AX, Kang Y, Yen C, 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.J Clin Oncol. 2018;36(suppl; abstr 4003)