Bekaii-Saab Breaks Down Approach for Navigating Among Available Options in HCC

The emergence of novel agents in the hepatocellular carcinoma (HCC) treatment paradigm in recent years has somewhat complicated treatment and sequencing decisions, according to Tanios S. Bekaii-Saab, MD, FACP, but as more phase 3 data come to light, navigating among the options available will become easier.

“When we think about all these first-line options, the question that now comes to mind is: ‘How do I pick my second-line therapy?’ asked Bekaii-Saab, leader of the Gastrointestinal Cancer Program at the Mayo Clinical Cancer Center. “We have several options available in the second-line setting and they all came on the heels of sorafenib (Nexavar). We don't have much data that informs us about what to do following atezolizumab (Tecentriq) and bevacizumab (Avastin). As such, we need to go with what we have.”

The combination of atezolizumab plus bevacizumab is the standard frontline treatment for patients with HCC, according to Bekaii-Saab. For the second-line setting, the choice is between cabozantinib (Cabometyx) and regorafenib (Stivarga), although both appear to be viable options, said Bekaii-Saab.

In the third-line setting, limited data are available, as the majority of patients do not reach this line of treatment. For those who do, depending on whether they received cabozantinib or regorafenib in the second line, they could receive the other agent in the third line. “You could also argue that this may be a reasonable place for ipilimumab (Yervoy) and nivolumab (Opdivo), if patients were exposed to a TKI in the second-line setting,” noted Bekaii-Saab.

In an interview with OncLive, Bekaii-Saab, who is also medical director of the Cancer Clinical Research Office, the vice chair, and section chief for Medical Oncology in the Department of Internal Medicine at Mayo Clinic, discussed the rapidly changing HCC treatment landscape and shared advice on how he navigates among the options available for these patients.

OncLive: Could you shed light on first-line combinations therapies currently under investigation in HCC?

Bekaii-Saab: For the longest time we've had 2 agents, sorafenib and lenvatinib (Lenvima). Sorafenib was the first to be approved in 2007, and then it took more than a decade to have the second agent approved in the first-line setting based on a phase 3 noninferiority study. I won’t spend much time on those agents because they are relatively equivalent in terms of activity, although they do have different toxicity profiles.

With the data on the [combination of] the PD-L1 inhibitor atezolizumab and the VEGF inhibitor bevacizumab, 2 agents that have been commonly used in other malignancies, we see that outcomes have been significantly improved versus sorafenib alone. Now, that replaces the discussion on the single-agent TKIs. [These data] also come at the heels of 2 negative trials with nivolumab, in the first-line setting, and pembrolizumab (Keytruda), in the second line, which was a major setback for the role of immunotherapy [in this space]. Overall, [the success seen with] this combination reinvigorates the whole discussion about immunotherapy and where this approach stands in terms of treating patients with HCC.

The question now is, “Can we enhance this [benefit] further in the first-line?” Several studies are underway. For example, there is COSMIC-312 trial, which is looking at cabozantinib in combination with atezolizumab. Then, there is the LEAP study, which is looking at lenvatinib plus pembrolizumab. Other studies are looking at immune checkpoint inhibitors in combination. The CheckMate-9DW trial is examining ipilimumab plus nivolumab in the first-line setting versus sorafenib or lenvatinib. Also, the HIMALAYA trial is looking at durvalumab (Imfinzi) and tremelimumab versus sorafenib; it is a 4-arm study with different dosages. This is becoming quite an area for drug development.

Unfortunately, all these studies are comparing the experimental doublet versus sorafenib or sorafenib and lenvatinib. Even when we have the results of these studies, and they should all read out in the next couple of years, we will unfortunately not learn whether any of these combinations will replace atezolizumab and bevacizumab in the first line.

This is the challenge: All these studies are running in parallel or somewhat in parallel. These are important because when we saw some of the failures with single-agent nivolumab and pembrolizumab, the question was, “Can we enhance the activity of a single-agent PD-1 inhibitor or a single-agent immune checkpoint inhibitor?” The answer goes back to basic science and the understanding of what can enhance that immune milieu in a way that makes it more favorable for recruiting more T-cells or facilitating some of these agents to have that effect at the local level.

Could you discuss the role of VEGF in the first-line treatment landscape?

It turns out that, if you block VEGF, you essentially enhance the activity significantly. Now, whether it's cabozantinib or lenvatinib, both agents actually have anti-VEGF activity. Cabozantinib targets MET in addition to VEGF and others. Lenvatinib hits FGFR in addition to VEGF. These agents are a little different in terms of their reach. Whether these additional hits will enhance the activity further is unknown, as is whether it matters to go beyond VEGF. We assume that the improvement has been primarily because of VEGF. At this point in time, even if those studies turn out to be positive, in order for them to change the landscape, there's quite a burden of proof that is needed to showcase these agents in combination to move beyond atezolizumab and bevacizumab.

With immunotherapy, has the focus shifted away from single-agent approaches to dual inhibition?

With the other combinations—ipilimumab plus nivolumab and durvalumab plus tremelimumab—we are asking a different question. Rather than asking the question of VEGF plus X, we are asking the question of dual immune checkpoint inhibitor with a PD-1 inhibitor for of PD-L1 inhibitor plus a CTLA-4 inhibitor. The thought is that doubling up on the immune checkpoint inhibition would further enhance the activity of the singlet. We've seen some data during the 2020 ASCO Virtual Scientific Program with durvalumab and tremelimumab that looked interesting, with a response rate that's approximately 20% to 23%. This is interesting enough, but not incredibly impressive.

Single-agent data with nivolumab and ipilimumab led to an accelerated approval in the second-line setting; [these agents also induced] high response rates. All in all, these studies are telling us that there will probably be more than 1 option for patients with HCC. The question is, “How do we choose one over the other?” Today, our standard is atezolizumab plus bevacizumab in the first-line setting and that has essentially displaced single-agent sorafenib and lenvatinib.

What are some of the second-line treatment approaches that are under investigation?

Today, the options in the second-line setting are regorafenib, cabozantinib, and ramucirumab (Cymraza), if [the [patient’s] alpha-fetoprotein is greater than or equal to 400 ng/mL. Then there is ipilimumab and nivolumab, as well as pembrolizumab, based on an accelerated approval. Some argue that sorafenib and lenvatinib could potentially move to the second-line setting. I would argue that, at this point in time, we don't have enough data to support sorafenib or lenvatinib beyond the first-line setting. As such, I don't consider them as options.

The main question is: “Is pembrolizumab, even in the running after the negative phase 3 KEYNOTE-224 study?” The answer is no; that study was negative, and it seals the deal. Pembrolizumab was shown to be no better than placebo, so that eliminates one option to choose from.

How about ramucirumab [in patients with] alpha-fetoprotein of more than 400 ng/mL? The challenge with this is, following exposure to an agent like bevacizumab, which is a pure VEGF inhibitor, is the pure VEGFR2 inhibitor ramucirumab going to be able to pull activity? The answer is that this is unlikely. Pure VEGF[R2], following VEGF, may have its own challenges. I'd say ramucirumab falls [to the wayside] at this point in time and may not continue to be an option anymore following atezolizumab and bevacizumab.

Now what about lenvatinib? I believe this agent suffers the same fate that ramucirumab does. Lenvatinib is a very potent VEGF inhibitor with less activity across other targets, and so it becomes less favored. So now we’re left with sorafenib, regorafenib, cabozantinib, and then ipilimumab and nivolumab. The question for ipilimumab and nivolumab is, “Can we justify using another immunotherapy combination, following the failure of atezolizumab and bevacizumab?” The answer is, we just don't know. It’s very difficult to justify that. Because we do not have phase 3 data on any dual immune checkpoint inhibitors, I would not consider it.

It ends up being regorafenib or cabozantinib. I'd say sorafenib is a non-player since regorafenib has established itself in the second-line setting and it's likely to be at least as effective as sorafenib. One can argue, perhaps, that [regorafenib] a little better than sorafenib. My decision making has become much simpler now; I have atezolizumab plus bevacizumab in the first-line setting and my second-line is limited to either regorafenib or cabozantinib. These are the primary agents of choice.

Now, how do you choose between them? There are not much data to inform you. Some folks have been favoring regorafenib, while others favor cabozantinib. I think you're justified to use one or the other, but these would be the 2 agents of choice, following atezolizumab plus bevacizumab.

There's one pathway, I should say, for patients who may not be eligible for atezolizumab plus bevacizumab. Let's say someone gets exposed to lenvatinib or sorafenib in the first line, the second line is going to be wide open for all these options. However, those are patients are rare. We're going to do everything possible to expose our patients to first-line atezolizumab plus bevacizumabbecause of the strength of the data.

What is your approach for the third-line setting?

For the third-line setting, [understanding how to proceed] is quite complicated because very few patients will make it to the third line. However, if they do, and they received regorafenib in the second-line setting, they can receive cabozantinib in the third-line setting. Conversely, if they got cabozantinib in the second line, then they could receive regorafenib in the third line.

That’s how I look at the landscape, in a simplified way with this clutter of agents, until we see more data from ongoing phase 3 studies. The challenge, of course, is how do we study second line at this point in time following atezolizumab plus bevacizumab? This is going to be our next challenge and focus for research.