Abou-Alfa Highlights Pending Approvals, Sequencing Concerns, and Future Directions in HCC

Ghassan K. Abou-Alfa, MD

The armamentarium in advanced hepatocellular carcinoma (HCC) has undergone rapid expansion in recent years following a significant lull in drug development, said Ghassan K. Abou-Alfa, MD.

"If somebody were to ask me what the standards of care in HCC are, I would ask whether they want them now or tomorrow because things are changing so fast," said Abou-Alfa.

For example, in March 2020, the FDA granted an accelerated approval to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the treatment of patients with HCC who have received prior sorafenib (Nexavar).

The approval was based on data from the phase I/II CheckMate-040 trial (NCT01658878), in which the combination elicited a 33% objective response rate (95% CI, 20-48) that included an 8% complete response rate and a 24% partial response rate.

Notably, 31% of these responses lasted ≥24 months, suggesting the combination may provide durable responses in a subset of patients.

Moreover, other novel combinations with PD-L1 inhibitors, CTLA-4 inhibitors, and VEGF inhibitors that are poised to enter this space may challenge historical sequencing strategies. According to Abou-Alfa, the basic science of HCC, the magnitude of benefit in overall survival (OS) with these regimens, and toxicity profiles will aid in guiding treatment selection.

In an interview with OncLive that took place prior to the nivolumab/ipilimumab approval, Abou-Alfa, a medical oncologist at Memorial Sloan Kettering (MSK) Cancer Center, discussed the most intriguing updates in HCC, anticipated sequencing challenges, and novel modalities on the horizon.

OncLive: What have been the most exciting updates in HCC in recent years?

Abou-Alfa: Many developments have been made [in the past few years]. It started with the FDA approval of sorafenib in 2007, followed by a lot of efforts from our colleagues around the world. We have also seen the introduction of TKIs.

Currently, we have lenvatinib (Lenvima) and sorafenib in the first-line setting. Regorafenib (Stivarga) is approved for patients who received prior sorafenib. Ramucirumab (Cyramza) [is also approved for use in the second-line setting, but in patients who have alpha fetoprotein (AFP) ≥400 ng/mL].

Then, we have cabozantinib (Cabometyx) in the third-line setting. That alone is already 5 treatment options.

Could you discuss research with checkpoint inhibitors in HCC?

In the United States, we have nivolumab and pembrolizumab (Keytruda), which are both anti—PD-1 therapies that are approved in the second-line setting.

We thought [the phase III CheckMate-459 trial] of nivolumab versus sorafenib in the first-line setting and [the phase III KEYNOTE-240 trial] of pembrolizumab versus placebo in the second-line setting would be positive studies. Of course, they were negative. This [sparked interest] in combination therapies with checkpoint inhibitors plus other agents like TKIs, as well as other checkpoint inhibitors. We are eager to see more data.

For example, at the 2019 ESMO Asia Congress, we saw positive data from the phase III [IMbrave150] trial with the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) [in the first-line setting]. We don't yet know the median [overall] survival because it [was not reached]. Nonetheless, we saw a major improvement in outcomes with the combination compared with sorafenib. That alone garnered a lot of interest in other combinations, such as pembrolizumab plus lenvatinib.

We should not forget about dual checkpoint inhibition. This approach is being evaluated in the phase III HIMALAYA study with the combination of durvalumab (Imfinzi) and tremelimumab. We are awaiting those results.

How might the potential approval of these combinations impact sequencing strategies?

With the advent of these therapies—and hopefully more to come—the question of how we pick and choose therapies for patients is undoubtedly going to arise.

As always, [our decisions] will be defined by the science. There’s no doubt that trial cutoffs will play a role. While we are not supposed to compare trials, the regimen [that elicits] the best OS improvement will likely be the [optimal] choice of therapy. We will have to wait and see what that is going to be.

After the science and survival outcomes, the adverse event [profiles of these agents or combinations] will signal what choice we should make. The comfort of the physician and [patient preference] will add to this as well.

A good example of this is the combination of atezolizumab plus bevacizumab because there is a certain toxicity concern for esophageal varices. These can occur in different cancers and can [lead to] bleeding. To be fair, this was not noted to a concerning extent in the [IMbrave150 trial], but prior experience with bevacizumab [suggests esophageal varices could be a potential toxicity]. As such, real-world experience [with bevacizumab] may bring up that concern again.

The other concern we have with this combination regards sequencing other drugs. If atezolizumab/bevacizumab becomes the first-line therapy, where do we put the other TKIs? Perhaps, for example, we skip sorafenib and lenvatinib and move to cabozantinib or ramucirumab in the second-line setting. I doubt we are going to do that because the other agents are very valuable assets.

We are not sure what is going to happen [with the checkpoint inhibitors] because we don't have experience regarding [treatment after] prior exposure to checkpoint inhibition. If we assume patients tolerate therapy but progress, is there potential value for checkpoint inhibitors after exposure to certain TKIs? What about for the patients who did not tolerate [checkpoint inhibitors] the first time? Could we give them another shot?

How might these challenges be addressed?

The good news is we have many drugs. We have 7 drugs approved in the United States with hopefully more to come. While this is great news for our patients, it reminds us that our ultimate goal is cure. Twenty years ago, I would not have brought that word up, but with the science we have, we [can] focus on [finding a] cure.

First, we need prevention. Second, we need advancement in surgery, transplant, and radiofrequency ablation. Finally, we need better delineation, which is evolving quite well with regard to local therapies like chemoembolization, bland embolization, and radioembolization. We have relatively limited experience with radiation therapy. Ultimately, systemic therapy is going to lead to cure.

Could you highlight other promising treatment modalities in the space?

We have a lot of potential for opportunities here. CAR T-cell therapy has some activity, and there are ongoing trials investigating CAR T. The main focus has been regarding certain antigens like AFP. While AFP is worth investigating, we are not going to settle with it. We need other antigens that have yet to be discovered, and MSK is focused on defining those antigens for CAR T-cell therapy.

Could you speak to the importance of a multidisciplinary approach in the treatment of patients with HCC?

We should not forget that HCC [causes] 2 problems in one. [We’re dealing with] the liver cancer itself and the liver functionality or liver condition to begin with. This is why a multidisciplinary approach is critical. We have to recognize and understand the complexity of this disease. Of course, we also have to make sure our patients are aware of the 2 components of their disease.

We need to improve the science [behind HCC] to pin down a potential cure and improve the management of patients’ liver function.

El-Khoueiry AB, Hsu C, Kang YK, et al. Safety profile of nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 40 study. Presented at: 2019 International Liver Cancer Association Annual Conference; September 20-22, 2019; Chicago, IL. Abstract O-13. ilca-online.org/wp-content/uploads/2019/09/ABSTRACTS-2019-min.pdf.