Frontline Therapy Selection in HCC Hinges on Bleeding Risk and Patient-Specific Factors

The selection of frontline systemic therapy for patients with unresectable hepatocellular carcinoma (HCC) requires careful consideration of patient-specific factors, particularly in the context of cirrhosis and complications such as bleeding, according to Mohammed Najeeb Al Hallak, MD, MS.

For patients without significant bleeding risk, he explains that atezolizumab (Tecentriq) plus bevacizumab (Avastin) remains a preferred first-line option. However, Al Hallak cautioned that the antiangiogenic properties of bevacizumab can elevate bleeding risk, particularly in patients with active or high-risk esophageal varices. Conversely, he noted that durvalumab (Imfinzi) plus tremelimumab (Imjudo) is another frontline approach that does not carry an increased risk of bleeding.

“Because [HCC] is a very unique cancer in a very unique organ, we cannot say [there is] a one-size-fits-all [regimen in the frontline setting].” Al Hallak explained.

In the interview with OncLive®, Al Hallak discussed the evolving landscape of frontline therapy for HCC, key considerations for treatment selection, and strategies for patient monitoring and diagnosis. Al Hallak serves as a hematologist/oncologist at the Karmanos Cancer Institute at Wayne State University in Detroit, Michigan.

OncLive: What are some of most recent advancements in the first-line treatment setting for unresectable HCC?

Al Hallak: It's an exciting time for HCC treatment because we have seen emergent first-line treatments [arrive] in the past 5 years, starting with [the combination of] atezolizumab with bevacizumab, then we had the tremelimumab [plus] durvalumab combination. Those are the two approved combination in the first-line [setting] as far as immunotherapy.

Now, we have other data showing that the dual checkpoint inhibitor [regimen] using ipilimumab [Yervoy] and nivolumab [Opdivo\ is also active in this setting; [however, this is still awaiting potential] FDA approval. Other combinations tested outside the United States, mostly in Asia, have also shown promising activity by combining immunotherapy with an oral TKI.

When a patient presents with advanced HCC, what factors do you consider when selecting treatment?

[This decision] is very individualized, case by case. [We] need to see the patient, examine the patient, and [complete] several tests, including blood tests, to check their liver function. What bulk of the disease do they have? Has it metastasized outside the liver, or is it [confined] to the liver? How is their portal vein patency?

The durvalumab and tremelimumab combination vs the atezolizumab with bevacizumab combination are usually the two main [treatment considerations in the frontline setting]. However, some patients are not eligible for [either] of those two, and we'll have to go back and use an oral TKI like lenvatinib [Lenvima]. I have not used sorafenib [Nexavar] for a long time, but it's still an available option in the first-line setting.

How can a patient's comorbidities affect treatment decisions?

Cirrhosis is a major problem, [and it is important for us to understand] what happened due to the cirrhosis, such as the development of] portal vein hypertension, esophageal varices, or potential bleeding. Usually when I see a patient who has active esophageal varices bleeding, especially despite several [attempts at] banding, this is not a good patient to give a bevacizumab[-containing regimen]. For those patients, I would go straight to the durvalumab and tremelimumab combination.

In my practice, I feel like durvalumab/tremelimumab treatment is easier to manage as a combination for most patients with HCC, just because there is really no risk of bleeding associated with this regimen compared [with] the bevacizumab [regimen], which [necessitates more careful patient selection]. When you select that [option], you have to [complete] an EGD for those patients prior to starting treatment to study their esophageal vertices status [and see if] they need any banding.

[With durvalumab/tremelimumab], we don't really need to do an EGD for patients when we start them on treatment. That actually makes it easier [for patients] to start treatment [sooner]. They don't have to wait another month for the EGD prior to starting treatment. [Treatment selection is] case by case, and that's how I [am using these agents] in my practice.

What key advice would you offer to community oncologists regarding the recognition and diagnosis of HCC?

Patients with hepatitis B and C, even if they are treated, if they have cirrhosis, they need to be followed. This is a common mistake I've seen in my practice when I see those patients with hepatitis C. They get the treatment for hepatitis C and they are cured, so they think they are safe from developing HCC. However, this is a very [common] misconception, because if they develop cirrhosis, even if they treat the hepatitis C with curative treatment, they [remain] at risk in the future for developing HCC because of the cirrhosis. When you treat hepatitis C, you slow the progression of the cirrhosis, but you do not [completely] [eliminate] the [risk of] HCC [developing].

Other reasons for cirrhosis can [include] metabolic disorders or fatty liver disease. Those patients will have cirrhosis over [the course] of their life, and it's going to progress slowly over the years. Therefore, general practitioners, gastroenterologists, and hepatologists [must] pay attention to those patients and monitor them closely.

If [a patient has] cirrhosis, [they] need to continue to be monitored with ultrasound and MRI, etc. It depends on the case to monitor for those nodules that are developing in the cirrhosis. A lot of them are usually not cancerous, but they can develop into cancer in the future, and giving careful consideration to the imaging is important.

What is the value of multidisciplinary care in the management of HCC?

HCC is one of those complex cancers we deal with in gastrointestinal [oncology]. For us, almost all cases go [before] a tumor board for discussion. In the tumor board, we will have [several] medical oncologists, surgeons, interventional radiologists, diagnostic radiologists, hepatologists, and pathologists to discuss [how best to proceed in each] case.

We spend usually 10 to 15 minutes [discussing each] HCC case because they are very unique. Patients can be cured in some cases, and they cannot be cured in other cases. [However], if they're not cured, we have [other] ways to approach them. We have the liver-directed therapy approach, for example, with liver embolization. [There is] also ablation with cryoablation or micro-ablation. There are different treatments in every setting, and [we] have to decide what is the best one for this [specific] patient.

We can talk about surgery [during the tumor board]. [Determining whether] it's localized disease and resectable, [and whether patients are candidates for] liver transplant is a very complex decision.

If none of those options are fit for a patient, then we talk about systemic treatment. This is where the medical oncologists come to give their opinion on which regimen would be better: the tremelimumab/durvalumab combination, the atezolizumab/bevacizumab combination, or other oral TKIs. This is where the hepatologist [assessed] the liver function and calculates the Child-Pugh score for this patient.

What agents are you most looking forward to seeing potentially gain FDA approval within the HCC space?

The combination of ipilimumab with nivolumab [has the potential to] get approval from the FDA. This has been an important combination that has proved that dual checkpoint inhibitors work for this disease. It's not the first [dual checkpoint inhibitor combination]. as you know, with tremelimumab and durvalumab being the first. However, ipilimumab plus nivolumab coming here is helpful to confirm that [durvalumab/tremelimumab] was not just the only combination [of this kind to show efficacy] in HCC.