Expansion of First-Line Treatment Options in Unresectable HCC Requires Consideration of High-Risk Disease Features

Reena J. Salgia, MD

The combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) has become one of the standard-of-care, immunotherapy-based regimens for patients with unresectable or metastatic hepatocellular carcinoma (HCC); however, selection between this regimen and alternative checkpoint inhibitor-– or TKI-based options could be determined by a patient’s high-risk features, pointing to the importance of an individualized treatment approach, according to Reena J. Salgia, MD.

Atezolizumab plus bevacizumab previously gained FDA approval in May 2020, for the treatment of patients with unresectable or metastatic HCCwho were not previously exposed to systemic therapy. The regulatory decision was based on the combination’s superior reduction in the risk of death or disease progression vs the TKI sorafenib (Nexavar; HR, 0.58; 95% CI, 0.42-0.79; P = .0006) in the phase 3 IMbrave150 study (NCT03434379).

“It's an exciting time in HCC because of how much the frontline treatment [armamentarium] has expanded in terms of our options for [eliciting] a meaningful clinical response for patients,” said Salgia, a member of the Henry Ford Cancer Institute, the medical director of the liver cancer clinic, and the program director for the gastroenterology and transplant hepatology fellowship at Henry Ford Health in Detroit, Michigan. “Knowing the data, making an informed decision in terms of which treatment regimen would be best for the patient, and thinking about the algorithm as a patient may progress [is key].”

In an interview with OncLive®, Salgia discussed the advantages of utilizing an atezolizumab plus bevacizumab backbone as standard frontline therapy in unresectable HCC; how factors such as Child-Pugh B score, bleeding, and other high-risk features impact treatment selection; and the unmet needs that still need to be addressed for this patient population.

OncLive: Could you briefly highlight the current standard of care for the first-line treatment of patients with unresectable HCC and where the combination of atezolizumab and bevacizumab fits into this landscape?

Salgia: Currently, the first-line standard of care is to initiate immunotherapy, generally as a combination approach, with atezolizumab and bevacizumab for patients who are Child-Pugh A in terms of their liver function, who [typically’ have a good ECOG performance status of 0 to 1, and don't have any clear contraindications to using that regimen. As long as they don't have any high-risk varices, a history of recent bleeding from varices, portal hypertension—related bleeding, prohibitive hypertension, or any significant autoimmune condition, this is generally the route that we would go.

How might your approach to treatment change for patients with high-risk disease features or a Child-Pugh B score?

That's a scenario that we do encounter. If patients have Child-Pugh B liver dysfunction at the onset [of therapy], we would typically initiate TKI-based therapy. Multi-kinase inhibitors such as lenvatinib [Lenvima] and sorafenib are our go-to choices. The decision between those 2 is based on any adverse effects [AEs] from the medication that could be prohibitive to the use of 1 drug over the other or make 1 more favorable than the other.

What differentiates atezolizumab plus bevacizumab from other treatment regimens in the frontline setting?

Compared with some of the other regimens, we don't exactly know the magic behind why atezolizumab and bevacizumab is the combination that showed the best overall survival [OS] results and statistical significance vs the comparator arm [in clinical trials]. However, the combination of an anti–PD-1 therapy and a VEGF inhibitor seems to have been most favorable with the atezolizumab plus bevacizumab [regimen] compared with durvalumab [Imfinzi] and tremelimumab [Imjudo], or even pembrolizumab [Keytruda} and lenvatinib.

We [currently] don't have enough biomarker evidence to guide our decision making [in this space], but statistically, this combination [of atezolizumab and bevacizumab] seemed to outperform the comparator of sorafenib. Notably, we don't have head-to-head data of comparing 2 different checkpoint inhibitor–based regimens. In this case, [it would be great] if we had the opportunity to compare the regimen from IMbrave150 with the phase 3 HIMALAYA trial [NCT03298451] regimen [of durvalumab plus tremelimumab], but at this point, we don't have those data.

What is the prevalence of bleeding events in the real-world setting for patients with advanced HCC? How is bleeding mitigated or managed in these patients?

The presence of esophageal varices is quite common in patients with underlying cirrhosis. Generally, we think of that risk increasing over time as one's liver dysfunction progresses. If we focus on our Child-Pugh A population, the risk of varices is large and clinically significant, [and] portal hypertension is not 100%. [Accordingly], we consider performing an endoscopy for all patients with cirrhosis at the time of diagnosis, and then ideally within 3 years or every 3 years after that to determine the presence of varices. If a patient does have large varices with any high-risk features that suggest a higher risk [of bleeding], such as red wale signs, we would think that bevacizumab use is going to be contraindicated in those patients or put them at prohibitive risk.

What unmet needs still need to be addressed for in the frontline setting for patients with unresectable HCC?

Having some head-to-head data for different checkpoint inhibitor–based regimens would certainly be beneficial to the field, especially if we [need] to decide which regimen would be best for the individual patient in front of us. Currently, we're [making this decision] based on the significance of the data and the statistical results. Beyond that, there are likely preferences based on the patient's unique tumor characteristics [as well as] biomarkers that would hopefully be relevant in the future. [The biomarkers] would allow us to tie the best regimen to their individual tumor. Importantly, [we need] more opportunities for our Child-Pugh B patient population, particularly those who are early Child-Pugh B.

As we see more and more patients moving forward with treatment, specifically with checkpoint inhibitor therapy, a number of patients will progress from [categorization as] Child-Pugh A to B, or potentially start off as Child-Pugh B and change to Child-Pugh A on treatment. [It is therefore important to] understand what our options are in that space to utilize checkpoint inhibitor therapy if they are Child-Pugh B.

Lastly, [we need to improve] understanding of whether use of checkpoint inhibitor–based therapy in the frontline can be followed with any regimen of a similar mechanism in the second line, [and if that will] offer clinical benefit and efficacy. [Those] data will hopefully mature in the future, [providing us with] more answers to how we can consider that.

What continued developments in the frontline treatment of patients with HCC are coming down the pike?

Another exciting thing that we're encountering is [that] patients who do have an objective response to frontline therapy may be considered in the future for locoregional therapies or potentially surgical resection, and the "holy grail" of potentially being considered for liver transplant. [This is becoming increasingly feasible as] we gain more data on and a better understanding of how to position treatments, such as checkpoint inhibitors, followed by surgical options like liver transplant or even resection.

Reference

FDA approves atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. News release. FDA. May 29, 2020. Accessed November 1, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-plus-bevacizumab-unresectable-hepatocellular-carcinoma