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 HCC

who 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; 

 = .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].”

®, 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.

: 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?

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.

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

Articles

Reena J. Salgia, MD, discusses 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.

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

Treatment with IO–based combination regimens or single-agent TKIs in the first-line setting fo advanced, unresectable hepatocellular carcinoma (HCC).

Dr Li on Frontline Treatment Considerations With IO-Based Combinations in Unresectable HCC

Daneng Li, MD, associate professor, Department of Medical Oncology & Therapeutics Research, co-director, Neuroendocrine Tumor Program, City of Hope, 

discusses considerations when choosing between treatment with immuno-oncology (IO)–based combination regimens or single-agent TKIs

 in the first-line setting for patients with advanced, unresectable hepatocellular carcinoma (HCC), highlighting which patient and disease factors influence these decisions.

The IO-based combinations of atezolizumab (Tecentriq) plus bevacizumab (Avastin) and durvalumab (Imfinzi) plus tremelimumab (Imjudo) are both approved by the FDA for the first-line treatment of patients with unresectable HCC; however, there has not yet been a head-to-head comparison between these two regimens, Li begins. Selecting between these 2 treatments depends on several factors, he states. In the phase 3 IMbrave150 trial (NCT03434379), the combination of atezolizumab and bevacizumab elicited an overall response rate (ORR) of 27.3% (95% CI, 22.5%-32.5%) in patients with unresectable HCC. Conversely, in the phase 3 HIMALAYA trial (NCT03298451), treatment with the combination of durvalumab and tremelimumab led to a 20.1% ORR in this population. In situations where patients present with bulky tumors or significant symptoms, a treatment associated with a higher ORR may be considered, he notes, adding that this strategy aims to reduce tumor size and potentially improve patients' well-being early in the treatment phase.

Furthermore, for patients with specific comorbidities, such as a history of variceal bleeding, extensive varices at high risk of bleeding, prior stroke or other thrombotic events, or poorly controlled hypertension, a treatment that does not target the VEGF pathway is advisable, he expands. In such cases, the use of dual immune checkpoint inhibitors, such as durvalumab plus tremelimumab, becomes a suitable option, Li says.

Patients with contraindications to immunotherapy may benefit from oral TKIs, making those a reasonable alternative to immunotherapy, he emphasizes. When treating patients with bulkier tumors and seeking a higher ORR, considering lenvatinib (Lenvima) instead of sorafenib (Nexavar) is prudent, given that lenvatinib is associated with a notably high ORR, Li continues.

Ultimately, the decision-making process between different frontline regimens revolves around individual patient considerations, including tumor size, symptoms, specific comorbidities, and contraindications to certain treatments, he says. Tailoring the treatment to suit the unique medical profile of each patient is pivotal for achieving the best possible outcome, Li concludes.

Videos

Daneng Li, MD, discusses considerations when choosing between treatment with immuno-oncology-based combination regimens or single-agent TKIs in the first-line setting for patients with advanced, unresectable hepatocellular carcinoma, highlighting which patient and disease factors influence these decisions.


FDA approval of atezolizumab (Tecentriq) plus bevacizumab (Avastin

) for the treatment of patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy,

 the combination has become a staple in the standard of care of this patient population, and ongoing studies are examining the addition of other agents to this backbone with the goal of continuing to improve outcomes for this patient population, according to Daneng Li, MD.

“The regimen of atezolizumab plus bevacizumab is building on the backbone of having 2 mechanisms of action. On the one hand, you are inhibiting VEGF and inhibiting angiogenesis, which we know can potentially cause an immune suppressive environment, and then combining it with an antibody against the PD-1/PD-L1 pathway to stimulate immune cells to create that synergistic effect for our patients,” Li said. “The dual mechanism tries to help to penetrate the tumor and [generate] a response against the tumor.”

, Li discussed the current options available for the frontline treatment of patients with unresectable HCC, discussed the factors to consider when selecting a treatment regimen for this patient population, highlighted how Child-Pugh B score and bleeding could affect these decisions, and detailed ongoing research using the atezolizumab/bevacizumab backbone in novel combinations. Li is an associate professor in the Department of Medical Oncology & Therapeutics Research and co-director of the Neuroendocrine Tumor Program at City of Hope, in Duarte, California.

: Where does atezolizumab/bevacizumab fit into the current standard of care for the first-line treatment of patients with unresectable HCC?

: The current landscape in terms of first-line treatment for patients with unresectable HCC is broken down in terms of the immunotherapy combination regimens vs TKIs. For the immunotherapy combination regimens, we have the combination of atezolizumab and bevacizumab, which demonstrated an improvement over sorafenib [Nexavar] in the phase 3 IMBRAVE 150 study [NCT03434379] in terms of overall survival, progression-free survival [PFS], and objective response rate [ORR].

For patients who usually would not be eligible for [atezolizumab/bevacizumab], we have another regimen, which is a combination of dual immune checkpoint inhibitor therapy with durvalumab [Imfinzi] plus tremelimumab-actl [Imjudo]. For whatever reason, if a patient is not eligible for any type of immunotherapy [due to] concerns with prior liver transplantation or autoimmune conditions, we still have oral TKIs, whether that is with lenvatinib [Lenvima] or sorafenib the first-line setting.

What are some of the factors you consider when selecting between these frontline regimens?

For the 2 immunotherapy combination regimens, they haven't been compared head-to-head; both are truly options for our patients. The decision to select either of them depends on certain things. Certainly, the ORR was high with the combination of atezolizumab/bevacizumab, with an ORR of 30% [(95% CI, 25%-35%) in updated data from IMbrave150]2 compared with the combination of durvalumab plus tremelimumab, which had an ORR of 20.1% [in the phase 3 HIMALAYA trial (NCT03298451)].

 Sometimes, for patients who have very bulky tumors or are quite symptomatic, you might consider using a treatment that maybe has a higher ORR to try to shrink those tumors to potentially help patients feel a bit better.

Additionally, if patients have certain comorbid medical conditions, such as a history of variceal bleeding, extensive varices that are at high risk of bleeding, a history of stroke or other thrombotic events, or poorly controlled hypertension, then you may want to consider a treatment that is not targeting the VEGF pathway. This is where dual immune checkpoint inhibitors with durvalumab plus tremelimumab makes a lot of sense.

For anyone who has any contraindication to immunotherapy, the oral TKIs, whether it's lenvatinib or sorafenib, would make sense. If a patient [with contraindications to immunotherapy] has a bulkier tumor and you're looking for a higher ORR, consider lenvatinib over sorafenib, given the fact that lenvatinib has a high ORR.

When patients have a Child-Pugh B score, is that a factor that goes into making treatment decisions?

There are not as much data for patients who are Child-Pugh B. What we know is that there are data with single-agent immune checkpoint inhibitors. In cohort 5 of the phase 1/2 CheckMate 040 trial [NCT01658878] with single-agent nivolumab [Opdivo], data showed that it was found to be safe and potentially efficacious in patients who were Child-Pugh B in that setting.

A lot of our data in patients with a Child-Pugh B score arises from the use of TKIs. [This includes] data for sorafenib from the [observational] GIDEON registry study that showed there was [positive] data in terms of safety and efficacy. There have been some subgroup analyses of safety and efficacy for other agents such as lenvatinib for patients who have transitioned from Child-Pugh A to Child-Pugh B, and it appears that there was some continued efficacy. However, some of these patients may have slightly increased risk of toxicity, as we anticipate for patients who potentially have liver dysfunction.

In terms of these various treatments for patients who are Child-Pugh B, it depends on what is causing the Child-Pugh B status. Is it due to disease? If it's due to disease, then potentially, as you control the disease, Child-Pugh status could improve, so that's something to consider. Or is [Child-Pugh status] due to underlying cirrhosis? If it's due to the underlying cirrhosis and a treatment doesn't have much data in the Child-Pugh B population, then maybe you need to take a step back and ask if that going to be potentially safe for that population.

How prevalent is bleeding within patients with unresectable HCC? What are some of the strategies used to mitigate and manage bleeding for these patients?

Bleeding risk is always something that we consider in our patients with HCC. It depends on the underlying degree of cirrhosis, tumor burden, or whether they have extensive portal obstruction or backup of the portal system that causes increased risk of development of varices. On clinical trials for patients who were treated with atezolizumab plus bevacizumab, the risk of very serious bleeding was low. When talking about bleeding from the GI tract, for example, it was [less than 1%] in those patients. What this tells you is that in the correct setting, if patients are managed with endoscopic surveillance and treated if they do have varices, then you can minimize potential bleeding risk.

What this means is that vigilance really matters. In any [patient] who is going on [atezolizumab/bevacizumab], we always perform upper endoscopy prior to the start of treatment no matter what. Depending on what we find—for example, if a patient has higher-risk varices—then they need to be treated, whether it's with beta blockers or endoscopic banding, and then they continue to have follow-up surveillance.

Many of our patients continue to have follow-up esophagogastroduodenoscopies to monitor for these varices to prevent these bleeding episodes. Yes, [bleeding] does happen, but it does happen in a subset of patients. In addition to that, if you have mitigation factors in play, then you can really minimize the risk of potential serious bleeding.

Given the different frontline treatment options available for patients with unresectable HCC, what unmet needs still remain to be addressed for this patient population?

We've made big strides in this area for our patients with unresectable HCC. In the past 3 to 5 years, we have been able to make key advances to improve survival in this patient population. However, at the end of the day, there is only a certain subset of patients that is responding to the treatments that we currently have.

How do we develop more therapies where more and more patients are able to respond to treatment and not only live longer, but also live better? One area [of exploration] is building on the backbone of the treatments that we have, such as atezolizumab plus bevacizumab, or even durvalumab plus tremelimumab.

For example, this past year, we shared data of the combination of atezolizumab and bevacizumab plus an anti-TIGIT antibody known as tiragolumab. In the initial phase 1b study [NCT04524871], it showed that there was an improvement in ORR and a very long PFS. This is a very encouraging early signal.

Now, [the combination of atezolizumab, bevacizumab, and tiragolumab] is advancing to the phase 3 IMbrave 152 trial [NCT05904886], which is comparing that triplet combination vs atezolizumab plus bevacizumab. We hope that if that is a positive trial, once again, it would have improved the standard of care for our patients with HCC and would have a big impact on their lives in the future.

We have made advances. I want any patient out there who has liver cancer to know that this field is expanding at a fast rate. When I started treating patients with HCC, we only had 1 FDA-approved treatment. Now, we've made incredible strides, and we continue to make and push for incredible strides daily. There is hope out there, and there's going to be a lot of things that are coming for our patients with liver cancer to not only allow patients to live longer, but to allow them to live better.

FDA approves atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. News release. FDA. May 29, 2020. Accessed October 11, 2023. 

Cheng AL, Qin S, Ikeda M, et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. 

. 2022;76(4):862-873. doi:10.1016/j.jhep.2021.11.030

Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. 

Daneng Li, MD, discusses the current options available for the frontline treatment of patients with unresectable HCC, factors to consider when selecting a treatment regimen for this patient population, how Child-Pugh B score and bleeding could affect these decisions, and ongoing research using the atezolizumab/bevacizumab backbone in novel combinations. 

Ongoing Research Could Add to Atezolizumab/Bevacizumab Backbone in First-Line Treatment of Unresectable HCC 

Stacey Stein, MD, associate professor of Internal Medicine, Department of Medical Oncology, Assistant Medical Director, Clinical Trials Office, Yale Cancer Center and Smilow Cancer Hospital, discusses key considerations when selecting a first-line treatment approach for higher-risk patients with hepatocellular carcinoma (HCC), as well as whether the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) is a viable approach in this population.

When navigating treatment options in HCC, physicians must evaluate whether the patient is a viable candidate for immunotherapy using standardized inclusion and exclusion criteria, Stein says. Although these guidelines have been well-established in the field, some situations may require clinical judgment, she notes. It is also critical to consider the management of any immunotherapy-related toxicities if selecting this option, Stein adds.

For physicians specifically considering the use of atezolizumab plus bevacizumab, the patients must first be identified as suitable for bevacizumab, Stein says. Oncologists often have experience with bevacizumab use in diseases like colon cancer. Timing in relation to procedures and bleeding risk considerations are important factors when making this decision, Stein notes. Moreover, some conditions represent relative contraindications, while others are absolute, Stein emphasizes. For instance, patients with cirrhosis are at a higher risk of bleeding due to viral infections. However, cirrhosis is not the only source of bleeding in these patients, Stein explains. Accordingly, patient risk factors should be assessed holistically, she says.

In terms of safety, patients in the phase 3 IMbrave150 (NCT03434379) trials were required to undergo an esophagogastroduodenoscopy (EGD) within 6 months of starting treatment with atezolizumab and bevacizumab, Stein reports. This approach is now standard practice as per this protocol. Treatment following EGD is determined by institutional standards, which can vary, Stein notes.

Overall, patient eligibility, the management of adverse effects, and assessment of bleeding risk are central considerations when contemplating immunotherapy, especially in combination with agents like bevacizumab, ensuring both patient safety and treatment efficacy, Stein concludes.

Stacey Stein, MD, discusses key considerations when selecting a first-line treatment approach for higher-risk patients with hepatocellular carcinoma, and in what scenarios the combination of atezolizumab and bevacizumab is a viable approach in this population.
 

Updates on Progress Made in the HCC Treatment Paradigm | Supplements and Featured Publications

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

Dr Li on Frontline Treatment Considerations With IO-Based Combinations in Unresectable HCC

Ongoing Research Could Add to Atezolizumab/Bevacizumab Backbone in First-Line Treatment of Unresectable HCC

Dr Stein on Key Considerations When Selecting an Immunotherapy Approach in HCC