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

Following the May 2020 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,¹ 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.”

In an interview with OncLive^®, 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.

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

Li: 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)].³ 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.

References

1. FDA approves atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma. News release. FDA. May 29, 2020. Accessed October 11, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-plus-bevacizumab-unresectable-hepatocellular-carcinoma
2. Cheng AL, Qin S, Ikeda M, et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76(4):862-873. doi:10.1016/j.jhep.2021.11.030
3. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8). doi:10.1056/EVIDoa2100070