Amit Singal, MD, MS, discussess optimal models for multidisciplinary care in hepatocellular carcinoma in light of the practice-changing IMbrave150 trial.
Amit G. Singal, MD
The combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) for patients with hepatocellular carcinoma (HCC) highlights the need for multidisciplinary care because of the increased risk of gastrointestinal (GI) bleeding associated with the combination, according to Amit Singal, MD, MS.
“The availability of atezolizumab and bevacizumab for advanced-stage HCC is incredible. [IMbrave150] is the first trial in over a decade to show superior survival over sorafenib,” said Singal. “This is a game-changer for advanced HCC and it has caused a paradigm shift in terms of how we look at these patients.”
In January 2020, a supplemental biologics license application (sBLA) was submitted to the FDA for the combination of atezolizumab and bevacizumab for the treatment of patients with unresectable HCC who have not received prior systemic therapy. The sBLA was based on findings from the pivotal phase III IMbrave150 study.
Results from the trial showed that treatment with atezolizumab plus bevacizumab resulted in a statistically significant and clinically meaningful improvement in overall survival and progression-free survival. Specifically, the combination led to a 42% reduction in the risk of death compared with sorafenib (Nexavar; HR, 0.58; 95% CI, 0.42-0.79; P = .0006). Additionally, the combination showed a 41% reduction in the risk of disease progression or death versus sorafenib (HR, 0.59; 95% CI, 0.47-0.76; P <.0001).
“Although [the combination of atezolizumab and bevacizumab] is well tolerated overall, one thing we need to remember is that bevacizumab does increase the risk of GI bleeding, most notably in those with cirrhosis,” added Singal. Even in a patient who has Child-Pugh class A disease and minimal portal hypertension, Singal stressed the importance of collaborating with a gastroenterologist to ensure that the patient undergoes varices screening as those need to be treated prior to the administration of the combination.
In an interview with OncLive, Singal, associate professor of Internal Medicine in the Division of Digestive and Liver Diseases, medical director of the Liver Tumor Program, and clinical chief of Hepatology at UT Southwestern Medical Center, discussed optimal models for multidisciplinary care in HCC in light of the practice-changing IMbrave150 trial.
OncLive: Could you speak to the importance of using a multidisciplinary approach in the treatment of patients with HCC?
Singal: Multidisciplinary care is necessary in HCC. We have multiple therapies available, ranging from surgical therapies, to interventional radiology-type therapies, to systemic therapies, and all these options are given by different providers. The good news is that we have many options in our arsenal, but one of the things we need to be thoughtful about is what the best treatment is for each individual patient.
One of the best ways to [determine what the optimal approach looks like] that is to ensure that we practice multidisciplinary management. To this end, we have different providers in the same room or the same clinic, and they discuss all the treatment options available for a patient presenting at a certain stage. [Based on these discussions], we can identify the best treatment [approach] for each particular patient.
What providers should be included in these multidisciplinary meetings?
The setup for multidisciplinary management varies by each institution, although, the providers in the room tend to be fairly similar across [healthcare systems]. These providers include hepatologists, interventional radiologists, surgeons, medical oncologists, radiation oncologists, and diagnostic radiologists.
Could you discuss the different treatment approaches available in this space?
Right now, the treatments that we have tend to be pretty clean. If [a patient is diagnosed] at an earlier stage [of their disease], therapies such as surgical resection, liver transplantation, and local ablation are available. If [a patient has] liver-localized disease but larger, we are typically treating with chemoembolization, radioembolization, and external beam radiation therapy. [In] more advanced stages [of disease], we start to use systemic therapies.
However, one of the exciting things we are seeing in the field is not only stage migration to the left or right, so people starting on a certain therapy and then having to go on a different therapy, but also combination therapies. As you start to have stage migration as well as combination therapies, it is going to be even more important to have optimal communication [among your multidisciplinary group] to find the best therapy.
What are the biggest updates in the field regarding systemic therapy? How will you approach sequencing in the future?
We have seen many advances in terms of systemic therapies. Most notably, we had the IMbrave150 trial. We now have atezolizumab and bevacizumab as the new first-line therapy. We also have many second-line options available—primarily TKIs, VEGF inhibitors, and checkpoint inhibitors—that can all be considered in that setting.
However, one of the things to remember is that even though those therapies are typically given by medical oncologists, this is still a cancer that occurs in the setting of chronic liver disease and often cirrhosis. Even when you have those therapies being delivered by medical oncologists, there still needs to be communication with a hepatologist, so you can also appropriately manage the patient’s chronic liver disease.
Another exciting thing is that we are seeing an increase in response rates. When we used to have TKI-based therapies, we saw very low response rates and the goal was to keep the tumor in check and not have progression. Now, however, with atezolizumab and bevacizumab we start to see response rates that are approaching 30%. When you start to have these responses. some patients can actually be downstaged to an immediate stage [of disease]. You may then consider locoregional therapy or other therapies for that patient.
You mentioned the impact of the IMbrave150 data with atezolizumab and bevacizumab. Could you discuss the safety profile of that combination? How can a multidisciplinary approach help mitigate associated toxicities?
[The combination] was found to be well tolerated overall; however, bevacizumab does increase the risk of GI bleeding, most notably in patients with cirrhosis. We know that those patients are at risk for portal hypertensive bleeding or variceal bleeding. In the trial, the rates of GI bleeding were generally very low. In part, that is because the trial design mandated that all patients underwent an upper endoscopy and had their varices treated prior to receiving treatment with atezolizumab plus bevacizumab. As this rolls out into clinical practice, it is important for providers to remember that aspect.
The trial enrolled patients with Child-Pugh [class A] disease with minimal to no portal hypertension, so their platelet count was >75,000. The risk of GI bleeding in patients with more advanced liver disease is probably higher if you expand this out to Child-Pugh [class B] patients or those with lower platelet counts. The second thing to remember is, even if you have a patient who has Child-Pugh [class A] disease and minimal portal hypertension, it is important that you speak with a gastroenterologist and ensure that the patient undergoes varices screening. If the patient has varices, ensure those are treated prior to starting the combination.
Multidisciplinary care is practiced often in academic settings. Do you see this approach expanding into smaller practices?
Right now, multidisciplinary care is largely being done in academic institutions. We have seen some of this diffuse out to larger community practices. We are also starting to see some tumor boards in private or community practices be organized in this way, but it is much harder [to do in those settings].
A partnership between academic institutions and community practices is needed to facilitate this multidisciplinary management. The reason why I say that this is so important for a disease like HCC is because this is a disease where we now have data showing that multidisciplinary management isn’t just something that make us feel good; this approach improves appropriate treatment delivery, communication with a patient, and most notably, survival. As such, this is something that we need to work together on, so we can ensure [this care] is given to all patients with HCC, regardless of whether they are seen in academic institutions or in community practices.
What is your take-home message to your colleagues treating patients with HCC?
We have seen many improvements in the locoregional and systemic therapy space, but one of the most important aspects of management to remember for this disease is that early diagnosis is critical. To provide the best survival benefit possible, we need to identify and detect the disease at an early stage and refer these patients for curative treatment. Although we have seen amazing advances in the systemic therapy space, if we are fortunate enough to find a patient at an early stage, it is important that we refer them for consideration of surgical resection or liver transplantation.
This is particularly important as you start to consider checkpoint inhibitors because these agents can increase the risk of rejection posttransplant. That is why it is important that a patient being seen by a medical oncologist who may be eligible for transplant be referred to a transplant center and know that answer before they are started on systemic therapy.
Cheng A-L, Qin S, Ikeda M, et al. IMbrave150: efficacy and safety results from a ph III study evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Ann Oncol. 2019;30(suppl 9):ix186-ix187. doi: 10.1093/annonc/mdz446.002