 Dr Rich, atezolizumab-bevacizumab has been the standard of care. In which patients do you think that continues to be the standard of care? What has been your experience with this combination?

 Since it has come onto the scene quite spectacularly, it’s been the first-line option, particularly for patients with unresectable HCC [hepatocellular carcinoma], who mainly in our practice would have advanced-stage HCC or BCLC [Barcelona Clinic Liver Cancer] stage C. Although increasingly, we’re talking about the role of systemic therapy in general, including given the high objective response rates with atezolizumab-bevacizumab in patients with intermediate-stage HCC or BCLC B as well. Particularly those beyond up to 7 criteria, or those with more infiltrated tumors that aren’t as amenable to locoregional therapy. Those are the 2. It remains standard of care for advanced-stage patients, BCLC C, as well as some consideration in select Bs. It’s also used in patients who don’t have the contraindications you mentioned. We’ll get to that in a moment.

In our experience, this has been a well-tolerated regimen. The main limitation is the patient’s ability to travel to get their infusion. That would be 1 of the main concerns compared with a TKI [tyrosine kinase inhibitor], where it’s an oral regimen and maybe a little more convenient for the patient. But in general, it’s been well-tolerated. We haven’t seen many adverse events at our center.

 Great. To summarize your excellent point, who are the patients with HCC who should get systemic therapy? We use the BCLC staging very commonly, but this may not be something familiar to everyone. Patients with BCLC stage C have either main vascular invasion in the liver, meaning main portal vein invasion, or extrahepatic metastasis. That’s easy. Patients with BCLC B have liver-limited disease that’s usually multifocal, but that’s a very heterogeneous group. It could be 2 lesions; it could be 10 lesions. There could be a difference in the size and distribution of these lesions. Usually, patients who have a heavy burden of liver-limited disease and up to 7 criteria could be 1 thing to follow, or those with very large lesions in the liver. These patients can go to systemic therapy straight away because that’s the highest level of evidence for a survival benefit from any therapy for HCC.

The last subset of patients are those with BCLC B disease who have had liver-directed therapy and are no longer candidates, either because of progression or because they’re not tolerating it well. It’s important to note that this transition from liver-directed to systemic therapy is a critical transition because we don’t want to delay it and allow patients to have deterioration of their liver function and miss the opportunity of systemic therapy. Dr Rich, you alluded to this. Which patients shouldn’t get atezolizumab-bevacizumab? Where do we need more data?

 There are the contraindications in patients who were excluded from the trial. The main concern is bleeding concerns in cirrhotic patients, given the anti-VEGF that was mentioned before, the bevacizumab component. For this reason, all these patients were up to date on their endoscopy and variceal surveillance. They all had an EGD [esophagogastroduodenoscopy] within 6 months and appropriate treatment of varices, as you mentioned.

Patients with a history of repeated variceal bleeding would be something that would cause you to take a pause. This is especially important in patients with new macrovascular invasion or new portal vein thrombosis, even if they had had an EGD 6 months or a year before. They could have worsening of their portal hypertension in that time as a result of the tumor extension into the portal vein. Bleeding in a cirrhotic patient is an important consideration. Another important consideration is patients with cardiovascular disease that’s severe with recent ischemic events. That’s another population in which you would be worried about the bevacizumab component. The other issue that comes up is the patient’s liver function, which, as a hepatologist, is the area where I typically get involved with our medical oncologist and help comanage these patients. We have been using atezolizumab-bevacizumab in patients who are good Child-Pugh Bs. For example, Child-Pugh B7s in whom it may be because of albumin, not folks with ascites that’s not controlled. Those are the main considerations from my standpoint.

 Very good. Dr Gholam, what are concerns about treating Child-Pugh B patients with this combination? What data do we need?

 At this point, we remain somewhat limited in our data sets or clinical information that reflects safety and efficacy in the setting of people who receive immunotherapy. We have some data previously that were reported in the setting of nivolumab therapy. We have some data from Korea that were presented at the recent meeting that also reflect some questions regarding mitigating risk of bleeding and whether that might be too high a cost in terms of implementing such a treatment. But the bottom line is we remain somewhat without clear guidance about whether we would be able to safely and effectively treat those patients in that setting. This has been acknowledged by the NCCN [National Comprehensive Cancer Network] and others, where they have specifically allocated additional guidance regarding Child-Pugh score to reflect the paucity or relative abundance of data, especially for TKIs, in that setting.

 Great. Dr Rich, I’d like to go back to you about Child-Pugh B patients. Do you want to add anything else?

 I want to make 2 more points. One question is, should we even be using Child-Pugh as our way to risk stratify these patients? Child-Pugh is validated for prognosis in patients for cirrhosis, but there’s a lot of nuance there, and patients can be very different Child-Pugh Bs, as I mentioned. Perhaps the ALBI [albumin-bilirubin] score, which incorporates only the albumin-bilirubin, is a little more objective and something that we should definitely look at in future real-world studies.

The second point is that 1 of the components of Child-Pugh and ALBI is the bilirubin. I’d be curious to see what the rest of the panel thinks, but in our clinical practice, there’s a difference between these patients who have been decompensated for a long time with the bilirubin that’s been smoldering in the 3-to-4-mg/dL range, and they’re clearly decompensated vs a patient who has had good liver function and more acutely decompensates in the setting of tumor growth. Those would be patients in whom you’d consider overlooking that bilirubin—especially given the safety that Dr Gholam mentioned that we’ve seen with nivolumab in this population—and consider treating, with the rationale that as you shrink the tumor, perhaps you’ll see some improvement in the liver function.

 That’s a great point. I’ll summarize by saying that the advice to our colleagues in practice is that if you have a Child-Pugh B patient, not all Child-Pugh B patients are equal. There’s a huge heterogeneity. Those patients would benefit significantly from a multidisciplinary discussion to assess whether there’s a potential benefit from treating their cancer. I’d like to emphasize that the major prospective data that have been reported for Child-Pugh B are with sorafenib from the GIDEON registry and a small subgroup in the initial phase 2 study. There are some safety data for sorafenib. There are safety data from nivolumab from CheckMate040, where there are Child-Pugh Bs in cohorts 7 and 8.

We know those agents can be used safely. They’re single-arm studies, but compared with historical control, there may be some benefit with survival. There are emerging data, very small data sets with atezolizumab-bevacizumab, with 1 showing decent safety and 1 from Korea showing some higher risk of bleeding. We need more data for the combination of atezolizumab-bevacizumab, and as Dr Gholam mentioned, more clarity on mitigation of bleeding risk in those patients. Lastly, the noninferiority of durvalumab to sorafenib recently brought back the option of single-agent PD-1, and that complements the data set with nivolumab in Child-Pugh B patients as well. Dr Li, before we move on from this subject, is there anything you’d like to add?

 No, I absolutely agree with the group in the sense that there’s definitely heterogeneity in terms of our Child-Pugh B patients. As Dr Rich said, if it’s because of the underlying disease, then it’s potentially worthwhile to pursue aggressive treatment to try to control the cancer to hopefully improve that patient’s outcome.

 I’d add 1 more point. Some of the populations that have been unexplored in this area that were excluded from the trials are hepatitis B and C coinfected patients, and patients with HIV and hepatitis C coinfection. Those are some of the other areas of unmet need for further study, because we see a decent amount of coinfected patients in our clinical practice.

Videos

Nicole Rich, MD, reviews the patient selection for atezolizumab-bevacizumab and discusses patients in whom this regimen is contraindicated in the frontline setting in advanced HCC.

Which Patients With HCC Are Suitable for Treatment With Atezolizumab and Bevacizumab?

 Dr Li, would you also review the data from HIMALAYA as presented at the 2022 ASCO GI [American Society of Clinical Oncology Gastrointestinal Cancers Symposium]?

 Yes. Similar to COSMIC-312, this was 1 of the long-awaited trials for our patients with frontline unresectable HCC [hepatocellular carcinoma]. Here, we’re trying to target with a different mechanism of action. In the prior 2 studies that we mentioned, IMbrave150 and COSMIC-312, we’re targeting the combination of VEGF with an immune checkpoint inhibitor. In HIMALAYA, it’s looking at dual immune checkpoint inhibitors for HCC. This was based off earlier work in the phase 1 setting as well as a phase 2 expansion study looking at the combination of durvalumab, a PD-L1 inhibitor, plus tremelimumab, a CTLA4 inhibitor. Based off preliminary work, it showed that there was an estimated response rate of 20% in this population. It was felt that this was a potential synergistic regimen that could be tested in the phase 3 setting to go up against our prior standard of care, sorafenib.

The HIMALAYA trial was a large phase 3 trial that included over 1300 patients. It was much larger than many of the other clinical trials that we’ve had in the HCC field. Initially, the trial was designed comparing sorafenib as the control arm vs single-agent durvalumab vs the combination of tremelimumab at 75 mg for a total of 4 doses plus continuing with durvalumab. On initial analysis and earlier work, it was shown that the 75-mg dosing of tremelimumab wasn’t necessarily the ideal dose to help the patient, so the protocol underwent an amendment, essentially changing into the STRIDE [single tremelimumab regular interval durvalumab] regimen with a priming dose of tremelimumab at 300 mg. That’s a much higher dose of CTLA4 as a 1-dose regimen in the beginning during the first cycle of treatment followed by durvalumab.

It continued to enroll patients in that arm, whereas the 75-mg dose of the tremelimumab arm with durvalumab was closed. Ultimately, you have 3 arms with the tremelimumab at 300 mg plus durvalumab vs durvalumab vs sorafenib. The primary end point of this study was overall survival [OS]. The study met its primary end point of overall survival when you compare the single dose of tremelimumab plus durvalumab vs sorafenib. The median overall survival for the combination of durvalumab-tremelimumab was 16.4 months; for sorafenib, it was 13.8 months. They looked at single-agent durvalumab vs sorafenib from a noninferiority standpoint. That met its primary outcome in terms of noninferiority because durvalumab had an immediate overall survival of 16.6 months vs sorafenib of 13.8 months.

Interestingly, when we looked at progression-free survival [PFS], there was no difference with either durvalumab by itself or the single dose of tremelimumab plus durvalumab vs sorafenib. Median progression-free survival was about 4 months for sorafenib vs 3.65 months for durvalumab and 3.78 months for tremelimumab. Objective response was very consistent with the earlier studies. The combination had an objective response rate of 20%, and single-agent durvalumab had an objective response rate of 17%. That’s much higher compared with sorafenib. It causes some pause in the sense that it met its primary end point in terms of overall survival, but it didn’t meet its primary end point in terms of median progression-free survival, highlighting that potentially not enough patients derived significant tumor control in this population to translate to that PFS.

It will be interesting to look at the full data to see where we incorporate this regimen moving forward. It presents another option for us, given that it’s not targeting VEGF and has a completely different adverse-effect profile for our patients. But we need to take a deeper dive into the data to determine where it stands in the treatment landscape right now vs the new standard in terms of the combination of atezolizumab plus bevacizumab.

 Thank you for the excellent summary. I’ll add a couple of things to make it clear for the audience. The study was powered to compare the tremelimumab-durvalumab combination with sorafenib. That’s 1 comparison. The second comparison was durvalumab to sorafenib. The study wasn’t powered to compare the combination, which is tremelimumab-durvalumab to durvalumab. That’s just a caution for statistical design. That’s 1 issue. The second issue is this study excluded patients with main portal vein thrombosis. The REFLECT trial with lenvatinib did that as well, whereas the atezolizumab-bevacizumab IMbrave150 study didn’t exclude main portal vein thrombosis. Those are some caveats to consider as well.

There could be many potentially debatable reasons for the lack of benefit with PFS. There are some theories, including whether that could simply be because the study only includes I/O [immuno-oncology]–I/O therapy. There’s no combination with a VEGF or chemotherapy agent. The curve separated later, speaking to your point that the disease control was lower and the benefit happened later. It’s intriguing that this study had quite long follow-up, and there was almost a 31% overall survival rate at 36 months with the tremelimumab-durvalumab combination. It’s very interesting that we’re at a time where we’re seeing advanced HCC patients have a 30% OS rate at 3 years. It’s quite impressive and intriguing. We’re also awaiting longer follow-up with the other studies, including atezolizumab-bevacizumab. We have 2 first-line options with some nuances and caveats on how they’re going to be used. Maybe we’ll come back to that a bit later.

Dr Daneng Li reviews updated safety and efficacy results of durvalumab plus tremelimumab from the phase 3 HIMALAYA study in frontline unresectable HCC.

Phase 3 HIMALAYA Study in Advanced HCC

 Recently, there have been a couple of developments, with new data coming out from the COSMIC-312 and HIMALAYA studies. I’m going to ask my colleague Dr Li to briefly review those studies.

 Thanks so much, Dr El-Khoueiry. As you mentioned, we’ve had a lot of activity and continue to have a lot of activity for our patients with unresectable HCC [hepatocellular carcinoma]. The COSMIC-312 study was a large global phase 3 study. It included about 840 patients worldwide. These were targeting the same population that you highlighted in the IMbrave150 study. This was a first-line study for patients with advanced unresectable HCC. Patients were randomized 2:1:1 to receive cabozantinib at 40 mg—a lower dose of cabozantinib—plus atezolizumab vs sorafenib, which is our prior standard for advanced unresectable HCC. They also had an exploratory arm of frontline full-dose cabozantinib at 60 mg vs sorafenib as well. It had dual primary end points of progression-free survival [PFS] as well as overall survival [OS].

In terms of progression-free survival, the combination of 40-mg cabozantinib plus atezolizumab every 3 weeks led to improvement in progression-free survival from 4.2 months up to 6.8 months vs sorafenib. That’s very consistent with what we saw with the combination of atezolizumab plus bevacizumab in the IMbrave150 study. But what was surprising was that when they analyzed the data at interim analysis for overall survival, there was no statistical difference in terms of overall survival with cabozantinib at 40 mg plus atezolizumab vs sorafenib. The overall survival was 15.5 months for sorafenib and 15.4 months for the combination of cabozantinib plus atezolizumab. It appears that there’s improvement in tumor control with the frontline regimen compared with sorafenib, but that didn’t necessarily translate into an overall survival benefit.

 As you know, we’re still awaiting the mature overall survival data for that study, so this was interim survival. Longer follow-up is needed, but I agree. The discrepancy between PFS and OS is something to watch out for. I’d add that the response rate for the cabozantinib-atezolizumab combination was at 11%. That’s a bit lower than expected as well, but a very high disease control rate in the 80% range.

 Yes. This is maybe what we expected from cabozantinib. We’ll have to see the more mature data in terms of how many of these patients potentially had significant dose reductions. It was already starting at a lower dose of cabozantinib, 40 mg, based on initial phase 1 studies from the COSMIC-021 study. We’ll have to see how many of those patients required further dose reductions in that arm.

 For fairness, the study was designed statistically to be positive when either end point was met. PFS and OS were coprimary end points, so the fact that PFS met its end point by definition statistically makes it a positive study. We’ll see as the data evolve on that.

Daneng Li, MD, evaluates the use of cabozantinib plus atezolizumab in first-line advanced unresectable HCC as seen in the COSMIC-312 study.

Phase 3 COSMIC-312 Study in Advanced HCC

® titled “A New Wave of Progress in the Treatment of Hepatocellular Carcinoma.” I’m Anthony El-Khoueiry. I’m a GI [gastrointestinal] medical oncologist at the USC [University of Southern California] Norris Comprehensive Cancer Center in Los Angeles, California. I’m joined by 3 friends and colleagues who are experts in the field of treatment of hepatocellular carcinoma [HCC], and I ask them to introduce themselves. I’d like to start with Dr Nicole Rich.

 Hi. My name is Nicole Rich. I’m a transplant hepatologist at UT [University of Texas] Southwestern Medical Center in Dallas, Texas.

 My name is Pierre Gholam. I’m a professor of medicine at Case Western Reserve University School of Medicine, and I lead our multidisciplinary hepatobiliary tumor team at the NCI [National Cancer Institute]–designated Seidman Cancer Center in Cleveland, Ohio.

 Hi, everyone. I’m Daneng Li. I’m a GI medical oncologist, and I lead our hepatobiliary tumor program at City of Hope in Duarte, California.

 Welcome, everyone. We’re going to discuss a number of recent updates regarding the treatment of hepatocellular carcinoma, including some exciting abstracts and presentations from the 2022 ASCO GI [American Society of Clinical Oncology Gastrointestinal Cancers Symposium]. We’ll discuss the data in the context of other recent updates to the treatment landscape and their impact on clinical practice.

Let’s get started with our first topic, which is a review of the approved first-line systemic options for patients with advanced HCC. I’ll start by covering the data as of January 2022, and then ask some of my colleagues to update on other newer developments. I’ll start chronologically. For a long time, sorafenib was the only standard of care for advanced HCC. This was based on the SHARP trial as well as another international study known as the Asia-Pacific trial, both of which compared sorafenib with placebo. In the SHARP trial, sorafenib was superior to placebo with a median overall survival [OS] of between 10 and 11 months.

Then we had a long gap of close to 10 years of negative studies in which different compounds were either compared with sorafenib or added to sorafenib. They all failed until the REFLECT study was conducted, which was a noninferiority study comparing lenvatinib with sorafenib in patients with advanced HCC. These are patients with Child-Pugh A cirrhosis and good performance status. They had to be candidates for systemic therapy. Patients were randomized 1:1 to lenvatinib or sorafenib, and the study met its noninferiority end point. The median overall survival with lenvatinib was about 13 months, and with sorafenib, it was about 12 months. The confidence interval was below the threshold of 1.08, which was required to meet the noninferiority end point. Despite the median OS being quite similar, lenvatinib had a higher PFS [progression-free survival] and superior response rate compared with sorafenib. That may have influenced how it was used compared with sorafenib in the clinic.

After that came the data with single-agent anti–PD-1 therapy with nivolumab and pembrolizumab, with phase 1/2 studies showing promising response rates and durable responses. Those data led to the phase 3 study known as CheckMate 459. That study compared nivolumab with sorafenib in previously untreated patients with first-line advanced HCC. It was a superiority study. In that study, nivolumab led to a median overall survival of around 16 months, and sorafenib around 14 months, but the study didn’t meet the superiority end point. It wasn’t statistically significant. The response rate was confirmed. It was the same as what’s seen in the phase 1/2 data, with a response rate of around 16% or 17% for nivolumab. The responses were durable. The safety was confirmed as well. As a matter of fact, the quality-of-life data favored nivolumab for the duration of therapy in that trial. But it was a negative study, statistically speaking.

The next step was to add on to anti–PD-1 therapy. That brings us to the IMbrave150 study, in which atezolizumab, an anti-PD-L1 antibody, was combined with bevacizumab, the anti-VEGF antibody. Atezolizumab-bevacizumab was compared with sorafenib. This was a 2:1 randomization with Child-Pugh A patients, mostly BCLC [Barcelona Clinic Liver Cancer] stage C. The study was a positive trial at all levels. There was a superior overall survival, a superior PFS, and a superior response with the combination of atezolizumab and bevacizumab. The median overall survival was an unprecedented 19 months for the combination of atezolizumab-bevacizumab vs about 13 months with sorafenib. The PFS was about 6.9 months, and the response rate was about 30% with atezolizumab-bevacizumab.

Of note, because of the risk of bleeding with bevacizumab, this study required that patients undergo an endoscopy within 6 months prior to enrollment to ensure that if there were varices, the requirement was that they’d be treated based on institutional standard. It required variceal screening and therapy based on institutional standard. Those are the data as of January 2022. I focus mostly on efficacy, but based on this, atezolizumab-bevacizumab became the first-line standard for patients who have no contraindications to immunotherapy or bevacizumab. Otherwise, the options were to use TKIs [tyrosine kinase inhibitors], like sorafenib or lenvatinib.

Anthony B. El-Khoueiry, MD, provides insight on the evolution of care for frontline systemic therapy in advanced HCC and discusses currently approved first-line standard of care options.

First-Line Systemic Treatment for Advanced HCC

Daneng Li, MD, medical oncologist, assistant clinical professor, co-director, Neuroendocrine Tumor Program, Department of Medical Oncology and Therapeutics Research, City of Hope, discusses the 

subgroup analysis of the phase 3 IMbrave150 trial

 in patients with unresectable hepatocellular carcinoma (HCC). 

2020 ESMO World Congress on Gastrointestinal Cancers

, findings from an exploratory subgroup analysis of the IMbrave150 trial revealed that older adult patients with previously untreated, unresectable HCC derived similar benefit from the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) versus the intent-to-treat (ITT) population.

Moreover, the combination elicited a 42% reduction in the risk of death versus sorafenib (Nexavar) in the older patient population compared with a 41% reduction in the risk of death in the ITT population.

In the overall population, 50% of patients were over the age of 65 and had a median age of 71, says Li. 

Notably, the benefit with the combination was observed despite the older patient population having comorbidities such as hypertension and diabetes, as well as having a higher usage rate of concomitant medications, adds Li.

Ultimately, atezolizumab/bevacizumab is a valid frontline option for older adult patients with unresectable HCC with regard to efficacy, concludes Li.

Daneng Li, MD, discusses the subgroup analysis of the phase 3 IMbrave150 trial in patients with unresectable hepatocellular carcinoma.  



Dr. Li on the Subgroup Analysis of the IMbrave150 Trial in Older Patients With HCC 

Daneng Li, MD, an assistant clinical professor in the Department of Medical Oncology and Therapeutics Research, and a medical oncologist at City of Hope, discusses an ongoing study of preoperative immunotherapy in patients with hepatocellular carcinoma (HCC).

A lot of focus in HCC has been placed on the use of immunotherapy in the frontline metastatic setting, says Li. One particular study (NCT03222076) of interest evaluated the use of either nivolumab (Opdivo) monotherapy or the combination of nivolumab and ipilimumab (Yervoy) in patients with resectable disease in the preoperative or adjuvant setting. Results from a preliminary analysis conducted by The University of Texas MD Anderson Cancer Center showed 3 partial complete responses in 8 patients.

The responders were subsequently able to undergo a successful resection, says Li. These findings are pushing the bar for immunotherapy; this approach is now being tested in the frontline setting for patients with early-stage HCC to determine whether or not immunotherapy has a preoperative or adjuvant role.

Ultimately, physicians are hoping to understand whether frontline immunotherapy has any utility in patients with borderline resectable disease, adds Li, and whether there are any means of selecting the patients who stand the greatest chance of benefitting from these therapies in the long-run.

Daneng Li, MD

Articles

Which Patients With HCC Are Suitable for Treatment With Atezolizumab and Bevacizumab?

Phase 3 HIMALAYA Study in Advanced HCC

Phase 3 COSMIC-312 Study in Advanced HCC

First-Line Systemic Treatment for Advanced HCC

Dr. Li on the Subgroup Analysis of the IMbrave150 Trial in Older Patients With HCC

Dr. Li on Preoperative Immunotherapy in Hepatocellular Carcinoma