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Topics in Hepatobiliary Cancer Treatment
Experts Discuss Key Topics in Treating Hepatobiliary Cancers

Released: July 11, 2023

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Key Takeaways
  • All patients with liver cirrhosis and patients without cirrhosis with chronic hepatitis B should be screened for HCC.
  • Atezolizumab plus bevacizumab and durvalumab plus tremelimumab now are preferred first-line systemic therapy regimens for patients with advanced HCC, per the NCCN.
  • The NCCN-preferred regimen for patients with advanced BTCs is gemcitabine plus cisplatin and durvalumab.

With recent approvals of immunotherapy-based combinations, there now are exciting new treatment options and standards of care for patients with advanced hepatobiliary cancers. In this commentary adapted from a live satellite symposium at the 2023 American Society of Clinical Oncology Annual Meeting, Thomas A. Abrams, MD; Mitesh J. Borad, MD; and Stacey Stein, MD, address key questions on the management of hepatobiliary cancers, from screening to investigational therapies for early-stage disease to new treatment paradigms for advanced disease.

 What are best practices in screening for hepatocellular carcinoma (HCC)?

Thomas A. Abrams, MD:
The National Comprehensive Cancer Network (NCCN) recommends screening for HCC in those at increased risk for this cancer, including patients with liver cirrhosis from all causes and patients who have chronic hepatitis B, as HCC risk is increased in the absence of cirrhosis for these patients. For patients at risk, ultrasound and AFP testing should occur regularly. If an elevated AFP level is present or nodules >10 mm are found on ultrasound, the patient should receive additional imaging in the form of a multiphase CT scan or MRI. If nodules <10 mm are found, ultrasound and AFP testing should be repeated in 3-6 months. If the original ultrasound is negative, screening can occur every 6 months.

Stacey Stein, MD:
HCC screening is something that ideally should occur in primary care. Most patients in the United States now are being screened for hepatitis C, and hopefully everyone who is born here is vaccinated for hepatitis B. I think patients with nonalcoholic steatohepatitis (NASH) are the big group who may not be receiving optimal screening. These patients tend to be older with other medical comorbidities. I often look back at patients with NASH who present with HCC and see that they have had some small findings. For example, patients may have been referred to hematology for thrombocytopenia, but it was never put together that they may have elevated HCC risk. I think that if there were one group where we really were going to focus education in primary care, it would be that group in particular.

Mitesh J. Borad, MD:
I completely agree. I think primary care physicians have become really excellent at diagnosing diabetes. The next step is to think: “Well, this patient may have fatty liver. We should be assessing for that.” If a patient has a very slight transaminase elevation, one might consider evaluating this in more depth vs simply repeating HCC screening in 3 months.

Thomas A. Abrams, MD:
I think a key factor is that once a patient is identified as being at high risk for HCC, a hepatologist should be engaged for management or comanagement of next steps.

How do you manage patients with advanced HCC with systemic therapy? 

Stacey Stein, MD:
The NCCN guidelines now recommend atezolizumab plus bevacizumab and durvalumab plus tremelimumab as preferred first-line systemic therapy regimens for patients with advanced HCC. The recommendation and FDA approval of atezolizumab plus bevacizumab in this setting were based on findings from the phase III IMbrave150 trial, in which patients with locally advanced or metastatic or unresectable HCC, no previous systemic therapy, and Child-Pugh A liver function were randomized to receive either atezolizumab plus bevacizumab or sorafenib. In this study, atezolizumab plus bevacizumab was associated with improved overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) compared with sorafenib. In particular, there was a median OS of 19.2 months with atezolizumab plus bevacizumab vs 13.4 months with sorafenib, so this was really new and exciting for this disease. PFS also improved to 6.9 months with atezolizumab plus bevacizumab, and ORR was 11% with sorafenib and 30% with atezolizumab plus bevacizumab.

Durvalumab plus tremelimumab was approved by the FDA and recommended by the NCCN based on results from the HIMALAYA study. This was a randomized phase III study with an interesting design: Patients with advanced HCC and no previous systemic therapy received the combination of durvalumab plus tremelimumab or durvalumab monotherapy or sorafenib. Patients receiving the durvalumab plus tremelimumab combination, also called the STRIDE regimen, received a single dose of tremelimumab 300 mg and durvalumab 1500 mg every 4 weeks. The hope with this study was that a single priming dose of the anti‒CTLA-4 antibody tremelimumab would be associated with increased responses while avoiding some of the toxicity associated with more frequent dosing of an anti‒CTLA-4 antibody, as noted in studies of nivolumab plus ipilimumab.  

Durvalumab plus tremelimumab improved median OS vs sorafenib (16.43 vs 13.77 months; 36-month OS rate of 30.7% vs 20.2%). I think what we are seeing with median OS rates in this study reflects many other studies looking at immune therapies, in that the median values do not really tell the entire story, but rather that the tail of the survival curve is very important. Durvalumab plus tremelimumab also was associated with improved ORR vs sorafenib (20.1% vs 5.1%). It is amazing to me that 1 priming dose of tremelimumab really can make a difference in some patients.

Thinking about safety with immunotherapy, we are of course interested in adverse events (AEs) related to immune therapy, especially those requiring steroids. In IMbrave150, these occurred in 12% of patients; in HIMALAYA, these occurred in 9.5% of patients with durvalumab alone and 20.1% of patients with durvalumab plus tremelimumab. Of course, cross-trial comparisons should be approached with caution. Correspondingly, levels of some immune-related AEs can be elevated with the addition of tremelimumab to durvalumab, including rash. Of course, the addition of bevacizumab to atezolizumab caused an increase in specific AEs vs sorafenib, including hypertension and bleeding, which is not observed with durvalumab plus tremelimumab.

Let’s consider a few additional questions on first-line therapy. When do you consider using single-agent immune therapy such as durvalumab, nivolumab, and pembrolizumab? Are there any patients for whom you recommend first-line sorafenib or lenvatinib?

Thomas A. Abrams, MD:
I do not recommend single-agent immune checkpoint inhibitors (ICIs) very often, but for patients who have specific concerns, such as marginal performance status or marginal liver function whereby they might classify as Barcelona Clinic Liver Cancer (BCLC) stage D, I have used nivolumab and had some tremendous responses. Unfortunately, these patients often die because of liver function impairment, so there is always a question as to whether to treat these patients with systemic therapy.

Mitesh J. Borad, MD:
We did observe good median OS with durvalumab monotherapy in HIMALAYA.

Stacey Stein, MD:
Sometimes my approach is to consider how a person would do if they needed to receive high-dose steroids; could they encounter a setback that they could not come back from? Per the HIMALAYA data, there was a need for steroids in approximately 10% of patients receiving monotherapy and 20% receiving combination therapy, which in my mind is not insignificant. So, I think that group might benefit from ICI monotherapy, but there is no sure way to identify them.

What about the tyrosine kinase inhibitors in the first line?

Mitesh J. Borad, MD:
There are some scenarios where these might be the agents we use. Patients who have received a transplant for whom there may be concern that using ICIs could cause graft rejection would fall into this category, as would patients who have known severe autoimmune disease in whom you would be worried about severe autoimmune toxicities. 

Stacey Stein, MD:
A final question: Have you observed patients with more advanced disease that has been downstaged with systemic therapy to facilitate either transplant or resection ablation?

Mitesh J. Borad, MD:
There is a growing population in which patients may have fallen off the transplant list because of the stage of their disease, and then they receive systemic therapy and have a very robust response, after which they are sent back for transplant reconsideration.

Thomas A. Abrams, MD:
I have seen quite a few patients who initially have not been considered candidates for surgery and whose cancers did respond well to the point that they received surgery and did well. It is phenomenal when you see that.

Stacey Stein, MD:
I had a patient more than 10 years ago—when sorafenib was the only systemic therapy option—who began treatment with sorafenib but tolerated only a very low dose, as she had burning in her hands and feet. However, her tumor actually regressed, and she went for a resection. It’s amazing. When I started practicing, the BCLC staging system was very much left to right; it was like reading a sentence across a page, and I think especially as we get to thinking about neoadjuvant and adjuvant combination therapy, what is very exciting to me is that we are able to move back and forth across the BCLC staging system now. I think we are going to see more patients who have had a great response with immunotherapy, and when we bring them back to tumor board, we can say, “Okay, what can we think about now?” And that’s really exciting.

What are some of the identifiers or keys you use in practice to transition patients from transarterial chemoembolization (TACE) to systemic therapy? Do you ever combine these modalities?

Stacey Stein, MD:
I find this is such a gray area, and this is something I struggle with. Patients get presented at tumor board all the time, and interventional radiology might say, “Well, we could do Y90 radioembolization to this area.” And I’ll say, “Well, what about just starting on systemic therapy?” And they might say, “Well, what if I do the Y90 and then you start systemic therapy?” I wish there were more data to guide these decisions. My gestalt is often that we just should be starting more people on systemic therapy sooner. Then again, there are data with TACE that make it kind of compelling to say, well, for some single, large tumors, maybe TACE makes sense. I think, however, that once patients start having an increased number of tumors, etc, I do not see a role for local therapy. When we had only sorafenib as a systemic therapy, it made sense to keep pushing for more local therapy, but I think with better systemic therapies, things are slowly moving in that direction—however, it can be hard to know where the line is.

Thomas A. Abrams, MD:
It has not been my practice to combine the modalities. We have ongoing trials looking at this question, but even from a feasibility standpoint, it is not the simplest thing in the world to start.

How have the IMbrave050 data with adjuvant atezolizumab plus bevacizumab vs surveillance for HCC affected your clinical practice?

Thomas A. Abrams, MD:
IMbrave050 was a randomized phase III trial in which adjuvant atezolizumab plus bevacizumab was compared with active surveillance for HCC after curative-intent resection or ablation. Patients were considered to be at high risk for HCC recurrence. This trial met its primary endpoint of improved recurrence-free survival with adjuvant atezolizumab plus bevacizumab (HR: 0.72; P = .012).

Mitesh J. Borad, MD:
These data are in that stage where they are percolating, where the use of adjuvant systemic therapy may become more widespread over time.

Stacey Stein, MD:
I think a key question will be how we treat patients who receive this regimen and then experience disease recurrence. Will we retreat with this regimen or shift to another systemic therapy? How long of an interval would we want to have between end of treatment and recurrence to consider retreating with the same regimen?  

How do you approach first-line therapy of advanced biliary tract cancers (BTCs)?

Mitesh J. Borad, MD:
Per the current NCCN guidelines, the preferred regimen for this population of patients is gemcitabine, cisplatin, and durvalumab. Of course, there could be patients for whom you might not be able to apply some components of this regimen, such as the platinum or the ICI, so other recommended regimens include just the cytotoxic doublets.

Data supporting the use of gemcitabine, cisplatin, and durvalumab came from the TOPAZ-1 study, a randomized, double-blind phase III study in which patients with unresectable, locally advanced, or metastatic BTCs who were previously untreated in the advanced setting received gemcitabine plus cisplatin with or without durvalumab. After 8 cycles, patients switched to durvalumab or placebo maintenance. This might not be the typical practice in the United States, but globally this is considered reasonable. 

Looking at the primary endpoint, there was a 1.3-month improvement in median OS with the addition of durvalumab (12.8 vs 11.5 months with gemcitabine plus cisplatin alone; HR: 0.80; P = .021). With immunotherapies, it is less about the median OS and more about the tail on the survival curve. In this particular study, the separation of the curves seemed to start around 6 months, with 24-month OS of 25% with gemcitabine, cisplatin, and durvalumab vs 10% with gemcitabine plus cisplatin alone. Regarding safety, the big message is that when adding the ICI to gemcitabine plus cisplatin, there is not a tremendous increase in the toxicity profile, with similar tolerability. 

Recently, data from the KEYNOTE-966 trial were presented. This randomized phase III trial was similar to TOPAZ-1, with patients with unresectable, locally advanced, or metastatic BTCs who were previously untreated in the advanced setting receiving gemcitabine plus cisplatin with or without pembrolizumab. With more than 1000 patients, this was the largest study of BTCs to date and demonstrates that you can do these very large studies rather quickly with immunotherapy combinations in a disease that is considered somewhat uncommon. 

In this trial, the median OS was 12.7 months with gemcitabine plus cisplatin and pembrolizumab vs 10.9 months with gemcitabine plus cisplatin alone (HR: 0.83; P = .0034; 24-month OS: 25% vs 18%). The separation of the survival curves starts a bit early, in the 2- to 3-month range. This regimen is not currently approved but may become an approved/recommended option in the future.

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What are some key considerations in your practice when approaching treatment for a patient with advanced HCC or BTCs? How do you currently approach treatment of earlier-stage HCC? Please answer the polling question and join the conversation by posting a comment in the discussion section.

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