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FAQ: HCC Treatment
Experts Answer HCP Questions on Contemporary HCC Therapy

Released: March 21, 2022

Expiration: March 20, 2023

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The treatment landscape for hepatocellular carcinoma (HCC) continues to evolve at a rapid pace. In this commentary based on a webinar series, Adam M. Burgoyne, MD, PhD; Lipika Goyal, MD, MPhil; and Stacey M. Stein, MD, discuss best practices and emerging strategies in treating advanced HCC and answer questions from healthcare professionals on this topic.

What is the current paradigm for first-line systemic therapy in patients with advanced HCC?

Adam M. Burgoyne, MD, PhD:
In May 2020, the FDA approved the PD-L1 inhibitor/VEGF inhibitor combination of atezolizumab plus bevacizumab as first-line systemic treatment for patients with unresectable or metastatic HCC. This approval was based on findings from the phase III IMbrave150 trial, in which patients with advanced HCC (Child-Pugh A liver function) and no previous systemic therapy were randomized to receive either atezolizumab plus bevacizumab or sorafenib. Atezolizumab plus bevacizumab was associated with improved overall survival (OS; median 19.2 vs 13.4 months), progression-free survival (PFS), overall response rate, and quality of life compared with sorafenib.

Certainly, clinical trials are always appropriate, and I strongly encourage patients to consider participation in research studies, but in clinical practice, atezolizumab plus bevacizumab should be considered the gold standard frontline regimen. If a patient walks into my clinic, I’m asking myself whether they are a candidate for atezolizumab plus bevacizumab.

Lipika Goyal, MD, MPhil:
Of importance, the IMbrave150 trial required that all patients undergo an esophagogastroduodenoscopy within 6 months to evaluate for varices; patients were excluded from the study if they had untreated or incompletely treated varices or a high risk of bleeding from their varices. This was because bevacizumab, which is a monoclonal antibody against VEGF, has been associated with an increased risk of bleeding. 

Is portal vein thrombosis a contraindication to bevacizumab? 

Lipika Goyal, MD, MPhil:
Portal vein thrombosis is not a contraindication for bevacizumab. The IMbrave150 trial accepted patients with left portal vein, right portal vein, or main portal vein thrombosis.

Are there concerns with using immunotherapy in transplant-eligible patients?

Lipika Goyal, MD, MPhil:
When considering any immunotherapy regimen for a patient with HCC, it is important to consider whether the patient had an organ transplant. Obviously, some patients have recurrence of HCC after liver transplant. We do not currently recommend atezolizumab post transplant, but some centers are trialing immunotherapy pre transplant during the bridging process with very close monitoring.

Stacey M. Stein, MD:
We worry about organ rejection with immunotherapy in patients who have received a transplant, so the traditional answer has been to not recommend immunotherapy for patients who have received a liver transplant. This is a timely question, as I received an email yesterday from our transplant group that the guidance on this topic may be starting to change, with some healthcare professionals more open to the idea of immunotherapy being given prior to transplant with a certain washout period. I think what is most exciting about this is that you could potentially expand the group of patients who are transplant eligible, as immunotherapy can allow patients to be downstaged. Traditionally, we have thought about downstaging only with locoregional therapy, but with the better response rates we see with systemic immunotherapy, we are now thinking about the goal of downstaging patients with systemic regimens such that curative options become available, and that is incredibly exciting.

Would you consider atezolizumab plus bevacizumab as second-line therapy following treatment with a VEGF-targeted tyrosine kinase inhibitor (TKI)? 

Stacey M. Stein, MD:
I would. When the regimen was approved, I had a number of patients who were receiving a VEGF-targeted TKI such as sorafenib or lenvatinib for whom I did recommend atezolizumab plus bevacizumab as later-line therapy. I typically wouldn’t sequence it that way now and would recommend atezolizumab plus bevacizumab as first-line therapy for most of my patients.

Adam M. Burgoyne, MD, PhD:
I would sort of echo what you said. New regimen approvals happen at various time points in the longitudinal care of our patients. I do have people whom I had started on lenvatinib prior to the atezolizumab plus bevacizumab approval who had relatively prolonged periods of disease control. And then what do you do after those patients progress? I have considered those people for atezolizumab plus bevacizumab and have even considered this regimen in a few people who were long-term responders with nivolumab.

What recent data have emerged with novel immunotherapy combination strategies for advanced disease?

Adam M. Burgoyne, MD, PhD:
Exciting data were presented at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium on HIMALAYA, a global, randomized phase III study comparing the combination of durvalumab (a monoclonal antibody targeting PD-L1) plus tremelimumab (a monoclonal antibody targeting CTLA-4) with durvalumab or sorafenib in patients with unresectable HCC. This study enrolled 1324 patients and included patients who had not received previous therapy and had good performance status and Child-Pugh A liver function. No main portal vein thrombosis was allowed. The combination of durvalumab plus tremelimumab was administered as 1 dose of tremelimumab plus durvalumab given every 4 weeks (the STRIDE regimen). The primary endpoint was OS with the STRIDE regimen vs sorafenib.

Regarding the primary endpoint data: This was another positive phase III trial in the HCC space. The OS median with the durvalumab plus tremelimumab arm was 16.4 months compared with 13.8 months with the sorafenib arm, with a statistically significant HR of 0.78. The 36-month OS was 30.7% with durvalumab plus tremelimumab vs 20.2% with sorafenib. The response rate with durvalumab plus tremelimumab was 20.1% compared with 5% with sorafenib. Some responses were ongoing even at the 2- and 3-year marks with the combination.

Looking at safety with durvalumab plus tremelimumab, the grade 3/4 treatment-related adverse event rate was 25.8%, with 20.1% of patients who received the combination requiring high-dose steroids. Of note, only 5.7% of patients experienced an immune-mediated adverse event leading to discontinuation of treatment. Although cross-trial comparisons are problematic and should be done with caution, we have data with another immune checkpoint inhibitor strategy using both PD-1 and CTLA-4 blockade in HCC. The phase II CheckMate 040 study of nivolumab plus ipilimumab for patients with advanced HCC found that nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W treatment was associated with a median OS of 22.2 months; however, this dosing also was associated with grade 3/4 treatment-related adverse events in 53% of patients. Of note, nivolumab plus ipilimumab is currently being assessed as first-line therapy in a phase III trial (CheckMate 9DW) in patients with advanced HCC.

Although durvalumab plus tremelimumab is not yet approved for patients with advanced HCC, when might you consider using this regimen should it be approved?

Lipika Goyal, MD, MPhil:
I would certainly consider this regimen for patients who have any contraindications to VEGF-targeted therapy—so patients who have varices, recent bleeding, uncontrolled hypertension, recent surgery, or fistula formation. This will be a great option for any patient for whom I would be nervous about giving bevacizumab and a little less worried about giving immunotherapy in terms of autoimmune issues.

Adam M. Burgoyne, MD, PhD:
I would echo those sentiments. We now also have seen data from COSMIC-312, a randomized phase III study of cabozantinib, another TKI, plus or minus atezolizumab vs sorafenib for patients not amenable to curative treatment with no prior systemic therapy. Patients in this trial had Child-Pugh A liver function and good performance status. The primary endpoints were PFS and OS with cabozantinib plus atezolizumab vs sorafenib, with the final PFS analysis and interim OS analysis presented.

The median PFS with cabozantinib plus atezolizumab was 6.8 months vs 4.2 months with sorafenib, with a statistically significant HR of 0.63. Unfortunately, in the interim survival analysis, the median OS with cabozantinib plus atezolizumab (15.4 months) was not different from that observed with sorafenib (15.5 months; HR: 0.90; P = .438). The OS analysis is ongoing, but the sponsor of the study has communicated via press release that they estimate there being a low probability of a significant difference in OS between the cabozantinib plus atezolizumab and sorafenib groups at final analysis.

The LEAP-002 study of lenvatinib plus pembrolizumab is another phase III study assessing a first-line immunotherapy combination for advanced HCC that we are excited about and watching closely, with readouts anticipated soon. The combination of lenvatinib plus pembrolizumab preliminarily looks to be relatively impressive, with the phase III trial supported by data from the open-label phase Ib KEYNOTE-524 study, which assessed lenvatinib plus pembrolizumab for patients with unresectable HCC with no prior systemic therapy (N = 100). Lenvatinib plus pembrolizumab was associated with an overall response rate of 36%, including some complete responses, with a median OS of 22 months. 

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