IMbrave150 Trial: Combination Therapy in Advanced HCC

Anthony El-Khoueiry, MD: In regard to how we treat patients with hepatocellular carcinoma [HCC], specifically the case that we have here in front of us, is a patient with advanced disease—BCLC [Barcelona Clinic Liver Cancer] stage C. Therefore, the standard is to start with systemic therapy. Currently, we have 2 standard FDA-approved options. One is sorafenib, which has been approved for over 10 years at the moment. This is the oral multitargeted kinase inhibitor, where we know that it was found to be superior to placebo in 2 international trials. Then the REFLECT trial evaluated lenvatinib in a noninferiority study compared with sorafenib and showed that lenvatinib met the noninferiority criteria. So lenvatinib became a second option for first-line treatment of advanced HCC.

As a reminder, lenvatinib is another oral multitargeted kinase inhibitor. But in addition to targeting the VEGF, the vascular endothelial growth factor axis, and the MAP kinase pathway—that’s what sorafenib does—lenvatinib suppresses the VEGF receptors more potently, but it also targets the fibroblast growth factor receptor pathway, which is thought to play an important role in resistance to anti-VEGF therapy.

The atezolizumab-bevacizumab combination, which this patient was treated with, is an emerging combination based on phase 3 data that have been presented in the IMbrave150 clinical trial. This combination is under consideration at the FDA for approval, but it’s not approved at this time. The IMbrave150 trial compared the combination of atezolizumab and bevacizumab with sorafenib. Atezolizumab is an anti-PD-L1 antibody, and bevacizumab is an anti-VEGF antibody. There is ample rationale for this combination because we know that targeting the PD-1 or PD-L1 axis has activity in HCC. But then we know that targeting VEGF can modulate the immune microenvironment to potentiate the PD-1 response. We know the anti-VEGF therapy can lower some of the immune suppressive cells in the immune microenvironment, so they lower myeloid-derived suppressor cells as well as T-regulatory lymphocytes. Anti-VEGF therapy may contribute to the recruitment of cytotoxic T cells into the tumor and upregulate PD-L1 expression. So there is great rationale for this combination.

We know this combination had shown promising activity in the phase 1b setting, which led to the phase 3 trial. Let’s talk about the phase 3 study. The phase 3 study again compared atezolizumab-bevacizumab with sorafenib and was a positive trial. It showed a hazard ratio of 0.58 with a 42% reduction in the risk of death. The hazard ratio of 0.58 was for the primary end point of median overall survival. Similarly, there was a significant improvement in the median progression-free survival. Of note, the median overall survival for the sorafenib arm was 13 months. The median overall survival for the atezolizumab-bevacizumab combination had not been reached at the time of the presentation. We are awaiting further follow-up on that.

The response rate with the atezolizumab-bevacizumab combination was in the low 30% range compared with about 12% with sorafenib. Sorafenib performed better in this trial than what’s historically been known. Nonetheless, the combination was superior to sorafenib alone. This is likely to become an important first-line option as it gets regulatory approval potentially in the near future.

What is the rationale in this situation for choosing the combination versus a TKI [tyrosine kinase inhibitor], meaning sorafenib or lenvatinib? As we discussed, the atezolizumab-bevacizumab combination was shown to be superior to sorafenib with all end points being positive. Therefore, for the right patient, this combination would be the go-to option once approved and available because it is superior to the TKI. However, there are some areas of caution with this. This combination was evaluated in patients with Child-Pugh stage A cirrhosis. All patients must have had an endoscopy within 6 months prior to enrollment. If they had varices, those must have been treated according to institutional standard. The patient must meet those 2 criteria. I would be cautious about using this combination in patients with more advanced liver cirrhosis, especially Child-Pugh stage B and above, until we know that it would be safe. This is because the higher the Child-Pugh score, the higher the chance of liver cirrhosis and the higher the chance of more advanced portal hypertension and bleeding.

Lastly, one has to keep in mind the contraindication to atezolizumab and bevacizumab. Active autoimmune disease would be a contraindication. Similarly, recent bleeding in the past 6 months or recent arterial thrombotic events would be a contraindication to bevacizumab. In those situations, one would probably still choose to go with the TKI instead of the combination of atezolizumab and bevacizumab.

Transcript edited for clarity.

Case: A 69-Year-Old Man with Stage 4 Hepatocellular Carcinoma

Initial presentation

• A 69-year-old man presented with vague right upper quadrant abdominal discomfort, decreased appetite and occasional nausea and vomiting
• PMH: diabetes, medially controlled; hepatitis B virus diagnosed and treated 8 years ago
• SH: moderate amount of alcohol use (2-3 drinks a day)
• PE: abdominal discomfort on palpation
  
  

Clinical workup

• Labs: AFP 425 ng/mL, bilirubin 1.2 mg/dL, AST 102 U/L, ALT 116 U/L, ALP 380 U/L, INR 1.6, albumin 3.6 g/dL, BUN 15 mg/dL, creatinine 1.5 mg/dL, plt 205,000
• HBV+, HCV-
• Abdominal ultrasound revealed 2 hepatic lesions
• Chest/abdominal/pelvic CT scan confirmed 2 lesions in the right hepatic lobe measuring 3.2 cm and 5.5 cm, a suspicious lesion in the left lung lobe, and wide-spread lymphadenopathy noted
• Biopsy findings showed grade 3 HCC with marked fibrosis
• Surgical consult: unresectable due to tumor size and location
• Child-Pugh A; BCLC stage C
• ECOG 1
  
  

Treatment and Follow-Up

• Treatment with atezolizumab + bevacizumab was initiated
  • First imaging shows stable disease at 2 months; imaging at 4-month follow-up showed 2 new lung lesions
  • Treatment was subsequently changed to cabozantinib 60 mg PO qDay