Future Treatment Landscape of Advanced HCC

Anthony El-Khoueiry, MD: In closing, it is certainly exciting to see that we have many more treatment options available for patients with advanced HCC [hepatocellular carcinoma] at this time. It’s important to note, however, that because of the availability of multiple options, we have some challenges ahead of us—I have already alluded to 1 of them—as to what would be the optimal sequence of these agents. There are going to be more studies needed in that regard. I believe that many of us face the challenge of seeing patients with more advanced liver cirrhosis, such as Child-Pugh stage B cirrhosis, and a lot of these agents have been studied in Child-Pugh stage A setting only. This is an area that requires more studies going forward.

We have some limited data that are emerging. We have some safety data for sorafenib in Child-Pugh stage B based on registry data. We also have a small cohort of 40 patients with nivolumab that was part of the CheckMate040 trial where nivolumab was studied as a single agent for patients with Child-Pugh stage B, with a score of 7 and 8. The response rate was comparable to Child-Pugh stage A, about 12% in that cohort, and the toxicity profile was comparable, with a slightly higher risk of AST [aspartate aminotransferase]/ALT [alanine aminotransferase] elevation. But the therapy was relatively well tolerated. For the patients with Child-Pugh stage B who responded to the therapy, many of them converted from Child-Pugh stage B to stage A. But this will be a continuing area of investigation.

I will note that there are many other combinations under consideration, especially in the first-line setting. These include combinations of PD-1 with TKIs [tyrosine kinase inhibitors], such as pembrolizumab with lenvatinib and pembrolizumab with regorafenib. The pembrolizumab-lenvatinib combination is currently in a phase 3 setting being compared with lenvatinib alone. The phase 1 data with this combination looks quite promising as well, with a response rate in the mid-30% range and a median PFS [progression-free survival] that’s at 9 months.

There is the combination of durvalumab and tremelimumab, the HIMALAYA trial, which is comparing DURVA-TREME [durvalumab-tremelimumab] with durvalumab alone and with sorafenib alone. We are awaiting the readout for this. For the nivolumab-ipilimumab combination, I mentioned the accelerated approval in the second line already, but there’s actually a first-line study comparing this combination with sorafenib or lenvatinib, investigator choice.

Lastly, I’d like to comment on the fact that these active systemic therapies are being evaluated in earlier stages of disease. There are adjuvant trials ongoing, looking at nivolumab in the adjuvant setting, pembrolizumab post resection as well in the adjuvant setting, and atezolizumab and bevacizumab post resection. Combination studies with local regional therapy, with liver-directed therapy, are ongoing as well.

Critically important is to start thinking about the time to transition from liver-directed therapy to systemic therapy. Because we have more systemic therapy options available, it is important that we do not overtreat patients with TACE [transarterial chemoembolization] or with Y90 radioembolization, which could become futile at some point. Liver function may deteriorate, and then we may miss the opportunity to sequence the systemic therapies.

This is an area of continuing evaluation. The criteria for shifting from liver-directed to systemic therapy are not all standardized, but there are some widely accepted ones. If the patient develops worsening liver function on liver-directed therapy, they should be switched to systemic therapy if they’re still candidates. If they develop extrahepatic disease, if they develop portal vein invasion, they should be switched to systemic therapy. But there are also more data that after 2 TACEs to the same lesion, if we do not achieve a complete response, the likelihood of additional TACE being helpful is very low. Therefore, this may be an indication again to switch to systemic therapy if the patient still has active disease. Similarly, if patients present with liver-limited disease that’s quite bulky or multifocal, the likelihood of local regional therapy achieving long-term control is low. A subset of these patients with BCLC [Barcelona Clinic Liver Cancer] stage B, with multifocal high-burden disease, may qualify to start systemic therapy up front.

In summary, this is an exciting time for the disease, with more treatment options for our patients. But certainly there is a continuing need for more enrollment in clinical trials and more learning in this space. Thank you very much.

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