Approaching Second-Line Therapy for Advanced HCC

Pierre Gholam, MD: Patients who reach second-line status in the setting of HCC [hepatocellular carcinoma] used to be few and far between. But increasingly, as our ability to treat patients effectively in the first line with therapies that maintain good liver function and good functional status are improving, we are seeing a fairly significant increase in the number of patients who get the second-line therapy. This is again good news for patients who have advanced HCC, because they’re hopefully able to benefit from potentially life-extending therapies.

By the time a patient gets a second-line therapy, clearly, we have to make a reassessment of liver function and ensure that these patients continue to have an adequate liver function that would allow them to benefit from treatment without jeopardizing their overall life expectancy because of the worsening of liver disease.

We want to see a patient with a reasonable bilirubin level. We want to see a patient with a MELD [model for end-stage liver disease] score, which I referred to before, that has not shot up very high—certainly not above 15 or 20, which would be potentially problematic in some of those patients.

We want to see a patient who doesn’t have massive uncontrolled ascites, bleeding, or major complications of liver disease. We definitely want to see a patient who’s got some reasonable preservation of functional status as reflected by the ECOG performance status.

When we think about second-line therapy, there is now a long list of therapies that are approved and endorsed by the NCCN [National Comprehensive Cancer Network]. These include individual immuno-oncology [I/O] drugs such as pembrolizumab and nivolumab, as well as tyrosine kinase inhibitors [TKIs], including regorafenib, cabozantinib, and ramucirumab. All these are treatments that could be good options in the appropriate patient for a specific clinical situation.

It is generally acceptable, though by no means proven without any shadow of a doubt by evidence, that if someone had received an immuno-oncological therapy as first line, this is not necessarily something that is currently clearly approved by any FDA indication. Assuming that a patient received immuno-oncology in the first line, the precedent for initiating another I/O drug in the second line certainly does not exist in HCC and probably rarely exists in any other cancers that I’m aware of.

Therefore, if a patient has received that therapy, or if they had received a tyrosine kinase inhibitor in the first line—which, as I mentioned, would be sorafenib or for lapatinib—a reasonable second-line agent could be 1 of the tyrosine kinase inhibitors that I mentioned: cabozantinib and regorafenib, and monoclonal antibodies such as ramucirumab, which addresses vascular pathways.

But if a patient has received a therapy in kinase inhibitor in the first line, immuno-oncology drugs such as pembrolizumab and nivolumab would potentially be appropriate. That is a fork in the road where one could use clinical judgment to decide which choice of treatment to offer the patient.

Another important consideration is how well a patient has tolerated first-line therapy, especially if it’s a TKI. If a patient did well with sorafenib for a long time, many months without experiencing major adverse events, consideration of another TKI such as regorafenib or cabozantinib for second line is certainly very reasonable.

If they have not and potentially are struggling with adverse effects of TKIs—fatigue, for example, would be something across the board—TKIs would be potentially a cause of it. Then perhaps shifting to an I/O option is reasonable.

Although there is a fair amount of common sense and just clinical judgment that need to be exercised, there are some general rules of the road that the clinician could benefit from when thinking about initiating second-line therapy.

Transcript edited for clarity.

Case: A 61-Year-Old Man with Stage 4 Hepatocellular Carcinoma

Initial presentation

• A 61-year-old man presented with nausea, vomiting, decreased appetite and occasional generalized itching
• PMH: diabetes, medially controlled; hepatitis C and B coinfection diagnosed and treated 6 years ago; diagnosed with HCC December 2018
• PE: scleral icterus; jaundice; spleen palpable 4-cm below the costal margin
  
  

Clinical workup

• Labs: AFP 436 ng/mL, bilirubin 1.6 mg/dL, AST 105 U/L, ALT 110 U/L, ALP 390 U/L, INR 1.9, albumin 3.8 g/dL, BUN 13 mg/dL, creatinine 1 mg/dL, plt 95,000
• HBV+, HCV+
• Abdominal ultrasound revealed 3 small hepatic lesions
• Chest/abdominal/pelvic CT scan confirmed 2 focal nodules in the right and 1 in the left hepatic lobe measuring 3.6 cm, 4.9 cm and 5.2 cm, a suspicious lesion in the right lower lung lobe; wide-spread lymphadenopathy was noted
• Biopsy findings showed grade 3 hepatocellular carcinoma with marked fibrosis
• Surgical consult: unresectable due to tumor size and location
• Child-Pugh A; BCLC stage C
• ECOG 1
  
  

Treatment and Follow-Up

• 2018: treated with lenvatinib 400 mg PO q12hr; he experienced diarrhea for 2 weeks which resolved; achieved PR
• 2020: Imaging showed a new lung lesion
  • Treatment was with cabozantinib 60 mg PO qDay was initiated