Choosing a TKI in Second-Line Metastatic HCC

Michael A. Morse, MD, FACP:In terms of immunotherapies and TKIs [tyrosine kinase inhibitors], clearly you can say they have very different mechanisms of action. But among the TKIs, what they all have in common is targeting the VEGF receptor TKI function, so at a baseline they all do that. But among the different drugs, there are some other targets. It’s rare to have a TKI that only hits 1 target. Many of them are calleddirty. They hit multiple tyrosine kinases, and in reality, that may be why they’re beneficial—they don’t just target 1 function. With cabozantinib, what’s distinctly different is in addition to the VEGF receptor tyrosine kinase function, it also targets c-MET and AXL. C-Met is relevant for the ability of tumors to invade and spread, and AXL may also have some similar activities. But AXL also seems to have some effects on the immune system.

In reality, cabozantinib is not just targeting the vascular supply and affecting invasiveness but also may be affecting the immune response. To be clear, we do not use these as biomarkers. We aren’t testing the tumors and making sure that they have c-Met before we treat them with this drug because that has not been borne out in any of the trials. I also have to point out that we don’t know if these additional functions of cabozantinib explain its efficacy. That’s still being studied.

Cabozantinib was very appropriate for this patient as a second-line therapy. While the CELESTIAL trial did require people to have prior sorafenib, as I mentioned earlier, we now think of sorafenib and lenvatinib similarly when we’re considering second-line therapies. They’ve had a prior TKI, they also had extrahepatic spread, which patients on the CELESTIAL trial, some of them did have extrahepatic spread. They had Child-Pugh A liver function, which patients in the CELESTIAL trial were required to have. They fit the inclusion criteria for the trial, and CELESTIAL did include patients who had hepatitis B.

In terms of efficacy, what I would explain to a patient starting on cabozantinib, I would tell them that in the CELESTIAL trial, the median overall survival for the entire patient population receiving cabozantinib was 10.2 months versus 8.0 months for the people receiving placebo. Interestingly, this is a second-line patient. The CELESTIAL trial allowed people to have 1 or 2 prior therapies. There were patients on the study who were actually third-line. In fact, some of them had had prior immunotherapy.

In the case of all the patients on the CELESTIAL trial, the overall survival was 10.2 months versus 8 months for the placebo group. However, if you look purely at the second-line patients, the survival was 11.4 months for the patients treated with cabozantinib versus 7.7 months for the people treated with placebo.

Some patients are also concerned about how long it might take for the cancer to grow. In the case of the overall population on the CELESTIAL trial, this was 5.2 months for people receiving cabozantinib versus 1.9 months for people receiving placebo.

Transcript edited for clarity.

Case: 63-Year-Old Male with R/R mHCC

February 2018: Initial presentation

• A 63-year-old man with chronic HBV infection referred for further imaging studies based on suspicious findings during routine ultrasound for HCC

Initial Clinical Workup

• AFP: 300 IU/mL
• Child-Pugh A
  • Platelets: 210,000 cells/mcL
  • Bilirubin: 1.2 mg/dL
  • Albumin: 3.6 g/dL
  • INR: 1.1
  • No hepatic encephalopathy
  • Ascites not present
• Imaging: CT revealed 2 lesions in right hepatic lobe (2cm, 5cm); no extrahepatic disease; no cirrhosis; no portal hypertension
• BCLC: B
• PS: 0

Treatment

• Patient underwent right hepatectomy; negative margins; no vascular invasion
• AFP: WNL

December 2018

• On routine follow-up, imaging showed new lesion in left hepatic lobe (~2.3cm)
• Chest CT showed 3 small lesions (<1cm) in upper left lobe of lung
• Patient started on lenvatinib 12 mg QD; experienced moderate diarrhea and fatigue
• Imaging at 3 and 6 months showed partial response
• AFP: 100 IU/mL
• BCLC: C
• PS: 0

August 2019

• Routine follow-up blood sample reveals AFP 450 IU/mL
• CT scan showed progression in the lung and 2 new liver lesions; remains Child-Pugh A
• Patient started on cabozantinib 60 mg QD
• Patient developed grade 2 diarrhea; dose-reduction to 40 mg QD
• Imaging at 3 months showed stable disease
• Imaging at 6 months showed partial response