Expert Discusses Sequencing TKI Strategies in Hepatocellular Carcinoma

With 5 tyrosine kinase inhibitors approved for the treatment of patients with hepatocellular carcinoma, the next step for research in this treatment paradigm is focused on identifying the appropriate sequence of these agents.

Ghassan Abou-Alfa, MD

With 4 tyrosine kinase inhibitors (TKIs) approved for the treatment of patients with hepatocellular carcinoma (HCC), the next step for research in this treatment paradigm is focused on identifying the appropriate sequence of these agents.

“TKIs are the first choice of therapy, but within that context, the only TKIs that are applicable in the first-line setting are lenvatinib and sorafenib,” said Ghassan Abou-Alfa, MD. “The choice may be preferential for a specific physician and patient.”

Sorafenib (Nexavar) and lenvatinib (Lenvima) are the only 2 FDA-approved TKIs for frontline treatment in HCC. In the non-inferiority REFLECT trial, while lenvatinib showed non-inferiority to sorafenib with a median OS of 13.6 months and 12.3 months with sorafenib (HR, 0.92; 95% CI, 0.79-1.06).1Lenvatinib also improved progression-free survival (PFS) compared to sorafenib. These data demonstrated that both TKIs are good treatment options in the first-line setting for patients with HCC with different safety profiles with hand foot syndrome as most common side effect for sorafenib and hypertension for lenvatinib.

Second-line options following progression on either lenvatinib or sorafenib include TKIs and checkpoint inhibitors. In the second-line, physicians have the choice of regorafenib (Stivarga), cabozantinib (Cabometyx) and ramucirumab (Cyramza); also FDA approved in the second-line setting are 2 checkpoint inhibitors, nivolumab (Opdivo) and pembrolizumab (Keytruda).

Abou-Alfa explained that all of the second-line TKIs are possible choices with 2 particularities. Regorafenib is applicable only for patients with prior exposure to sorafenib with good tolerance and who progressed on sorafenib. Ramucirumab requires an elevated alpha-fetoprotein (AFP) level ≥400 ng/mL, despite a controversial role of AFP.2,3

Ongoing clinical trials are also looking into combining checkpoint inhibitors and combinations of checkpoint inhibitors and TKIs to further improve upon survival benefits in patients with HCC.

In an interview withTargeted Oncology, Abou-Alfa, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed key points about the sequencing of TKIs in HCC based on his presentation at the 2019 World Congress on Gastrointestinal Cancer. He highlighted the current treatment options and how much the role of TKIs have evolved in this space over the last few years.

TARGETED ONCOLOGY: What is the current role of TKIs in the treatment of HCC?

Abou-Alfa:TKIs have evolved very quickly in liver cancer. As we all know, we started back in 2008 with 1 drug, sorafenib, and now, we have 5 drugs in the TKI category, of which 4 became FDA-approved in the last 3 years.

TARGETED ONCOLOGY: What were the main points in your discussion at World GI this year?

Abou-Alfa:The biology and scientific arguments behind the use of each drug. It was also pointed out that all drugs are applicable irrespective of the etiology of liver cancer. It appears, though, that the sequence may matter, and it may be more pertinent to certain choices versus others. For example, regorafenib was approved on the sole condition that prior sorafenib was tolerated and patients progressed on it.

TARGETED ONCOLOGY: How do you go about making decisions in terms of sequencing these agents?

Abou-Alfa:However, the sequence of the TKIs still needs to be better defined. With the reported negative outcome of the 2 trials evaluating nivolumab in the first-line setting and pembrolizumab in the second-line setting, a more simplified version map of HCC treatments emerged where, at least for now, nivolumab and pembrolizumab are only applicable in the second-line setting based on the FDA approval. TKIs are thus the first choice of therapy, between lenvatinib and sorafenib.

TARGETED ONCOLOGY: How is the role of TKIs evolving in current research?

Abou-Alfa:The key research efforts are currently focused on combination therapy. While anti—PD-1s did not improved survival in the 2 nivolumab and pembrolizumab phase III clinical trials, one may wonder about adding anti–CTLA-4 therapy. We are all eagerly waiting to see the outcome of the Himalaya study. The other combination being evaluated is anti–PD-1 and anti-PD-L1 plus different TKIs.

TARGETED ONCOLOGY: How would you advise a community oncologist treating a patient with HCC?

Abou-Alfa:Most importantly, the community oncologist has to ensure that the patient and loved ones are well aware of the complexities of the disease. It is strongly recommended that physicians are well versed of the critical role TKIs have in the treatment of liver cancer, and recognize the continued research work of checkpoint inhibitors.


  1. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomized phase 3 non-inferiority trial.Lancet. 2018;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.
  2. Abou-Alfa GK. Ramucirumab and the controversial role of α-fetoprotein in hepatocellular carcinoma.Lancet Oncol. 2019;20(2):177-179. doi: 10.1016/S1470-2045(19)30009-9.
  3. Zhu AX, Finn RS, Galle PR, Llovet JM, Kudo M. Ramucirumab in advanced hepatocellular carcinoma in REACH-2: the true value of α-fetoprotein.Lancet Oncol. 2019;20(4):e191. doi: 10.1016/S1470-2045(19)30165-2.