Study Supports TKI Response as Predictor of Survival in HCC

Published: Monday, Jan 21, 2019

Masatoshi Kudo, MD
Masatoshi Kudo, MD
Patients with previously untreated hepatocellular carcinoma (HCC) lived twice as long if they responded to TKI therapy as compared with patients who did not achieve an objective response, according to a retrospective analysis of a randomized trial.

Response to lenvatinib (Lenvima) or sorafenib (Nexavar) was associated with a median overall survival (OS) of 22.4 months versus 11.4 months for patients who did not achieve a partial or complete response.1 Multivariate analysis identified response to treatment as an independent predictor of (OS).

The survival difference between responding and nonresponding patients emerged as early as 2 months and persisted throughout follow-up, Masatoshi Kudo, MD, of Kindai University Faculty of Medicine in Osaka, Japan, reported at the 2019 Gastrointestinal Cancers Symposium.

“Objective response by modified RECIST criteria was an independent predictor of overall survival in patients with hepatocellular carcinoma, regardless of treatment,” Kudo said in conclusion. “The association between objective response and overall survival was consistent with results reported in previous studies…Therefore, patients who achieve an objective response can potentially expect a longer overall survival.”

Nonetheless, additional studies are needed to validate the association between objective response and survival, he added.

Several studies demonstrated a significant association between objective response and survival in HCC. Data from the phase III REFLECT trial, comparing lenvatinib and sorafenib, afforded an opportunity to validate and possibly clarify the nature of the association.

The REFLECT trial demonstrated noninferiority of lenvatinib versus sorafenib in patients with previously untreated HCC. The results showed a median overall survival of 13.6 months among patients treated with lenvatinib and 12.3 months for patients randomized to sorafenib.2 Additionally, results for the overall patient population showed a doubling of median progression-free survival from 3.7 months with sorafenib to 7.4 months with lenvatinib.

Treatment with lenvatinib led to an investigator-assessed overall response rate of 24% versus 9% for the sorafenib arm. By independent review, response rates were 41% with lenvatinib and 12% with sorafenib. Both analyses utilized modified RECIST criteria.

By way of background, Kudo noted that recommendations from a European Association for the Study of the Liver consensus conference led to modifications of traditional RECIST criteria for tumor response to treatment. The modified criteria specified use of contrast-enhanced imaging to differentiate viable from necrotic tumor tissue to assess reduction in tumor burden. Authors of the guideline suggested a need for additional studies to validate the approach.

As previously reported, the REFLECT trial was a global, randomized, open-label study powered to demonstrate the noninferiority of lenvatinib versus sorafenib for untreated HCC. The post-hoc analysis reported by Kudo evaluated survival by response status, including landmark analyses of objective response status a 2, 4, and 6 months.

The analysis of overall survival by objective response provided confirmation for previous data, showing a 39% reduction in the survival hazard ratio (HR) among patients who responded to assigned treatment (95% CI, 0.49-0.76, P <.001). The landmark analysis of response at 2, 4, and 6 months all showed a significant survival advantage for patients who responded to treatment, ranging from about 5 to 7 months (P = .033 to P = .009).

A multivariate analysis confirmed objective response as an independent predictor of improved overall survival (HR, 0.611; P <.0001).


  1. Kudo M, Finn RS, Qin S, et al. Analysis of survival and objective response (OR) in patients with hepatocellular carcinoma in a phase III study of lenvatinib (REFLECT). J Clin Oncol. 2019;37 (suppl; abstr 186).
  2. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.
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