A phase II study of the efficacy and safety of the combination therapy of the MEK inhibitor refametinib (BAY 86-9766) plus sorafenib for Asian patients with unresectable hepatocellular carcinoma

Ho Yeong Lim, Jeong Heo, Hye Jin Choi, Cheng Yao Lin, Jung Hwan Yoon, Chiun Hsu, Kun Ming Rau, Ronnie T.P. Poon, Winnie Yeo, Joong Won Park, Miah Hiang Tay, Wen Son Hsieh, Christian Kappeler, Prabhu Rajagopalan, Heiko Krissel, Michael Jeffers, Chia Jui Yen, Won Young Tak

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Abstract

Purpose: There is an unmet need for treatment options in hepatocellular carcinoma (HCC). Sorafenib is currently the only approved systemic treatment for HCC. Refametinib, an oral, allosteric MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in vitro and in vivo. A phase II study evaluated efficacy and safety of refametinib plus sorafenib in Asian patients with HCC (NCT01204177). Experimental Design: Eligible patients received twice-daily refametinib 50 mg plus twice-daily sorafenib 200 mg (morning)/400 mg (evening), with dose escalation to sorafenib 400 mg twice daily from cycle 2 if no grade ≥2 hand-foot skin reaction, fatigue, or gastrointestinal toxicity occurred. Primary efficacy endpoint: disease control rate. Secondary endpoints: time to progression, overall survival, pharmacokinetic assessment, biomarker analysis, safety, and tolerability. Results: Of 95 enrolled patients, 70 received study treatment. Most patients had liver cirrhosis (82.9%) and hepatitis B viral infection (75.7%). Disease control rate was 44.8% (primary efficacy analysis; n = 58). Median time to progression was 122 days, median overall survival was 290 days (n = 70). Best clinical responders had RAS mutations; majority of poor responders had wild-type RAS. Most frequent drug-related adverse events were diarrhea, rash, aspartate aminotransferase elevation, vomiting, and nausea. Dose modifications due to adverse events were necessary in almost all patients. Conclusions: Refametinib plus sorafenib showed antitumor activity in patients with HCC and was tolerated at reduced doses by most patients. Frequent dose modifications due to grade 3 adverse events may have contributed to limited treatment effect. Patients with RAS mutations appear to benefit from refametinib/sorafenib combination.

Original languageEnglish
Pages (from-to)5976-5985
Number of pages10
JournalClinical Cancer Research
Volume20
Issue number23
DOIs
Publication statusPublished - 2014 Dec 1

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Lim, H. Y., Heo, J., Choi, H. J., Lin, C. Y., Yoon, J. H., Hsu, C., Rau, K. M., Poon, R. T. P., Yeo, W., Park, J. W., Tay, M. H., Hsieh, W. S., Kappeler, C., Rajagopalan, P., Krissel, H., Jeffers, M., Yen, C. J., & Tak, W. Y. (2014). A phase II study of the efficacy and safety of the combination therapy of the MEK inhibitor refametinib (BAY 86-9766) plus sorafenib for Asian patients with unresectable hepatocellular carcinoma. Clinical Cancer Research, 20(23), 5976-5985. https://doi.org/10.1158/1078-0432.CCR-13-3445