Current Evidences and Future Perspectives for the Treatment of Advanced Hepatocellular Carcinoma = Current Evidences and Future Perspectives for the Treatment of Advanced Hepatocellular Carcinoma
저자
발행기관
학술지명
권호사항
발행연도
2020
작성언어
-자료형태
학술저널
수록면
14-15(2쪽)
제공처
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer deaths worldwide. For most patients with HCC, the diagnosis is delayed and the prognosis is poor, especially in patients with advanced HCC. Until recently, few therapies have shown to effectively improve the prognosis of advanced HCC.
Since it was first approved as a treatment option in 2007, sorafenib has remained the only therapy with proven efficacy in advanced HCC over the past decade. In 2018, the phase III trial of lenvatinib showed non-inferior survival versus sorafenib and remains another first-line option for advanced HCC. Other tyrosine kinase inhibitors (TKI), regorafenib and cabozantinib, also provided significantly improved survival in the second-line setting in patients who were refractory to sorafenib. Ramucirumab, a VEGF inhibitor, was also shown to offer survival benefits as a second-line option specifically for sorafenib-refractory patients with AFP ≥ 400 ng/dL.
More recently, another type of therapeutics, immune check point inhibitors (ICI), has presented a major breakthrough in treatment of advanced HCC. Nivolumab and pembrolizamab, an anti-PD-1 inhibitor, showed promising results and durable responses in Phase II trials, and thus achieved conditional FDA-approval as the second- line option. However, recent phase III tirlas of these agents have failed to meet their prespecified endpoints on treatment outcomes. Other immuno-targets, such as PD-L1 (durvalumab, atezolimumab, avelumab) or CTLA4 (tremelimumab, Ipilimumab) are currently being studied in clinical trials of advanced HCC.
The favorable treatment outcomes and acceptable toxicity profiles of ICI brought a treatment paradigm shift from a single therapy to combination strategies: ongoing trials are evaluating combination of anti-PD-1/anti-PD-L1/anti-CTLA4 as a backbone with TKIs, VEGF inhibitors, locoregional therapies, or even other ICI agents in hopes of further increasing objective responses and overall survival in this patient population. The IMbrave150 trial investigating the combination of atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF antibody) in patients with advanced HCC with no history of prior systemic therapy demonstrated a significant improvement in both OS and PFS over sorafenib. Based on the promising results, atezolizumab plus bevacizumab regimen was granted FDA approval for patients with unresectable HCC who have not received prior systemic therapy. This regimen not only gives insights into a new standard of first-line therapy for advanced HCC but also changing landscape of systemic therapy.
Currently, several combinations of anti-PD-1/anti-PD-L1 plus TKIs are being tested in different stages of HCC, including lenvatinib + pembrolizumab, camrelizumab + apatinib, atezolizumab + cabozantinib. These TKIs have reportedly immune modulatory effects as well as anti-angiogenic effects in tumor microenvironment, and thus are expected to enhance the antitumor property of ICI. Another promising combination strategy includes anti-PD-1/anti-PD-L1 plus anti-CTLA4 combination agents to achieve antitumor synergy. Trials of nivolumab plus ipilimumab, durvalumab plus tremelimumab, and triplet combination of cabozantinib, nivolumab, and ipilimumab for patients with sorafenib failure or advanced HCC are underway. Preliminary results of some studies are promising with more than twice objective response rates than a single agent as well as acceptable toxicity profiles, highlighting the increased antitumor effects of ICI combination therapy.
With the recent introduction of effective TKIs and ICIs, therapeutic options for advanced HCCs are rapidly expanding. While this progress is likely to offer improved outcomes for patients with advanced HCC, it has raised important issues regarding the optimal selection and sequencing of individual treatments. Based on a better knowledge of HCC therapeutics and differences in trial design, future efforts should be directed toward the development of biomarker-based therapy and new combination or sequential therapies with synergistic antitumor effects that can target multiple oncogenic pathways, which will provide the best therapeutic option for individual patients.
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