Posttreatment after lenvatinib in patients with advanced hepatocellular carcinoma.
Authors: Koroki Keisuke , Kanogawa Naoya , Maruta Susumu , Ogasawara Sadahisa , Obu Masamichi , Itokawa Norio , Inoue Masanori , Haga Yuki , Okabe Shinichiro , Seki Atsuyoshi , Atsukawa Masanori , Itobayashi Ei , Ito Kenji , Mizumoto Hideaki , Kobayashi Kazufumi , Kondo Takayuki , Suzuki Eiichiro , Chiba Tetsuhiro , Arai Makoto , Kato Naoya 
Published: January 2021

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Background: In clinical practice, the major disadvantage of lenvatinib to treat advanced hepatocellular carcinoma (HCC) is the lack of a posttreatment agent that has shown clear effectiveness. Thus, the establishment of second-line treatment after lenvatinib treatment failure is an urgent clinical issue to be addressed in systemic therapy in patients with advanced HCC. The study used real-world clinical data to explore candidate drugs that might be appropriate as second-line treatment after lenvatinib. Methods: We retrospectively reviewed the medical records of all patients with advanced HCC who received lenvatinib as the first-line agent in seven institutions in Japan between 23 March 2018 and 31 September 2019. Results: During the study period, 178 patients with advanced HCC received lenvatinib as first-line systemic therapy. At the time of lenvatinib administration, most patients were Eastern Cooperative Oncology Group Performance Status grade 0 or 1 (94.9%) and Child–Pugh class A (84.3%). According to the baseline radiological assessments, 25.3% and 36.0% of patients had macrovascular invasion and extrahepatic metastasis, respectively. Overall survival and progression-free survival (PFS) for lenvatinib treatment were 13.3 months (95% CI: 11.5–15.2) and 6.7 months (95% CI: 5.1–8.3), respectively. Of the 151 patients who discontinued lenvatinib, 71 (47.0%) converted to posttreatment. The conversion rates from lenvatinib to a second-line agent and from a second-line agent to a third-line agent were 41.4% and 42.4%, respectively. Based on multivariate analysis, lenvatinib response was defined as complete or partial according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Lenvatinib discontinuation due to radiological progression, according to mRECIST, was associated with a significantly higher probability of conversion to posttreatment after lenvatinib. Of the 63 patients who received second-line systemic therapy, 53 (84.1%) were administered sorafenib, with a PFS, response rate (RR), and disease control rate (DCR) of 1.8 months (95% CI: 0.6–3.0), 1.8%, and 20.8%, respectively. According to the Cox proportional hazards regression model, lenvatinib discontinuation due to radiological progression, Child–Pugh class B, and intrahepatic tumor volume > 50% at the time of sorafenib administration significantly contributed to a shorter PFS. Of the 22 patients who received regorafenib after lenvatinib discontinuation, five cases were as second-line therapy, and 17 were as third-line therapy. PFS, RR, and DCR for regorafenib treatment were 3.2 months (range, 1.5–4.9 months), 13.6%, and 36.3%, respectively. Conclusions: Sorafenib was not considered a candidate posttreatment agent after lenvatinib, except in a limited number of patients who discontinued lenvatinib without radiological progression. Regorafenib is a potential posttreatment agent after lenvatinib.