Atezolizumab/bevacizumab and lenvatinib for hepatocellular carcinoma: A comparative analysis in a European real-world cohort
T. de CastroSabrina WellandLeonie JochheimCatherine LeyhKateryna ShmankoFabian FinkelmeierPetia JeliazkovaAndré JefremowMaria A. González-CarmonaArne KandulskiDaniel RoesslerNajib Ben KhaledStefan EnßleMarino VeneritoThorben W. FründtMichael SchultheißAngela DjananiMaria PangerlA MaieronThomas WirthJens U. MarquardtRichard GreilChristina FrickeRainer GüntherAndreas SchmidererDominik BettingerHenning WegeBernhard ScheinerMartina Müller‐NurasyidChristian P. StrassburgJürgen SieblerUrsula EhmerOliver WaidmannArndt WeinmannMatthias PinterChristian M. LangeAnna SaborowskiArndt Vogel
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Background: Immunotherapy-based combinations are currently the standard of care in the systemic treatment of patients with HCC. Recent studies have reported unexpectedly long survival with lenvatinib (LEN), supporting its use in first-line treatment for HCC. This study aims to compare the real-world effectiveness of LEN to atezolizumab/bevacizumab (AZ/BV). Methods: A retrospective analysis was conducted to evaluate the effectiveness and safety of frontline AZ/BV or LEN therapy in patients with advanced HCC across 18 university hospitals in Europe. Results: The study included 412 patients (AZ/BV: n=207; LEN: n=205). Baseline characteristics were comparable between the 2 treatment groups. However, patients treated with AZ/BV had a significantly longer median progression-free survival compared to those receiving LEN. The risk of hepatic decompensation was significantly higher in patients with impaired baseline liver function (albumin-bilirubin [ALBI] grade 2) treated with AZ/BV compared to those with preserved liver function. Patients with alcohol-associated liver disease had poorer baseline liver function compared to other etiologies and exhibited a worse outcome under AZ/BV. Conclusions: In this real-world cohort, survival rates were similar between patients treated with LEN and those treated with AZ/BV, confirming that both are viable first-line options for HCC. The increased risk of hepatic decompensation in patients treated with AZ/BV who have impaired baseline liver function underscores the need for careful monitoring. Future trials should aim to distinguish more clearly between metabolic dysfunction–associated steatotic liver disease and alcohol-associated liver disease.Keywords:
Lenvatinib
Atezolizumab
The aim of this retrospective proof-of-concept study was to compare different second-line treatments for patients with hepatocellular carcinoma and progressive disease (PD) after first-line lenvatinib or atezolizumab plus bevacizumab.A total of 1381 patients had PD at first-line therapy. 917 patients received lenvatinib as first-line treatment, and 464 patients atezolizumab plus bevacizumab as first-line.49.6% of PD patients received a second-line therapy without any statistical difference in overall survival (OS) between lenvatinib (20.6months) and atezolizumab plus bevacizumab first-line (15.7months; p = 0.12; hazard ratio [HR]= 0.80). After lenvatinib first-line, there wasn't any statistical difference between second-line therapy subgroups (p = 0.27; sorafenib HR: 1; immunotherapy HR: 0.69; other therapies HR: 0.85). Patients who underwent trans-arterial chemo-embolization (TACE) had a significative longer OS than patients who received sorafenib (24.7 versus 15.8months, p < 0.01; HR=0.64). After atezolizumab plus bevacizumab first-line, there was a statistical difference between second-line therapy subgroups (p < 0.01; sorafenib HR: 1; lenvatinib HR: 0.50; cabozantinib HR: 1.29; other therapies HR: 0.54). Patients who received lenvatinib (17.0months) and those who underwent TACE (15.9months) had a significative longer OS than patients treated with sorafenib (14.2months; respectively, p = 0.01; HR=0.45, and p < 0.05; HR=0.46).Approximately half of patients receiving first-line lenvatinib or atezolizumab plus bevacizumab access second-line treatment. Our data suggest that in patients progressed to atezolizumab plus bevacizumab, the systemic therapy able to achieve the longest survival is lenvatinib, while in patients progressed to lenvatinib, the systemic therapy able to achieve the longest survival is immunotherapy.
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Two tyrosine kinase inhibitors, lenvatinib and sorafenib, are available systemic therapies for patients with metastatic differentiated thyroid carcinoma. However, the treatment options for carcinoma refractory to both lenvatinib and sorafenib are limited. Here, we present a case of metastatic papillary thyroid carcinoma that showed resensitization to rechallenge with lenvatinib. A 72-year-old woman who had been diagnosed with papillary thyroid carcinoma with multiple lymph node and lung metastases progressed with the emergence of subcutaneous metastasis after 3 years of response to initial lenvatinib. Five months after switching to sorafenib, the tumor was enlarged with increased contrast enhancement on computed tomography, suggesting progressive disease. Three months after the reintroduction of lenvatinib, marked tumor shrinkage and a decrease in its contrast enhancement were seen. Rechallenge with lenvatinib showed tumor resensitization. Therefore, rechallenge with lenvatinib may be a treatment option in patients who have experienced progressive disease after initial response to lenvatinib and subsequent sorafenib.
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症例は慢性C型肝炎に罹患し飲酒習慣もある60歳代男性で,原発性肝細胞癌の一部に破裂予防の肝動脈塞栓術施行後,lenvatinib 8 mg/日を開始した.約1カ月で腫瘍に感染し,抗生剤治療不応かつ経皮的ドレナージ困難にて,lenvatinibを一週間休薬し,開腹下感染腫瘍切除術を施行した.術後創部治癒に問題なく,lenvatinibを4 mg/日で再開したが,肝障害,倦怠感,食思不振で35日間休薬した.dexamethasone併用して再開し,8 mg/日まで増量したが動脈血流減少せず,lenvatinib血中濃度が低値であった.12 mg/日に増量後,有害事象なしに血中濃度は上昇し,動脈血流も低下した.腫瘍感染の治療困難例は耐術能が許せば,lenvatinibの適切な休薬で外科的治療も選択でき,また,lenvatinib血中濃度による投与量の調整は有効な可能性がある.
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There is no standard posttreatment for patients with advanced hepatocellular carcinoma (HCC) in whom lenvatinib therapy has failed. This study aimed to investigate rates of migration to posttreatment after lenvatinib and to explore candidates for second-line agents in the patients with failed lenvatinib therapy.We retrospectively collected data on patients with advanced HCC who received lenvatinib as the first-line agent in 7 institutions.Overall survival and progression-free survival (PFS) of 178 patients who received lenvatinib as the first-line agent were 13.3 months (95% confidence interval [CI], 11.5-15.2) and 6.7 months (95% CI, 5.6-7.8), respectively. Sixty-nine of 151 patients (45.7%) who discontinued lenvatinib moved on to posttreatment. The migration rates from lenvatinib to the second-line agent and from the second-line agent to the third-line agent were 41.7 and 44.4%, respectively. Based on multivariate analysis, response to lenvatinib (complete or partial response according to modified RECIST) and discontinuation of lenvatinib due to radiological progression, as well as male were associated with a significantly higher probability of migration to posttreatment after lenvatinib. On the other hand, alpha-fetoprotein levels of 400 ng/mL or higher was correlated with a significantly lower probability of migration to posttreatment after lenvatinib. Of 63 patients who received second-line systemic therapy, 53 (84.2%) were administered sorafenib. PFS, objective response rate (ORR), and disease control rate (DCR) for sorafenib treatment were 1.8 months (95% CI, 0.6-3.0), 1.8%, and 20.8%, respectively. According to the Cox regression hazard model, Child-Pugh class B significantly contributed to shorter PFS. PFS, ORR, and DCR of 22 patients who received regorafenib after lenvatinib in any lines were 3.2 months (range, 1.5-4.9 months), 13.6%, and 36.3%, respectively. Similarly, PFS, ORR, and DCR of 17 patients who received regorafenib after lenvatinib in the third-line (after sorafenib) were 3.8 months (range, 1.1-6.5 months), 17.6%, and 41.2%, respectively.Sorafenib may not be a candidate for use as a posttreatment agent after lenvatinib, according to the results of the present study. Regorafenib has the potential to become an appropriate posttreatment agent after lenvatinib.
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