Lenvatinib for Hepatocellular Carcinoma Patients with Nonviral Infection Who Were Unlikely to Respond to Immunotherapy: A Retrospective, Comparative Study

Oncology ◽  
2021 ◽  
pp. 1-11
Author(s):  
Takeshi Hatanaka ◽  
Satoru Kakizaki ◽  
Tamon Nagashima ◽  
Masashi Namikawa ◽  
Takashi Ueno ◽  
...  

<b><i>Aim:</i></b> Atezolizumab plus bevacizumab (atezo + bev) shows a good overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients. However, the OS of patients with nonviral infection is quite worse than that in those with viral infection. The present study investigated the efficacy and safety of lenvatinib in patients with nonviral infection, who were unlikely to obtain benefit from atezo + bev. <b><i>Methods:</i></b> We conducted a multicenter retrospective study that included 139 advanced HCC patients treated with lenvatinib between March 2018 and September 2020. <b><i>Results:</i></b> The median age was 72 years, and 116 patients (83.5%) were male. Based on the etiology of liver disease, 84 (60.4%) and 55 patients (39.6%) were assigned to the viral infection and nonviral infection groups, respectively. The significant extents in patient characteristics were not observed in both groups. The objective response rate per mRECIST and progression-free survival (PFS) did not differ significantly between the viral infection and nonviral infection groups (36.0 vs. 33.0%, <i>p</i> = 0.85; and 7.6 vs. 7.5 months, <i>p</i> = 0.94, respectively). The 1-year survival rates were 68.7% (95% confidence interval [CI] 57.7–79.7%) in the viral infection group and 59.5% (95% CI 45.2–73.8%) in the nonviral infection group. The viral infection group was not a significant factor associated with the PFS or OS in a multivariate analysis. <b><i>Conclusions:</i></b> Lenvatinib shows no significant difference in response between patients with and without viral infection. Treatment strategies based on the etiology of liver disease may lead to good clinical outcome.

2020 ◽  
Vol 13 ◽  
pp. 175628482093248
Author(s):  
Dongxu Wang ◽  
Xu Yang ◽  
Jianzhen Lin ◽  
Yi Bai ◽  
Junyu Long ◽  
...  

Background: The prospect for targeted therapies in advanced hepatocellular carcinoma (HCC) has dramatically changed since several recent clinical trials have yielded promising results. The number of second-line therapies is increasing, though the consequent challenge is to consider differences between these interventions. This is a comparative investigation of presently approved second-line drugs for HCC based on findings from phase III randomized controlled trials. Methods: Data related to treatment efficacy including overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were extracted and compared using a Bayesian approach. Adverse events (AEs) and the rate of discontinuation due to AEs were assessed and compared with provide a more complete understanding. OS and PFS in patients with alpha fetoprotein (AFP) values greater than 400 were compared and ranked as a subgroup. Results: A total of five trials involving 2571 patients were included. The comparison suggests that regorafenib and cabozantinib significantly prolong OS compared with placebo. The rate of AEs and treatment discontinuation did not significantly differ, although the types of AEs varied substantially. Subgroup analysis did not highlight a significant OS difference between regorafenib [hazard ratio (HR) 0.68; 95% confidence interval (CI) 0.50–0.92], cabozantinib (HR 0.71; CI 0.54–0.94) and ramucirumab (HR 0.69; CI 0.57–0.84). Conclusion: Among the four second-line HCC therapies compared, regorafenib and cabozantinib appear to be better choices in terms of OS. Cabozantinib, regorafenib and ramucirumab have similar levels of efficacy for those with AFP >400, although ramucirumab has fewer side effects. No significant difference was observed in AEs, but some AEs related to each of these interventions should be given further consideration.


2021 ◽  
Vol 9 (2) ◽  
pp. e001945 ◽  
Author(s):  
Jeffrey Sum Lung Wong ◽  
Gerry Gin Wai Kwok ◽  
Vikki Tang ◽  
Bryan Cho Wing Li ◽  
Roland Leung ◽  
...  

BackgroundProgrammed cell death protein 1 (PD-1) pathway blockade with immune checkpoint inhibitors (ICIs) is a standard therapy in advanced hepatocellular carcinoma (HCC) nowadays. No strategies to overcome ICI resistance have been described. We aimed to evaluate the use of ipilimumab and anti-PD-1 ICIs (nivolumab or pembrolizumab) combinations in patients with advanced HCC with progression on prior ICIs.MethodsPatients with advanced HCC with documented tumor progression on prior ICIs and subsequently received ipilimumab with nivolumab/pembrolizumab were analyzed. Objective response rate (ORR), median duration of response (DOR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed.ResultsTwenty-five patients were included. The median age was 62 (range: 51–83). About 68% were of Child-Pugh (CP) Grade A and 48% had primary resistance to prior ICI. At median follow-up of 37.7 months, the ORR was 16% with a median DOR of 11.5 months (range: 2.76–30.3). Three patients achieved complete response. The median TTP was 2.96 months (95% CI: 1.61 to 4.31). Median OS was 10.9 months (95% CI: 3.99 to 17.8) and the 1 year, 2 year and 3 year survival rates were 42.4%, 32.3% and 21.6%, respectively. The ORR was 16.7% in primary resistance group and 15.4% in acquired resistance group (p=1.00). All responders were of CP A and Albumin-Bilirubin (ALBI) Grade 1 or 2. CP and ALBI Grades were significantly associated with OS (p=0.006 and p<0.001, respectively). Overall, 52% of patients experienced TRAEs and 12% experienced Grade 3 or above TRAEs.ConclusionsIpilimumab and nivolumab/pembrolizumab can achieve durable antitumor activity and encouraging survival outcomes with acceptable toxicity in patients with advanced HCC who had prior treatment with ICIs.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Atsushi Hiraoka ◽  
Takashi Kumada ◽  
Toshifumi Tada ◽  
Joji Tani ◽  
Kazuya Kariyama ◽  
...  

AbstractIt was recently reported that hepatocellular carcinoma (HCC) patients with non-alcoholic steatohepatitis (NASH) are not responsive to immune-checkpoint inhibitor (ICI) treatment. The present study aimed to evaluate the therapeutic efficacy of lenvatinib in patients with non-alcoholic fatty liver disease (NAFLD)/NASH-related unresectable-HCC (u-HCC). Five hundred thirty u-HCC patients with Child–Pugh A were enrolled, and divided into the NAFLD/NASH (n = 103) and Viral/Alcohol (n = 427) groups. Clinical features were compared in a retrospective manner. Progression-free survival (PFS) was better in the NAFLD/NASH than the Viral/Alcohol group (median 9.3 vs. 7.5 months, P = 0.012), while there was no significant difference in overall survival (OS) (20.5 vs. 16.9 months, P = 0.057). In Cox-hazard analysis of prognostic factors for PFS, elevated ALT (≥ 30 U/L) (HR 1.247, P = 0.029), modified ALBI grade 2b (HR 1.236, P = 0.047), elevated AFP (≥ 400 ng/mL) (HR 1.294, P = 0.014), and NAFLD/NASH etiology (HR 0.763, P = 0.036) were significant prognostic factors. NAFLD/NASH etiology was not a significant prognostic factor in Cox-hazard analysis for OS (HR0.758, P = 0.092), whereas AFP (≥ 400 ng/mL) (HR 1.402, P = 0.009), BCLC C stage (HR 1.297, P = 0.035), later line use (HR 0.737, P = 0.014), and modified ALBI grade 2b (HR 1.875, P < 0.001) were significant. Lenvatinib can improve the prognosis of patients affected by u-HCC irrespective of HCC etiology or its line of treatment.


2017 ◽  
Vol 35 (6) ◽  
pp. 611-617 ◽  
Author(s):  
Kazuomi Ueshima ◽  
Naoshi Nishida ◽  
Masatoshi Kudo

Objectives: Previously, no therapeutic agent has been known to improve the overall survival compared with placebo in patients with hepatocellular carcinoma (HCC), who have progressed after sorafenib. In this patient population, regorafenib was first demonstrated to confer a survival benefit in the RESORCE trial, and subsequently it was approved as a second-line treatment for patients with advanced HCC. An open-label expanded access program (EAP) of regorafenib was implemented for compassionate use. We investigated the efficacy and safety of regorafenib based on our experience of the RESORCE trial and the EAP. Methods: Data from 5 patients from the RESORCE trial and 6 from the EAP were analyzed retrospectively. All patients had tolerated prior sorafenib and were progressing during sorafenib treatment. Results: The median progression-free survival was 9.2 months (95% CI 2.3-16.1). One patient achieved a partial response and 7 achieved stable disease. The objective response rate was 9.1%, and the disease control rate was 72.7%. No treatment-associated mortalities were observed. Grade 3 hypophosphatemia was observed in 2 patients, grade 2 anorexia was observed in 5 patients, and grade 3 neutropenia was observed in 2 patients. Grade 2 and grade 3 thrombocytopenia were observed in 2 and 3 patients, respectively. All treatment-related adverse events were improved by reduction or interruption of regorafenib. Five patients showed decreased serum albumin levels. Conclusion: Sorafenib and regorafenib sequential therapy presents a safe and effective treatment option for patients with advanced HCC.


2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 317-317
Author(s):  
Kazufumi Kobayashi ◽  
Sadahisa Ogasawara ◽  
Aya Takahashi ◽  
Yuya Seko ◽  
Satoshi Tsuchiya ◽  
...  

317 Background: There have been considerable advances in systemic chemotherapy for hepatocellular carcinoma (HCC) in recent times. Currently, four molecular target agents (MTA) are available for HCC treatment in Japan. Sequential therapy using multiple MTAs is being considered as the gold standard of treatment. However, the effectiveness of the treatment strategy transition for HCC remains unclear. The present study aimed to clarify the current practical use of MTAs and its effectiveness in HCC treatment. Methods: In this multicenter, retrospective study, we collected and analyzed the clinical data of 877 patients who underwent MTA therapy for HCC from June 2009 to March 2019 at several institutes in Japan. The patients were classified into 3 groups as per the period of initial MTA treatment beginning (period 1: 2009–2012, n = 267; period 2: 2013–2016, n = 352; period 3: 2017–2019, n = 258). These 3 periods were defined to have approximately same term. Period 3 means the era of multiple MTAs because of the approval of regorafenib in Japan in 2017. We assessed the patient characteristics, MTA use, and prognosis of the 3 groups. Results: The proportion of patients with advanced-stage HCC, defined according to the Barcelona Clinic Liver Cancer staging system, in each period was 70.1%, 66.5%, and 62.0% in period 1, 2, and 3, respectively. MTA use for intermediate stages increased with the passage of time ( p = 0.052). The proportion of multiple MTAs use was remarkably increased in the 3 groups (1.1%, 10.2%, and 42.6%, respectively, p < 0.0001). Child-Pugh score, proportion of macrovascular invasion, extrahepatic metastasis, and α-fetoprotein (AFP) ≥400 ng/mL showed no significant difference among the 3 groups. The median overall survival was 11.9 months for the entire cohort and 10.4, 11.3, and 15.2 months, for period 1, 2, and 3, respectively. It is noteworthy that the prognosis of patients with HCC improved over time ( p = 0.016). With respect to progression-free survival, the median value was 3.0 months for the entire cohort and 2.7, 2.8, and 4.7 months for period 1, 2, and 3, respectively ( p < 0.0001). The treatment duration was also prolonged with time (2.7, 3.2, and 6.6 months for period 1, 2, and 3, respectively; p < 0.0001). Multivariate analysis using Cox proportional hazard model showed that HCV infection, Child-Pugh score, performance status, α-fetoprotein ≥400 ng/mL, presence of macrovascular invasion, and period 3 for initial MTA introduction were independent prognostic factors. Conclusions: Sequential therapy with multiple MTAs has gained popularity with time and is considered to improve patient prognosis. The development of MTA therapy for HCC is expected to continue. Therefore, further studies are needed to help determine the appropriate drugs, the sequence of MTA use, and the precise transition time.


2018 ◽  
Vol 17 (5) ◽  
pp. 0-10
Author(s):  
Rogério Camargo-Pinheiro-Alves ◽  
Daniele E. Viera-Alves ◽  
Arthur Malzyner ◽  
Otavio Gampel ◽  
Thaisa de F. Almeida-Costa ◽  
...  

Introduction and aim. Sorafenib has been the standard of care for first-line treatment of advanced hepatocellular carcinoma, a complex disease that affects an extremely heterogenous population. Thereby requiring multidisciplinary individualized treatment strategies that match the disease characteristics and the patients’ specific needs. Material and methods. Data for 175 patients who received sorafenib for hepatocellular carcinoma in three different hospitals in Sao Paulo, Brazil over a span of nine years were retrospectively analyzed. Results. The median age was 62 years. Percentages of patients with Child-Pugh A, B and C liver cirrhosis were 61%, 31% and 5%, respectively. Approximately half of the patients had Barcelona Clinic Liver Cancer stage B disease, and the other half had stage C. The median treatment duration was 253 days. Sorafenib dose was reduced to 400 mg/day in 41% of the patients due to toxicity. Overall objective response rate as per Response Evaluation Criteria in Solid Tumors and its modified version was 39%. Patients who received transarterial chemoembolization (TACE) at any point during sorafenib therapy were significantly more likely to experience an objective response. After a median follow-up of 339 days, the median overall survival was 380 days. Child-Pugh cirrhosis, tumor response and concomitant chemoembolization were independent prognostic factors for overall survival in multivariate analysis. Conclusion. Our results suggest that, in experienced hands, sorafenib therapy may benefit carefully selected hepatocellular carcinoma patients for whom other therapies are initially contraindicated, including those patients with Child-Pugh B liver function and those patients who are subsequently treated with concomitant TACE.


2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 339-339
Author(s):  
S. Lee ◽  
S. Yoon ◽  
S. Shin ◽  
H. Choi

339 Background: Prior to the sorafenib era, most of the advanced hepatocellular carcinoma (HCC) patients had to rely only on conventional cytotoxic chemotherapy. But the introduction of sorafenib in 2008 had given HCC patients additional option for their treatment. However, given that sorafenib has been a nonreimbursable drug under the Korea public health system, most of treatment strategy has largely been determined by patients' affordability of the drug rather than by difference in efficacy and toxicity of the two treatments. Therefore, we compared the efficacy and toxicity of the two treatments by observing HCC patients. Methods: From January 2002 to December 2009, 173 patients with unresectable HCC had been retrospectively analyzed. Among them, 44 (25.4%) had been treated with sorafenib and the remaining had received cytotoxic chemotherapy. We evaluated objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicity profiles. Results: The median OS of sorafenib group was 23.0 weeks (95% CI, 8.1-37.9) vs. 43.6 weeks (95% CI, 34.0-37.9) for cytotoxic chemotherapy group. The median PFS for sorafenib group was 11.1 weeks (95% CI, 6.5-15.8) versus 12.4 weeks (95% CI, 8.1-16.7) for cytotoxic chemotherapy group. However, the difference in both findings had not been statistically significant (p=0.105 and p=0.496, respectively). ORR and DCR for sorafenib group were 2.3% and 52.3% versus 6.2% and 43.4% for cytotoxic chemotherapy group, respectively. Patients treated with chemotherapy had shown higher frequencies of grade 3 or 4 neutropenia, 19.7%, (vs. 0% for sorafenib). However, the group with sorafenib had reported a higher rate of all grade dermatologic toxicities such as hand-foot skin reaction, rash and pruritus. Conclusions: Our analysis indicates that efficacy of conventional chemotherapy is not inferior to that of sorafenib. Further research including novel target agent and cytotoxic chemotherapy is needed to improve clinical outcomes for advanced HCC. No significant financial relationships to disclose.


2017 ◽  
Vol 35 (4_suppl) ◽  
pp. TPS504-TPS504 ◽  
Author(s):  
Andrew X. Zhu ◽  
Jennifer J. Knox ◽  
Masatoshi Kudo ◽  
Stephen L. Chan ◽  
Richard S. Finn ◽  
...  

TPS504 Background: The tyrosine kinase inhibitor sorafenib is the standard of care for first-line hepatocellular carcinoma (HCC). For patients with HCC after disease progression on sorafenib or for those with intolerance to sorafenib, no approved therapies are available. Because HCC is often driven by inflammation and is also associated with a suppressed immunoenvironment, there is a strong rationale to evaluate immunotherapy in patients with this type of cancer. The single-arm, multisite, phase 2 KEYNOTE-224 study (ClinicalTrials.gov, NCT02702414) was designed to evaluate the efficacy and safety of the anti–PD-1 antibody pembrolizumab in patients with previously treated advanced HCC. Methods: Approximately 100 patients will be enrolled. Inclusion criteria include age ≥18 years, histologically or cytologically confirmed diagnosis of HCC Barcelona Clinic Liver Cancer (BCLC) stage C disease or BCLC stage B disease not amenable to or refractory to locoregional therapy, and disease not amenable to a curative treatment approach (eg, transplantation, surgery, or ablation). Patients must also have measurable disease based on RECIST v1.1 as confirmed by central imaging vendor review, documented objective radiographic progression after stopping treatment with sorafenib or intolerance to sorafenib, Child-Pugh liver score A, ECOG performance status 0-1, and predicted life expectancy > 3 months. Patients will be allocated to receive pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles (~2 years) or until disease progression, unacceptable toxicity, patient withdrawal of consent, or investigator decision. Response will be assessed every 9 weeks per RECIST v1.1 by central imaging vendor review. Adverse events (AEs) will be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. The primary end point is objective response rate per RECIST v1.1 by central imaging vendor review. Secondary end points are overall survival; safety and tolerability; and duration of response, disease control rate, time to progression, and progression-free survival per RECIST v1.1 by central imaging vendor review. Enrollment in KEYNOTE-224 is ongoing. Clinical trial information: NCT02702414.


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14701-e14701
Author(s):  
Min Hua Chen ◽  
Wei Yang ◽  
Jie Wu ◽  
Wei Wu ◽  
Kun Yan

e14701 Background: To investigate the application value and strategies of ultrasound-guided percutaneous radiofrequency ablation (RFA) in treating advanced hepatocellular carcinoma (HCC) which is common in china. Methods: A total of 655 patients with unresectablely advanced HCC underwent percuatenous RFA therapy and 92 patients with 136 tumors among them were enrolled into the study. According to the 6th UICC/AJCC-TNM system, 82 and 10 patients were in stage III and IV, respectively. The tumor size ranged from 1.5 to 8.0 cm (mean±SD, 4.5±1.6 cm). 59 patients had solitary tumor and the remaining 33 patients had multiple tumors. The Child-Pugh classification of A, B and C were 58,32 and 2 patients, respectively. Established strategies included: (1) select RFA indications based on the contrast-enhanced ultrasound (CEUS) results; (2) design radical protocols based on invasive range showed by CEUS; (3) multiple overlapping ablations based on mathematical protocol; (4) two or three bipolar RFA electrodes with three dimensional localization; (5) color US guided percutaneous ablation of tumor feeding artery (including TACE) + RFA for HCC with rich supply. The patients underwent follow-up using enhanced CT at one month, and then every three months after RFA. The ablation was considered a success if no abnormal enhancement or wash-out was detected in the treated area on the CT scan at one month. All patients after RFA received liver protection treatments. Overall survival was estimated by Kaplan-Meier analysis. Results: Early complete tumor necrosis rate after initial RFA was 90.4% (123/136 tumors). Serious complications were developed in two patients (2.2%) and no treatment-related death occurred. 3~129 months were followed up. Local recurrence rate was 15.4 %(21/136 tumors). The 1-, 3-, 5-year overall survival rates were 83.3 %, 48.3 %, 21.9%, respectively, and the median survival time was 35 months. Conclusions: RFA treatment of advanced HCC proved to be feasible. Paying attention to apply treatment strategies and liver protection therapies in RFA can effectively improve the survival.


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15643-e15643 ◽  
Author(s):  
Nibash Budhathoki ◽  
Binay Kumar Shah

e15643 Background: Sorafinib was approved for advanced hepatocellular carcinoma in 2007. This study was conducted to study relative survival in elderly patients with advanced hepatocellular carcinoma in presorafinib and sorafinib era. Methods: We selected elderly patients (age ≥ 65 years) with advanced hepatocellular carcinoma (distant metastasis based on SEER’s LRD staging) from the Surveillance, Epidemiology, and End Results (SEER) database diagnosed during January 2000 to December 2013. We calculated one year and five year relative survival rates in pre- (2000-2006) and post- sorafinib (2008-2013) era by sex and ethnicity (Caucasians, African-Americans (AA) & Other) using SEER*Stat software. Results: There were total of 1533 patients in presorafinib era and 1694 patients in postsorafinib era. Of the total population, 71.30% were male and 28.70% female, 71% were Caucasian, 10% African-American and 19% were other race. Median age of patients was 73 years (65-99 years) and medial follow up period was 3 months (0-167 months) Survival rates improved significantly from pre- to post- sorafenib era (1 year RS: 10.60% ±0.80% vs 12.10±0.90%, p value = 0.001; 5 year RS: 1.10%±0.30% vs 1.8%±0.6%, p value = 0.001 ). The survival rate improved significantly for male (1 year RS: 11.60%±1.00% vs 12.30%±1.00%, p value = 0.006; 5 year RS: 1.00%±0.40% vs 1.3%± 0.6% , p value = 0.007) and Caucasian (1 year RS: 10.60%±1.00% vs 12.60%±1.10%, p value = 0.0008; 5 year RS: RS = 1.20%±0.40% vs 1.4%±0.7%, P value = 0.001) patients in post sorafenib era. There was no significant difference in the survival rates among any other cohorts examined.However in black (N = 153 vs 158 , RS = 6.80%±2.10% vs 7.80%±2.40% , p value = 0.77) or other races (N = 311 vs 311, RS = 12.20%±1.90% vs 12.80%±2.10%, p value = 0.30 ) , no significant improvement in survival was noted. Conclusions: Our study showed that relative survival rates of elderly patients with advanced hepatocellular carcinoma with distant metastasis has improved in the post-sorafenib compared to pre-sorafenib era. The improvement in survival is limited to male and Caucasian patients.


Sign in / Sign up

Export Citation Format

Share Document