u-HCC Patients Research Articles

When will it be better? Lenvatinib combined with TACE for unresectable hepatocellular carcinoma: A retrospective analysis of real-world evidence in China.

281 Background: TACE and lenvatinib has each shown to prolong overall survival in patients with unresectable HCC, combination of which may also improve clinical outcomes and have been widely used in the real world accordingly. However, the optimal timing of adding on lenvatinb to TACE remains unclear. We are aiming to evaluate the efficacy and safety between two combination strategies. Methods: From Nov 2018 to Jun 2020, 79 consecutive patients had received a combination treatment of lenvatinib and TACE. Patients followed up for more than 2 months were included in this analysis. They were classified as early-combination group(add on lenvatinib before or after the first TACE ) and late-combination group(add on lenvatinib after at least two procedures of TACE ). Tumor response and progression-free survival (PFS,time from the first day of prescribing lenvatinib to progression or death) were assessed according to RECIST1.1 criteria. Liver function were also evaluated at baseline and every 2 months later. AEs were recorded during the combination treatment period according to CTCAE 5.0. Results: A total of 48 u-HCC patients was finally enrolled. Median follow-up in all patients was 9.3(5.3-14.3)months. Patients’ baseline characteristics were similar in two groups. For early-combination group(n=22)and late-combination group(n=26), the mean age was 65±9.7 and 61±11.6years(p=0.2);BCLC stage C HCC was 59% and 54%(p=0.89);and Child-Pugh A proportion was 81.8% and 77%(p=0.73) respectively. The objective response rate(ORR) was 22.9% in total 48 cases. There was no significant difference in response rate (18.2% vs 26.9%, P=0.51) or disease control rate (90.9% vs 92.3%, P=1.00). Median PFS was significantly longer in the early-combination group than that in late-combination group (14.5 vs 8.9 months; p=0.048). The safety profile was similar between two groups. Grade 3/4 adverse events were 3 (13.6%) and 2 cases(7.7%) respectively (P=0.65). Conclusions: This is to date the first real-world data of the combination timing of lenvatinib with TACE in u-HCC patients. Early-combination strategy may be a better option for the u-HCC patients with a longer mPFS.

Preliminary results of the phase II ALTER-H003 trial: Anlotinib plus toripalimab as a first-line treatment for patients with unresectable hepatocellular carcinoma.

314 Background: Hepatocellular carcinoma (HCC) is particularly prevalent in China because of the high prevalence of chronic hepatitis B infection. In the last decade, sorafenib was the first molecular target drug approved for the treatment of advanced liver cancer. Until recently, the combination of angiogenic inhibitor with anti-PD-1 /L1 monoclonal antibody has represented significant efficacy over sorafenib monotherapy in the first-line regimen of unresectable HCC. Nevertheless, there are still unmet needs in clinical practice due to limited choice of drugs. Anlotinib is a novel oral multi-targeted tyrosine kinase inhibitor that targets VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α and β, and c-kit, and has been approved for standard treatment of non-small cell lung cancer, small cell lung cancer and soft tissue sarcoma in China. Toripalimab, a humanized IgG4 mAb against PD-1, is the first Chinese-produced PD-1 inhibitor marketed, which has been approved as a second-line treatment for metastasis melanoma. This study aims to evaluate the efficacy and safety of anlotinib plus toripalimab as the first-line treatment for unresectable HCC. Methods: This was a single-arm, multicenter, phase II trial. 30 patients with unresectable HCC, Child-Pugh ≤7 and ECOG PS <2 will be enrolled if they had not been treated with prior treatment. Pts received anlotinib (12 mg, p.o., qd, d1-14, q3w) and toripalimab (240 mg, iv, d1, q3w) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by investigator according to mRECIST and irRECIST. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DoR) and safety. Results: By the cutoff date of September 21, 2020, 11 pts were enrolled and of those 8 pts were evaluable. 9 pts (81.8%) experienced treatment related adverse events (TRAEs) and grade 3 TRAEs occurred in 5 pts (45.5%). No grade 4 or above TRAEs occurred. The most common TRAEs were decreased appetite (n =6, 54.5%) and fatigue (n =5, 45.5%).Among 8 evaluable pts, unconfirmed ORR was 25% (95% CI 0.032-0.651) with 1 unconfirmed CR and 1 unconfirmed PR, and DCR was 87.5% (95% CI 0.473-0.997) according to mRECIST. Conclusions: Anlotinib in combination with toripalimab showed tolerant toxicity and preliminary anti-tumor efficacy in first-line regimen for uHCC patients. Furthermore, it is needed to be proved in update results and large scale studies. Clinical trial information: ChiCTR1900028295.

What Can Be Done to Solve the Unmet Clinical Need of Hepatocellular Carcinoma Patients following Lenvatinib Failure?

Background/Aim: An effective postprogression treatment of lenvatinib (LEN) against unresectable hepatocellular carcinoma (u-HCC) has not been established. We aimed to elucidate the clinical role of continuing LEN beyond progression of disease (PD). Methods: From March 2018 to October 2020, 99 u-HCC patients, in whom PD was confirmed (male:female = 78:21, median age 72 years, Child-Pugh A = 99, Barcelona Clinic Liver Cancer stage A:B:C = 2:43:54, LEN as first-line = 55), were enrolled (stopped LEN at PD [A group], n = 26; continued LEN beyond PD [B group], n = 73). Radiological response was evaluated with RECIST 1.1. Clinical features and prognostic factors for overall survival (OS) were retrospectively investigated using inverse probability weighting (IPW) calculated by propensity score. Results: Median time to progression, best response, and modified albumin-bilirubin grade (mALBI) at both baseline and PD did not show significant difference between the groups. Postprogression treatment in the A group was best supportive care in 17, sorafenib in 4, regorafenib in 3, ramucirumab in 1, and hepatic arterial infusion chemotherapy in 1. After adjusting with IPW, the B group showed better prognosis in regard to OS after PD and OS after introducing LEN than the A group (10.8/19.6 vs. 5.8/11.2 months, p < 0.001, respectively). In IPW-adjusted Cox hazard multivariate analysis, significant prognostic factors for OS after PD were mALBI 2b/3 at PD (HR 1.983, p = 0.021), decline of Eastern Cooperative Oncology Group performance status (ECOG PS) from baseline at PD (HR 3.180, p < 0.001), elevated alpha-fetoprotein (≥100 ng/mL) at introducing LEN (HR 2.511, p = 0.004), appearance of new extrahepatic metastasis (HR 2.396, p = 0.006), positive for hand-foot skin reaction (HFSR) before PD (any grade) (HR 0.292, p < 0.001), and continuing LEN beyond PD (HR 0.297, p < 0.001). Conclusion: When ECOG PS and hepatic reserve function permit, continuing LEN treatment beyond PD, especially in u-HCC patients showed HFSR during LEN treatment, might be a good therapeutic option, at least until a more effective drug as a postprogression treatment after LEN failure is developed.

Impact of Grip Strength in Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib.

Although sarcopenia is characterized by a loss of muscle strength and skeletal muscle mass, few studies have evaluated the effect of muscle strength on hepatocellular carcinoma (HCC) patients. We evaluated the impact of sarcopenia-related factors (grip strength (GS) and the skeletal muscle index (SMI)) on the survival among lenvatinib-treated unresectable HCC (u-HCC) patients. This single-center cohort study was conducted at a university hospital. The study population included 63 lenvatinib-treated u-HCC patients managed between April 2018 and April 2020. A decreased GS and decreased SMI were found in 21 (33.3%) and 22 (34.9%) patients, respectively. The overall survival (OS) of the normal GS group was significantly higher than that of the decreased GS group, while that of the normal and decreased SMI groups did not differ markedly. There were no significant differences in the progression-free survival between the normal GS and decreased GS groups or the normal SMI and decreased SMI groups. A multivariate Cox proportional hazards model showed that modified albumin-bilirubin-grade (mALBI) 2b (hazard ratio (HR) 4.39) and a decreased GS (HR 3.55) were independently associated with an increased risk of poor prognosis. In addition to the hepatic functional reserve, a decreased GS was a poor prognostic factor in lenvatinib-treated u-HCC patients.

Clinical effect of sequential therapy of LEN combination with anti-PD1 antibody in uHCC patients who progressed on LEN treatment: A real-world data in China.

e16654 Background: Lenvatinib (LEN) has been used in clinical practice because of its high response rate since administrated in China. However, no recommendation is available as second-line agents after LEN treatment. The combination therapy of anti-programmed death-1(PD1) antibodies with LEN have demonstrated promising clinical efficacy in advanced HCC. Some patients were used this combination treatment after progressed on LEN in real world settings in China. Preclinical studies also showed the immune-moderate effects of LEN. This study was retrospectively analyzed the efficacy and safety of 26 unresectable HCC patients treated with LEN and anti-PD1 antibody after progressed on LEN. Methods: Unresectable HCC (uHCC) patients who treated with the combination of LEN with anti-PD1 antibody after progressed on LEN were enrolled. Patients who combine other loco-treatment and systemic therapy during the LEN combination with PD-1 antibody treatment period were excluded. The efficacy of LEN and anti-PD1 antibody was evaluated by mRECIST criteria after 2 cycles of combination treatment. AE data were recorded during the combination treatment period. Results: From October 2018 to October 2019, 26 patients were finally enrolled. As of January 10, 2020, median follow-up was 6.7±3.19 months. Median age was 56.15±11.9 years old, 80.77% (21/26) was Child-pugh(CP) A while 19.23% (5/26) was CPB7 and 88.5% (23/26) was BCLC stage C. Before combination therapy, 11 patients (42.31%) used LEN only and the other 15 patients (57.69%) were experienced sorafenib/chemotherapy before LEN. Drugs of PD1 antibodies were Keytruda and Toripalimab. The median duration of combination treatment was 6.7±3.15months. The ORR was 26.9% in total 26 cases. 2 cases of them were complete response, and the disease control rate (DCR) was 88.5% (23/26). The most common adverse events (AEs) of combination treatment were hypertension (42.31%), diarrhea (38.46%), hypothyroidism (38.46%) and anorexia (34.62%). Grade 3 or higher AEs occurred in 6 (23.08%) patients. Conclusions: This was the first real-world data of sequential therapy of LEN combination with anti-PD1 followed LEN in uHCC patients. For advanced patients who have progressed after LEN treatment, the results were promising, showing high DCR and well tolerated. 2 cases even achieve complete response. Sequential therapy may be an option for these patients. The efficacy of combination treatment needs random clinical trial to be further studied.

Nutritional Index as Prognostic Indicator in Patients Receiving Lenvatinib Treatment for Unresectable Hepatocellular Carcinoma

Background/Aim: Few studies have examined the details of nutritional status in patients with unresectable hepatocellular carcinoma (u-HCC) undergoing systemic chemotherapy with lenvatinib. We evaluated the prognostic/predictive value of nutritional status using Onodera’s prognostic nutritional index (O-PNI) for overall survival among patients with u-HCC treated with lenvatinib. Methods: Three-hundred and seventy-five u-HCC patients treated with lenvatinib were enrolled (median age 72 years; Child-Pugh class A/B/C: n = 312/60/3; BCLC stage A/B/C/D: n = 2/159/212/2). We examined median survival time (MST) and time to progression (TTP) in all patients (n = 375), prognosis according to the O-PNI (high/low: >40/≤40) in 298 patients with lymphocyte findings, and the prognostic/predictive values of Child-Pugh stage, albumin-bilirubin (ALBI)/modified ALBI (mALBI) grade, and O-PNI for Chemotherapy grade (OPNIC grade 1/2/3: O-PNI >40/≤40 to >36/≤36). Results: The MST and TTP were 16.6 and 8.0 months, respectively. The MST and TTP according to the O-PNI (>40/≤40) were “not reached” (NR)/12.4 months (p < 0.001) and 10.0/6.1 months (p = 0.012), respectively. There was a good correlation noted between ALBI score and O-PNI (r = −0.939, p < 0.001). The predictive value of the O-PNI for mALBI grade 2a was 36.0 (specificity/sensitivity = 0.894/0.942; area under the curve [AUC] = 0.978), while that for mALBI grade 1 was 39 (specificity/sensitivity = 0.920/0.929; AUC = 0.972), which was very similar to a high O-PNI. The MST analyzed with the OPNIC in the 298 patients was NR/16.2/10.4 months for OPNIC grade 1/2/3 (p < 0.001), respectively, and the c-index was 0.632, the same as that for mALBI grade (0.632), while that for Child-Pugh class was 0.571. Conclusions: OPNIC grading might have a potential for easy substitution of mALBI grading. A good nutritional status (OPNIC grade 1) or mALBI grade 1 is the best indication for lenvatinib use, while with an OPNIC grade 3, lenvatinib might be not suitable.

Comparison of the frequency of adverse events requiring interventions determined by telephone follow up in hepatocellular carcinoma patients treated with sorafenib and lenvatinib.

507 Background: The REFLECT trial demonstrated that lenvatinib is non-inferior to sorafenib for first-line treatment of unresectable hepatocellular carcinoma (uHCC). However, no comparison of the frequency of adverse events (AEs) requiring interventions has been reported yet between uHCC patients receiving sorafenib and those receiving lenvatinib. At the National Cancer Center Hospital East, Japan, pharmacists conduct telephone follow-up (TF) during the first month after the start of treatment with sorafenib or lenvatinib in uHCC patients, for the purpose of detecting and treating AEs early. The aim of this study was to reveal the frequency of AEs requiring interventions between patients receiving sorafenib and those receiving lenvatinib, based on TF. Methods: The characteristics, AEs and contents of intervention by TF of 56 uHCC patients who had been started on treatment with sorafenib and lenvatinib were reviewed retrospectively. The study subjects were 33 patients initiated on sorafenib treatment and monitored by TF from March 2017 to March 2018 (Group S) and 23 patients initiated on lenvatinib treatment and monitored by TF from March 2018 to March 2019 (Group L). Results: The total numbers of TFs in Group S and Group L were 91 and 48, respectively. The rate of AEs requiring interventions was significantly higher in Group S as compared to Group L (Group S, 17.6% (16/91); Group L, 4.2% (2/48); p = 0.032). The frequencies of the interventions, including use of supportive treatments (A), withdrawal of sorafenib or lenvatinib (B), and medical examination (C), differed between the two groups (A/B/C: Group S, 8/5/3 times vs. Group L, 2/0/0 times). The most frequently observed AE that necessitated intervention in Group S was the hand-foot syndrome (HFS) (75.0%, 12/16). Conclusions: The frequency of interventions for AEs appears to be higher in uHCC patients receiving sorafenib than in those receiving lenvatinib. Although a great number of patients taking sorafenib had symptomatic AEs, such as HFS, early detection of the symptoms through TF contributed to prevention of treatment withdrawal on account of AEs.

Baseline liver function and outcomes in the phase III REFLECT study in patients with unresectable hepatocellular carcinoma (uHCC).

524 Background: Lenvatinib (LEN) is approved for first-line treatment of uHCC. Baseline (BL) liver function (Child-Pugh score [CPS] and albumin-bilirubin grade [ALBI]) was prognostic in uHCC patients (pts) who received sorafenib (SOR) but has not been assessed with LEN in uHCC. Here, we report post hoc analysis of BL liver function and efficacy/safety outcomes from the phase 3 REFLECT study. Methods: Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were stratified by BL ALBI or CPS. OS and PFS were estimated by Kaplan–Meier method. Independent radiologic review utilized mRECIST criteria for ORR. Safety was assessed using NCI-CTCAE, version 4.0. Results: Liver function measured by ALBI and CPS seemed to be prognostic for OS and ORR. Median OS was longer in ALBI grade 1 (ALBI-1) vs grade 2 (ALBI-2) pts or for CPS-5 vs CPS-6 on either treatment arm and was longer for LEN vs SOR. ORR was higher in pts with better ALBI or CPS and for LEN vs SOR. Rates of treatment-emergent adverse events grade ≥3 were lower with better BL liver function (ALBI-1 vs ALBI-2: 70% vs 86%; CPS-5 vs CPS-6: 72% vs 86%). Study-drug withdrawal, dose reduction, and dose interruption occurred more often in pts with worse BL liver function. Conclusions: This post hoc analysis suggests ALBI (by OS, PFS and ORR) and CPS (by ORR) may be prognostic in uHCC pts and that BL liver function may be linked with efficacy/safety outcomes. This analysis also found that LEN provided benefit vs SOR for uHCC, regardless of BL liver function. The benefit of LEN may be underestimated, as more ALBI-2 pts and fewer ALBI-1 pts received LEN vs SOR. Clinical trial information: NCT01761266. [Table: see text]

Adjuvant cytokine-induced killer cells with minimally invasive therapies augmented therapeutic efficacy of unresectable hepatocellular carcinoma.

To investigate the safety and therapeutic efficacy of adjuvant cytokine-induced killer (CIK) cells to minimally invasive therapies in unresectable hepatocellular carcinoma (u-HCC). Hundred patients diagnosed with having u-HCC in our department from January 1, 2001, to July 31, 2018, were recruited. Forty-three patients received microwave ablation (MWA) and transcatheter arterial chemoembolization (TACE) together with autologous CIK cell treatment (TACE + MWA + CIK group), whereas 57 patients received TACE and MWA only (TACE + MWA group). Postprocedural complications and cumulative therapeutic effects were assessed in all patients. The disease control rate, median survival time (MST), and cumulative survival rate were compared between the cohorts using the Kaplan-Meier method and unpaired Student's t-tests. The overall response (complete response [CR] + partial response [PR]) rate was 74.42% (32/43) and 77.19% (44/57) for TACE + MWA + CIK and TACE + MWA groups, respectively (P = 0.243). Those of the TACE + MWA + CIK group had better rates of disease control (CR + PR + stable disease) in contrast to the TACE + MWA group (87.72% vs. 79.07%, respectively) but this failed to achieve statistical significance (P = 0.748). Based on the Kaplan-Meier survival graphs, those of the TACE + MWA + CIK groups possessed markedly increased overall survival (41 months vs. 24 months, P = 0.002) and progression-free survival (17 months vs. 10 months, P = 0.023) rates in compared to the TACE + MWA group. Survival rates were raised also TACE + MWA + CIK group than in TACE + MWA group (P = 0.002), with a MST of 6.13 ± 0.83 months and 11.61 ± 1.59 months in the TACE + MWA + CIK and TACE + MWA groups, respectively. Patients in the TACE + MWA + CIK group were not reported to have any severe complications. CIK cell immunotherapy as an adjuvant to TACE and MWA enhanced long-term prognosis and improved quality of life in patients with u-HCC. This regimen may be recommended as a novel treatment regime in u-HCC patients.

Post-Progression Treatment Eligibility of Unresectable Hepatocellular Carcinoma Patients Treated with Lenvatinib

Background/Aim: Post-progression treatment following tyrosine-kinase inhibitor (TKI) failure in patients with unresectable hepatocellular carcinoma (u-HCC) is important to prolong post-progression survival (PPS), which has a good correlation with overall survival (OS). This study aimed to elucidate the clinical features of progressive disease (PD) in patients treated with lenvatinib (LEN). Materials/Methods: From March 2018 to June 2019, 156 u-HCC patients with Child-Pugh A were enrolled (median age: 71 years, Child-Pugh score 5:6 = 105:51, BCLC A:B:C = 8:56:92, modified albumin-bilirubin grade (mALBI) 1:2a:2b = 59:42:55, past history of sorafenib:regorafenib = 57:17). Clinical features were retrospectively evaluated. Results: The median observation period was 8.5 months. Median OS was not obtained, while median time to decline to Child-Pugh B (CPB) was 11.4 months, median time to progression (TTP) was 8.4 months, and the period of LEN administration was 7.3 months. When we compared predictive values for time to decline to CPB based on Child-Pugh score and mALBI, values for Akaike information criterion (AIC) score and c-index of mALBI were superior as compared to Child-Pugh score (AIC: 592.3 vs. 599.7) (c-index: 0.655 vs. 0.597). Of the 73 patients with PD, 32 (43.8%) showed no decline to CPB or death. After excluding 3 without alpha-fetoprotein data at PD determination, only 14 (20.0%) of 70 showed REACH-2 eligibility. Non-mALBI 1/2a at the start of LEN was a significant risk factor for decline to CPB during LEN treatment (HR 2.552, 95% CI: 1.577–4.129; p < 0.001). Conclusion: Introduction of TKI therapy including LEN for u-HCC patients with better hepatic function (mALBI 1/2a: ALBI score ≤–2.27), when possible, increases the chance of undergoing post-progression treatment, which can improve PPS.

Early Relative Change in Hepatic Function with Lenvatinib for Unresectable Hepatocellular Carcinoma

Background/Aim: Lenvatinib (LEN) has been developed for the treatment of unresectable hepatocellular carcinoma (u-HCC). We aimed to elucidate the relative change in hepatic reserve function early following LEN treatment in affected patients. Materials/Methods: From March 2018 to April 2019, 123 u-HCC patients (median age 71 years; male:female ratio 95:28; Child-Pugh score 5:6:7 = 65:50:8; modified albumin-bilirubin [mALBI] grade 1:2a:2b:3 = 44:28:50:1, Barcelona Clinic Liver Cancer stage A:B:C = 1:49:73) were enrolled. Relative changes in hepatic reserve function at 2 and 4 weeks after starting LEN were retrospectively evaluated. Results: The median survival was 11.3 months. The Child-Pugh score declined from the start to 4 weeks after commencing LEN (score 5:6:7:8:9:≥10 = 65:50:8:0:0:0 vs. 50:39:22:8:0:4, p < 0.001). A comparison among ALBI scores at the start of LEN and those at 2 and 4 weeks revealed significant relative changes (–2.36 ± 0.45 to –2.20 ± 0.49 at 2 weeks, –2.15 ± 0.50 at 4 weeks, p < 0.001, Bonferroni method), while there was no significant difference between those at 2 and 4 weeks (p= 0.210, Bonferroni method). Assessments of relative changes of ALBI score in patients divided by mALBI grade 1, 2a, and 2b or more showed a significant decline in score regardless of grade (–2.82 ± 0.17 to –2.53 ± 0.34, p < 0.001; –2.46 ± 0.10 to –2.31 ± 0.33, p = 0.017; and –1.90 ± 0.26 to –1.75 ± 0.42, p= 0.009, respectively). Conclusion: Decline in hepatic function is common in the early stage (≤4 weeks, especially within 2 weeks) after introducing LEN. It is important to introduce molecular targeting agent drugs for u-HCC in patients with better hepatic function, who show transarterial catheter chemoembolization failure, as much as possible, along with consideration of the negative influence of LEN on the early response of hepatic function.

Prognostic factor of lenvatinib for unresectable hepatocellular carcinoma in real-world conditions-Multicenter analysis.

Background/aimWe assessed suitable factors indicating newly developed lenvatinib (LEN) treatment for unresectable hepatocellular carcinoma (u‐HCC) by investigating real‐world clinical features of patients.Materials/methodsOne hundred fifty two u‐HCC patients, who receive LEN treatment from March to December 2018, were enrolled. (Child‐Pugh score [CPS] 5/6/7/8 = 76/61/13/2, modified albumin‐bilirubin grade [mALBI] 1/2a/2b/3 = 53/35/60/4). Clinical features were evaluated retrospectively.ResultsOverall‐response rate (ORR)/disease control rate (DCR) at 1 month after starting LEN were 38.7%/86.0%, respectively. Estimated median time to progression (TTP) was 7.0 months, while median survival time was not reached within the observation period. CPS (≥7) and past history of tyrosine‐kinase inhibitor (TKI) were not significant prognostic factors. mALBI ≥2b was an only significant prognostic factor (HR 4.632, 95%CI 1.649‐13.02, P = 0.004) in Cox‐hazard multivariate analysis. In patients with Child‐Pugh A, c‐index/Akaike's information criterion (AIC) of prognostic predictive value of mALBI were superior to CPS (0.682/135.6 vs 0.652/138.7), while those of stopping LEN also showed that mALBI was better (0.575/447.3 vs 0.562/447.8). Additional analysis of patients with good mALBI (1/2a) revealed that time to stopping LEN was significantly shorter in those with the adverse event (AE) of appetite loss (any grade) than those without (P = 0.006) and body mass index (BMI) was also lower in patients with that AE (20.3 ± 3.0 vs 23.6 ± 4.0kg/m2, P < 0.001), while patients with a hand‐foot skin reaction (any grade) showed good ORR/DCR (59.1%/86.4%) and longer TTP as compared to patients without (P = 0.007).ConclusionGood hepatic function (mALBI 1/2a) is the best indication for LEN, while potential appetite loss in association with low BMI should be kept in mind in such cases.

Cost-effectiveness analysis of lenvatinib treatment for patients with unresectable hepatocellular carcinoma (uHCC) compared with sorafenib in Japan

BackgroundLenvatinib demonstrated a treatment effect on overall survival by the statistical confirmation of non-inferiority to sorafenib for the first-line treatment of uHCC. The objective of this study was to evaluate the cost-effectiveness of lenvatinib compared with sorafenib for patients with uHCC in Japan.MethodsA partitioned-survival model was developed to estimate the cost-effectiveness of lenvatinib versus sorafenib when treating uHCC patients over a lifetime horizon and considering total public healthcare expenditure. Efficacy and safety data were extracted from the REFLECT trial. Utility values were derived from the European Quality-of-Life 5-Dimension Questionnaire, conducted with patients enrolled in the REFLECT trial. Direct medical costs, such as primary drug therapy, outpatient visits, diagnostic tests, hospitalization, post-progression therapy, and adverse-event treatments, were included. Cost parameters unavailable in the clinical trial or publications were obtained based on the consolidated clinical standards from a Delphi panel of four Japanese medical experts.ResultsFor lenvatinib versus sorafenib, the incremental cost was − 406,307 Japanese Yen (JPY), and the incremental life years and quality-adjusted life years (QALYs) were 0.27 and 0.23, respectively. Thus, lenvatinib dominated sorafenib, due to the mean incremental cost-effectiveness ratio falling in the fourth quadrant, conferring more benefit at lower costs compared with sorafenib. The probabilistic sensitivity analysis showed that 81.3% of the simulations were favorable to lenvatinib compared with sorafenib, with a payer’s willingness-to-pay-per-QALY of 5 million JPY.ConclusionsLenvatinib was cost-effective compared with sorafenib for the first-line treatment of uHCC in Japan.

A nationwide multicenter study in patients with unresectable hepatocellular carcinoma treated with lenvatinib in real world practice in Japan.

364 Background: Lenvatinib(LEN) has been approved as a single agent for patients with unresectable hepatocellular carcinoma (u-HCC) since Mar 2018 in Japan. A few results from a large sample size cohort of LEN therapy in real world practice has been reported. Therefore, we performed a retrospective nationwide multicenter study. Methods: A total of 116 u-HCC patients received LEN from March 2018 at 14 sites in Japan were registered. Tumour assessments in accordance with RECICT ver1.1 and modified RECIST were done using dynamic CT or MRI within 4-8 weeks and every 6-8 weeks thereafter. Adverse events (AEs) were graded according to the CTCAE ver4.0. Results: Median age was 72 (46-91)years, 88 (75.9%) patients were male, and median body weight was 60 (30-94) kg. The baseline liver function was Child-Pugh class A in 106 (91.4%) patients. Seventy-three (62.9%) patients were BCLC stage C. As the 2nd-line therapy (after sorafenib), 28 (24.1%) patients received LEN and 17 (14.7%) patients did as the 3rd-line (after regorafenib). Median observation time was 2.5 months and one patient died from HCC progression. The imaging findings of 49 (42.2%) patients were evaluated at 4-8weeks. Based on mRECIST, CR was shown in 3 (6.1%), PR in 14 (28.6%), SD in 23 (46.9%), and PD in 6 (12.2%). In the 3 patients, target lesions of liver showed PR, however bone metastases had progressed. [overall response rate (ORR) 34.7%, disease control rate (DCR) 81.6%]. ORR and DCR of tyrosine kinase inhibitor (TKI) naïve patients (n = 26) were 34.6% and 80.8%, while those of TKI experienced (n = 23) were 34.8% and 82.6%. The most common any-grade AEs were hypertension (52.0%), diarrhoea (32.1%), decreased appetite (63.5%) and fatigue (49.4%). Hand-food skin reaction (HFSR) was observed in 28% of patients. Conclusions: The efficacy of LEN therapy in real world practice in Japan was similar to the phase 3 clinical trial, even though elderly patients with lower body weight were included in this study. The incidence of HFSR during LEN in real world practice was lower than that of the sorafenib group in the phase 3 trial of LEN. Decrease appetite and fatigue must be carefully monitored and managed during LEN therapy.

Therapeutic potential of lenvatinib for unresectable hepatocellular carcinoma in clinical practice: Multicenter analysis.

Lenvatinib (LEN) has recently become available as a first-line tyrosine-kinase inhibitor (TKI) for unresectable hepatocellular carcinoma (u-HCC). In patients who showed intolerability or failure in other TKI treatments, alternative treatment options are needed. This retrospective study evaluated the therapeutic potential of LEN in clinical practice. We enrolled 57 u-HCC patients treated with LEN from March to June 2018. Lenvatinib was given orally to patients weighing <60kg at 8mg/day and at 12mg/day to those ≥60kg. Following the exclusion of patients whose initial LEN dose was reduced, 49 patients were evaluated in regard to their characteristics and early therapeutic response using modified Response Evaluation Criteria in Solid Tumors for findings of follow-up computed tomography (CT)/magnetic resonance imaging (MRI) examinations at 4weeks after introducing LEN. The average patient age was 72.4 ± 9.3years and 38 (77.6%) were men. The LEN dose was 8 and 12mg in 32 and 17 patients, respectively. Twenty-nine (59.2%) had history of treatment with sorafenib and six of them (20.7%) with regorafenib. Of the 49 patients, 27 were evaluated using findings obtained by enhanced CT/MRI at 4weeks after introducing LEN. Partial response was shown in 11, stable disease in 12, and progressive disease in four (overall response rate [ORR], 40.7%; disease control rate [DCR], 85.2%). The ORR and DCR of TKI-naïve patients (n= 8) were 50.0% and 87.5%, respectively, whereas those of TKI-experienced patients (n= 19) were 36.8% and 84.2%, respectively (P= 0.675 and P= 1.00, respectively). Early therapeutic response to LEN was favorable. This new TKI could have therapeutic potential both in patients with and without past TKI treatments.

PCN188 - ASSESSING THE ROBUSTNESS OF A COST-EFFECTIVENESS ANALYSIS OF LENVATINIB VERSUS SORAFENIB IN UNRESECTABLE HEPATOCELLULAR CARCINOMA IN JAPAN

In the REFLECT trial, lenvatinib demonstrated non-inferiority in overall survival (OS) compared with sorafenib in the first-line treatment of unresectable hepatocellular carcinoma (uHCC). At baseline, a greater proportion of lenvatinib patients had an α-fetoprotein (AFP) level of ≥ 200 ng/mL, an adverse prognostic factor. We evaluated the cost-effectiveness of lenvatinib versus sorafenib in uHCC in Japan over a lifetime horizon, adjusting for this imbalance in patient AFP levels. A partitioned survival model was developed with 3 health states: progression-free, post-progression, and death. Clinical outcomes, adverse events, and health state utilities were obtained from the REFLECT trial. Direct medical costs were based on Japanese data. We carried out deterministic sensitivity analysis (DSA), probabilistic sensitivity analysis (PSA), and scenario analyses to explore the potential influences of the different parameters in our analysis. The estimated quality-adjusted life years (QALYs) for lenvatinib were 1.46 QALY, and 1.23 QALY for sorafenib, respectively. The total costs of lenvatinib therapy were estimated at 5,088,957 JPY, while the sorafenib costs were 5,495,264 JPY. Therefore, treatment with lenvatinib led to 0.23 QALY improvement and lowered costs by 406,307 JPY. In DSA, the three most significant model parameters were OS curves, progression-free survival curves, and progression-free utility; varying these parameters still resulted in lenvatinib being favourable over sorafenib. In PSA, lenvatinib was favourable to sorafenib in 81% of 1,000 simulations, at the 5 million JPY willingness-to-pay per QALY threshold and 77% at the 10 million JPY per QALY threshold. Our conclusions were robust in scenario analyses. Results of this analysis suggested lenvatinib offered improved health outcomes (i.e., QALYs) with lower costs for uHCC patients compared with sorafenib. Our results were robust to sensitivity analyses and scenario analysis.

Prognostic factors for unresectable hepatocellular carcinoma treated with transcatheter arterial chemoembolisation combined with radiotherapy

Background: To assess the prognostic factors for unresectable hepatocellular carcinoma (uHCC) treated with transcatheter arterial chemoembolisation (TACE) combined with radiotherapy (RT). Methods: All 101 patients who had received TACE combined with RT from January 2010 to December 2015 were included in this retrospective study. Tumor response and overall survival rate was analysed for all patients. Univariate and multivariate analyses were used to determine prognostic factors. Results: The objective response rate was achieved for 73.3% of patients. The median survival time was 23 months (range: 3–60 months), and the overall survival rate at 1, 3, 5 years was 80.2%, 26.7% and 7.9%, respectively. Multivariate analysis showed that TNM stage, Child-Pugh classification, TACE times and the total liver volume receiving >20 Gy (V20) were independent prognostic factors for overall survival. Conclusions: The TNM stage, Child-Pugh classification, TACE times and V20 were independent prognostic factors for uHCC patients treated with TACE combined with RT.

Raltitrexed plus oxaliplatin-based transarterial chemoembolization in patients with unresectable hepatocellular carcinoma.

Raltitrexed has shown efficacy and safety in many tumor types; however, the clinical data on the treatment of hepatocellular carcinoma is rare. In this report, we aim to assess the efficacy and safety of raltitrexed plus oxaliplatin (OXA)-based transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (uHCC). Patients with uHCC were recruited from multi-centers in China and assigned randomly to raltitrexed+OXA-based (n=76), fluorouracil+OXA-based (n=76), and doxorubicin+OXA-based (n=75) TACE treatment. The primary end point was overall survival (OS). Tumor response was assessed using response evaluation criteria in solid tumors (RECIST), modified response evaluation criteria in solid tumors (mRECIST), and European Association for the Study of the Liver criteria (EASL). Safety and toxicity were evaluated using the National Cancer Institute Common Toxicity Criteria. The raltitrexed group showed a better disease control rate evaluated using RECIST (raltitrexed vs. fluorouracil vs. doxorubicin: 96.1 vs. 84.2 vs. 86.7%, P=0.05) and a better overall response rate on the basis of mRECIST (67.1 vs. 47.4 vs. 50.7%, P=0.03) and EASL (67.1 vs. 47.4 vs. 49.3%, P=0.02). The median OS and median progression-free survival (PFS) were higher in the raltitrexed group (median OS: 13.4 vs. 9.6 vs. 8.5 months; median PFS: 6.7 vs 4.9 vs 4.6 months). The most common toxicities included elevated aspartate aminotransferase (78.9 vs. 86.8 vs. 81.3%) and abdominal nonspecific pain (68.4 vs. 81.6 vs. 78.7%). No significant differences were found in the overall number of patients who experienced any toxicity. Raltitrexed plus OXA-based TACE suggested a safe and efficacious regimen in uHCC patients. The results warrant further clinical investigation.