Liver Cancer最新文献

Introduction: Atezolizumab-bevacizumab (Atezo-Bev) has become the standard first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC). However, data on subsequent treatment after Atezo-Bev failure are lacking. We aimed to investigate the efficacy and safety of regorafenib for uHCC progression after first-line Atezo-Bev.

Methods: This investigator-initiated, single-arm, phase 2 trial involved two academic centers in Korea. Eligibility criteria included a diagnosis of HCC, prior treatment with at least 2 cycles of Atezo-Bev, and Child-Pugh A liver function. Eligible patients received regorafenib 160 mg once daily for 3 weeks of every 4-week cycle (i.e., 3 weeks on, 1 week off) until progressive disease or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, disease control rate according to RECIST v1.1, overall survival (OS), and treatment-related adverse events.

Results: Forty patients were enrolled from December 2021 through May 2023. The median follow-up duration was 10.1 months (95% confidence interval [CI]: 8.3-12.0). The median PFS was 3.5 months (95% CI: 3.0-3.9). The median OS was 10.5 months (95% CI: 7.1-13.8), and the 6-month OS rate was 65.0%. The objective response rate and disease control rate were 10.0% and 82.5%, respectively. The most common grade 3-4 treatment-related adverse event was thrombocytopenia (5.0%). When stratified according to time to progression on prior Atezo-Bev (first quartile [<2.3 months] vs. second to fourth quartiles [≥2.3 months]), patients with longer time to progression on prior Atezo-Bev had better OS (15.0 vs. 3.6 months, p < 0.001), objective response rate (13.3% vs. 0%, p = 0.009), and a tendency toward better PFS with regorafenib (3.8 vs. 2.5 months; p = 0.054).

Conclusion: Second-line regorafenib was effective for treating uHCC progression after first-line Atezo-Bev. The efficacy and safety outcomes from our study were consistent with those observed in the pivotal phase 3 RESORCE trial, which included sorafenib-tolerant/-progressed patients.

Introduction: Patients born with congenital porto-systemic shunts have been shown to have a high risk of benign and malignant liver tumors in otherwise healthy livers. This study aimed to evaluate the genetic landscape of liver tumors in patients with congenital porto-systemic shunts (CPSS) and correlate genotype with histological findings.

Methods: Nodules from patients with CPSS and sporadic pediatric focal nodular hyperplasia (FNH) or FNH-like nodules were evaluated histologically and sequenced for a panel of 50 genes using next-generation sequencing.

Results: Thirty-eight nodules from 17 patients with CPSS were histologically classified as hepatoblastomas (n = 2), hepatocellular carcinomas (n = 4), HNF-1α-inactivated hepatocellular adenomas (HCAs) (n = 2), β-catenin-activated HCAs (n = 5), unclassified HCAs (n = 9), and FNH-like nodules (n = 16). CTNNB1 variants were detected in 26/38 nodules (68%) across different histological categories (2/2 hepatoblastomas, 4/4 HCCs, 10/16 HCAs, 10/16 FNH-like nodules), but not in sporadic FNH or FNH-like nodules (0/10). Less frequent variants were identified in APOB, GNAS, HNF1A, SERPINA1, MAML2, PTCH1, G6PC, KMT2C, DICER1, AXIN1, IL6ST and the promoter region of TERT. Germline variants were identified in AXIN1, HFE, SERPINA1, and ZNF521. CTNNB1 variants affecting amino acid positions 32 and 33 are more common in malignant tumors. Multiple CTNNB1 variants were identified in 6/7 (86%) of patients with multiple nodules, but no intratumoral variation was found.

Discussion: CPSS is strongly associated with nodules containing variants in CTNNB1, irrespective of the histological category. Areas in background liver containing these variants were also identified, and different variants could be identified in individual patients. The high proportion of CTNNB1 variants may explain the higher malignant potential of benign tumors found in CPSS.

Introduction: In the phase 3 RESORCE trial, regorafenib prolonged overall survival (OS) in patients with unresectable hepatocellular carcinoma (uHCC) whose disease progressed on prior sorafenib. The prospective, observational REFINE study aimed to evaluate the safety and effectiveness of regorafenib in a broader population of patients in real-world clinical practice, including patients with Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, Child-Pugh B liver status, and sorafenib intolerance.

Methods: This international, prospective, multicenter study (NCT03289273) enrolled patients with uHCC for whom the decision to treat with regorafenib was made by their physician before enrollment, according to the local health authority-approved label. The primary aim was to evaluate the safety of regorafenib, including the incidence of treatment-emergent adverse events (TEAEs) and dose modifications due to TEAEs.

Results: Of the 1,028 patients enrolled, 1,005 initiated regorafenib and were eligible for analysis. Median age was 66 years (range 21-94); most patients were male (83%), Child-Pugh A (61%), and had an ECOG PS of 0 or 1 (82%) at study entry. Overall, 47%, 11%, and 40% of patients initiated regorafenib at 160, 120, and 80 mg/day, respectively. Median treatment duration was 3.7 months (range 1 day to 38.9 months). Dose modifications and permanent discontinuation of regorafenib due to TEAEs occurred in 45% and 31% of patients, respectively. The most common drug-related TEAEs were hand-foot skin reaction (31%), diarrhea (26%), and fatigue (15%). Median OS was 13.2 months (95% confidence interval 11.6, 14.8).

Conclusion: The results of the real-world REFINE study confirmed the safety and effectiveness of regorafenib in a broad population of patients with uHCC. Of patients who received standard regorafenib dosing in REFINE, safety and efficacy findings were consistent with those reported in the RESORCE trial.

Introduction: Adjuvant immune checkpoint inhibitors (ICIs) may improve recurrence-free survival (RFS) in patients with hepatocellular carcinoma (HCC). This study evaluated the effects of adjuvant ICI treatment duration on RFS and overall survival (OS) among patients with HCC at high risk of recurrence.

Methods: The RFS and OS of patients from three centers who received either adjuvant ICI therapy or active surveillance after curative hepatic resection between January 1, 2019, and December 31, 2023, were analyzed. Further analysis was performed to evaluate the effects of ICI treatment duration on RFS and OS.

Results: A total of 1,271 patients were included, of whom 1,032 (81.2%) received active surveillance and 239 (18.8%) received adjuvant ICI therapy. The median RFS in the adjuvant therapy cohort was 22.6 months (95% CI 18.3-26.9), significantly higher than the RFS of 19.1 months (95% CI 16.4-21.4) in the active surveillance cohort (HR 0.79; 95% CI 0.66-0.95; p = 0.019). The median OS was not reached for either group, but OS tended to be better in the adjuvant therapy cohort than in the active surveillance group (HR 0.72, 95% CI 0.54-0.94; p = 0.010). Similar results were obtained after propensity score matching. Among patients who received adjuvant ICI therapy, those who received it for longer than 6 months had slightly higher RFS (HR 0.66; 95% CI 0.42-1.04; p = 0.071) and OS (HR 0.59; 95% CI 0.30-1.17; p = 0.128) than those who received it for up to 6 months.

Conclusions: Adjuvant ICI therapy significantly improves the prognosis of patients with HCC at high risk of recurrence after curative resection. Six months of adjuvant ICI treatment may be insufficient.

Background: CD8⁺ T cells are critical for the oncogenesis and progression of the hepatocellular carcinoma (HCC) tumor microenvironment, receiving antigen signals from antigen-presenting cells and directly contributing to antitumor responses.

Summary: CD8⁺ T cells mediate immunogenic cell death, facilitate immune signal transmission, and play a significant role in various treatments, including surgery, transarterial chemoembolization, and immunotherapy. Extensive research on the role of CD8⁺ T cells within the HCC microenvironment has shown considerable progress. Immunometabolic targets on CD8⁺ T cells have demonstrated potential in combination with immunotherapies for HCC; however, they have not yet reached the clinical trial stage.

Key messages: This review provides a comprehensive overview of recent research on immune and immunometabolic targets of CD8⁺ T cells within the HCC microenvironment. By highlighting advances and potential mechanisms, this review aims to support the development of effective clinical strategies in this field.

Introduction: The phase 3 LEAP-002 study (NCT03713593) of advanced hepatocellular carcinoma (HCC) suggested improved antitumor activity of lenvatinib plus pembrolizumab versus lenvatinib alone with manageable safety, although overall survival (OS) and progression-free survival (PFS) did not reach prespecified statistical significance. This post hoc analysis assessed efficacy and safety in Japanese patients.

Methods: Patients with advanced HCC without prior systemic treatment were randomly assigned 1:1 to receive 8 mg (body weight <60 kg) or 12 mg (body weight ≥60 kg) oral lenvatinib once daily plus 200 mg intravenous pembrolizumab or placebo every 3 weeks for up to 35 cycles. Dual primary end points were OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Secondary end points were objective response rate, disease control rate, duration of response, and time to progression per RECIST v1.1 by BICR and safety.

Results: Overall, 80 patients were enrolled in Japan (lenvatinib plus pembrolizumab, n = 39; lenvatinib plus placebo, n = 41). Median time from randomization to database cutoff (June 21, 2022) was 34.1 months (range: 26.9-39.6). Median OS was 31.4 months (95% CI: 21.2- not reached) for lenvatinib plus pembrolizumab and 21.4 months (95% CI: 14.4-25.4) for lenvatinib plus placebo (hazard ratio [HR] = 0.55 [95% CI: 0.31-0.96]). Median PFS for lenvatinib plus pembrolizumab was 10.4 months (95% CI: 6.2-18.5) and 6.5 months (95% CI: 6.0-8.3) for lenvatinib plus placebo (HR = 0.54 [95% CI: 0.32-0.90]). Grade 3 or 4 treatment-related adverse events occurred in 26 patients (67%) in the lenvatinib plus pembrolizumab group and 24 patients (59%) in the lenvatinib plus placebo group.

Conclusion: In Japanese patients enrolled in LEAP-002, findings were consistent with the global population where OS and PFS trended toward improvement; a similar safety profile was observed.

Introduction: In the realm of oncology, the pinnacle of therapeutic success is achieving a state where the patient is entirely free of cancer, i.e., "cancer free." This benchmark should not only apply to early-stage malignancies but should also be the standard aim for advanced-stage diseases, including hepatocellular carcinoma (HCC). However, there is a glaring gap in the research landscape concerning the understanding of what cancer-free status truly means for advanced-stage HCC. Our study sheds light on the profound implications of reaching a cancer-free by radiologic assessments in patients with advanced-stage HCC.

Methods: We established a database tracking the full clinical course of all patients with HCC (from 2003 to 2022). We identified the initial instances of macrovascular invasion or extrahepatic spread. We defined radiologic cancer-free (rCF) as cases in which no recurrence was observed for at least 2 months following curative treatment or complete response to systemic therapies. The frequency of achieving rCF status was investigated, categorized by patients' background.

Results: We identified 795 patients with advanced-stage HCC. The rCF rate was 8.7%. Patients who achieved rCF status had significantly better prognoses compared to those who did not (p < 0.001). In the decision tree analysis, the number of tumors ≥8 was the strongest factor, making it difficult to achieve rCF status. Analysis of stage progression patterns revealed varying background characteristics at the time of advanced-stage diagnosis, with discrepancies in rCF rates.

Conclusions: Despite the low rate of achieving rCF status, the prognostic impact was significant. Patients with certain tumor characteristics had a higher likelihood of achieving rCF status. The distribution of tumor conditions varies based on the pattern of progression, which affects the likelihood of achieving an rCF status.

Introduction: Immune checkpoint inhibitors (ICIs) are fundamental in treating advanced hepatocellular carcinoma (HCC). Considering previous reports implied varied responses among patient subgroups, such as patients with different hepatitis etiologies, we planned this meta-analysis to identify specific populations that might derive greater survival benefits from ICIs as a first-line treatment.

Methods: We conducted a comprehensive search in PubMed and the Cochrane Library for phase III clinical trials comparing ICIs and multikinase inhibitors (MKIs) as first-line therapies for advanced HCC. We extracted and synthesized hazard ratios (HRs) for overall survival across different patient subgroups mainly using the random-effect model.

Results: Our analysis included nine phase III trials involving ICIs, either alone or in combination with other treatments, compared with MKIs. The synthesized HRs for patients with hepatitis B virus, hepatitis C virus, and nonviral etiologies were 0.74, 0.77, and 0.86, respectively, showing no significant differences (p = 0.13). Such finding remained when we only analyzed clinical trials with positive results. HRs consistently favored ICIs across various demographics such as age, sex, geographic region, performance status, alpha-fetoprotein levels, and disease stage or extent. Notably, patients with extrahepatic spread showed a trend toward better outcomes (HR 0.73) compared to those without (HR 0.85, p = 0.07).

Conclusion: The efficacy of ICIs as a first-line treatment for advanced HCC was consistent across diverse patient subgroups, regardless of hepatitis etiology or other demographic factors. These findings do not support using these characteristics to determine the use of ICI therapy in advanced HCC.