Immunotherapy revolutionized the treatment of biliary tract tumors and tumors with high microsatellite instability (MSI-H). This paper reports a 52-year-old woman with recurrent perihilar cholangiocarcinoma. The tumor was initially microsatellite stable (MSS) and proficient mismatch repair (pMMR) but shifted to MSI-H and deficient mismatch repair (dMMR) after combined immunotherapy. Following laparoscopic radical resection for jaundice, stage IV recurrence was diagnosed. Genetic testing revealed the MSS status. Subsequent treatment with camrelizumab and lenvatinib led to a partial response. Ovarian metastases, removed due to abdominal symptoms, exhibited dMMR and MSI-H. The mismatch in MSI status between the primary tumor and metastases suggests tumor heterogeneity and the influence of spatial or temporal factors. This shift can have important clinical significance since MSI-H is associated with significant responses to immune checkpoint inhibitors. MSI-H should be systematically tested in tumors and metastases to personalize treatments. MSI heterogeneity is not only rare but potentially has implications for treatment personalization and prognosis in patients with cholangiocarcinoma. This case highlights the dynamic changes in tumor characteristics during immunotherapy.

Metastatic breast cancer (MBC) remains a therapeutic challenge due to the persistence of minimal residual disease (MRD) and tumor recurrence. Herein we utilize a model of MBC that is sensitive to inhibition of fibroblast growth factor receptor (FGFR), resulting in robust regression of pulmonary lesions upon treatment with the FGFR inhibitor pemigatinib. Assessment of the remaining MRD revealed upregulation of platelet-derived growth factor receptor (PDGFR). Functionally, we demonstrate increased response to PDGF ligand stimulation following pemigatinib treatment. Depletion of PDGFR did not alter tumor growth under control conditions but did delay tumor recurrence following a treatment window of pemigatinib. To overcome this therapeutic hurdle, we found that inhibition of DNA methyltransferase 1 (DNMT1) prevents pemigatinib-induced cellular plasticity. Combined targeting of FGFR and DNMT1 prevented induction of PDGFR, enhanced pulmonary tumor regression, slowed tumor recurrence, and prolonged survival. These findings enhance our understanding of cellular plasticity during states of treatment-induced MRD and suggest that inhibition of DNA methylation could augment current approaches being used to treat MBC.

The combination of immune checkpoint inhibitors targeting anti-programmed cell death-1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) with antiangiogenic agents has emerged as a revolutionary therapy for advanced hepatocellular carcinoma (aHCC). Key antiangiogenic medications encompass monoclonal antibodies targeting vascular endothelial growth factor (anti-VEGF mAbs) and multiple kinase inhibitors (MKIs). The aim of this study is to assess the difference of efficacy and safety between 2 combination therapies. This study retrospectively examined the outcomes of 57 patients with aHCC who underwent first-line treatment with a combination of immune checkpoint inhibitors and antiangiogenic therapy at the First Affiliated Hospital of Anhui Medical University, from September 2018 to July 2023. The analysis, conducted using SPSS software, focused on patient outcomes such as tumor response (assessed according to modified Response Evaluation Criteria in Solid Tumors criteria), objective response rate, disease control rate, progression-free survival, overall survival, and safety. Comparisons among different groups were also made. The anti-PD-1/anti-PD-L1-anti-VEGF mAbs group showed a trend of higher partial response rate (37.50% vs 22.45%), objective response rate (37.50% vs 24.49%), disease control rate (62.50% vs 59.18%), and seemed to achieve longer median progression-free survival (14.93 vs 14.90 months) and median overall survival (15.80 vs 11.10 months) without higher grade 3 or higher adverse events comparing to anti-PD-1/anti-PD-L1-MKIs group. Subgroup analysis showed that the anti-PD-1-lenvatinib group achieved longer median progression-free survival (23.97 months), while the anti-PD-1-regorafenib group achieved longer median overall survival (37.97 months). The anti-PD-1/anti-PD-L1 combined with anti-VEGF mAbs was effective and tolerable compared to anti-PD-1/anti-PD-L1-MKIs in aHCC. The addition of lenvatinib or regorafenib may provide promising incremental benefit for patients with aHCC.

Triple-negative breast cancer (TNBC) is one of the subtypes with the worst prognosis due to tumour heterogeneity and lack of appropriate treatment. This condition is a consequence of the distinctive tumour microenvironment (TME). The TME is associated with factors such as the promotion of proliferation, angiogenesis, inhibition of apoptosis, suppression of the immune system and drug resistance. Therefore, remodelling the TME is critical for the treatment of TNBC. A key role in the formation of the TME is played by the fibroblast growth factor/fibroblast growth factor receptor(FGF/FGFR) signalling pathway. Thus, the FGFRs may be a potential target for treating TNBC. Over-activated FGFRs promote growth, migration and drug resistance in TNBC by influencing the onset of TME events, tumour angiogenesis and immune rejection. A thorough comprehension of the FGF/FGFR signalling pathway's mechanism of action in the development of TNBC could offer valuable insights for discovering new therapeutic strategies and drug targets. Inhibiting the FGF/FGFR axis could potentially hinder the growth of TNBC and its drug resistance by disrupting crucial biological processes in the TME, such as angiogenesis and immune evasion. This review evaluates the potential of inhibiting the FGF/FGFR axis as a strategy for treating TNBC. It explores the prospects for developing related therapeutic approaches. This study explores the research and application prospects of the FGF/FGFR axis in TNBC. The aim is to provide guidance for further therapeutic research and facilitate the development of innovative approaches targeting TNBC.

Intrahepatic cholangiocarcinoma (iCCA) may be genomically subclassified by the presence of potentially actionable molecular aberrations, of which pathogenic alterations in isocitrate dehydrogenase (IDH)1 and fibroblast growth factor receptor (FGFR)2 are the most frequently observed. The impact of these molecular alterations on the tumor immune microenvironment remains incompletely understood.

We performed a high-parameter spatial immune phenotyping of iCCA samples with pathogenic FGFR2 or IDH1 alterations and FGFR2/IDH1 wild-type controls at the single-cell level using CO-Detection by indEXing.

A total of 24 tumors were examined. Tumors with FGFR2 alterations were characterized by fewer CD8+ T cells and "M2-like" macrophages but higher levels of polymorphonuclear myeloid-derived suppressor cells as compared to FGFR2 wild-type tumors. Spatial relationships between polymorphonuclear myeloid-derived suppressor cells and multiple other cell types in the tumor microenvironment (including tumor cells, CD4+, and CD8+ T cells) were enriched in tumors with FGFR2 alterations. Tumors with IDH1 mutations had a trend toward more fibroblasts and were characterized by a closer proximity of tumor cells to CD4+ T cells, and between macrophages and multiple structural tumor microenvironment components as compared to other subtypes.

iCCAs with pathogenic FGFR2 fusions/rearrangements and IDH1 mutations have distinct immunophenotypes. Tailoring immunotherapeutic approaches to specific molecular subsets could improve treatment outcomes across the divergent molecularly defined iCCA subtypes.

The combination therapy of lenvatinib and immunotherapy as first-line treatment remains controversial in unresectable hepatocellular carcinoma (uHCC). This research aimed to compare the efficacy and safety of lenvatinib monotherapy (L) and combination therapy of lenvatinib and immune checkpoint inhibitor (LI) in lenvatinib-insensitive patients with uHCC.

Two hundred fifty-five uHCC patients were enrolled in this study. Patients were classified into two groups: (1) Lenvatinib monotherapy (L); (2) Combination therapy (LI). Patients who remained stable disease (SD) but did not achieve complete response (CR) or partial response (PR) or progression disease (PD) for at least 3 months after receiving lenvatinib monotherapy were defined as lenvatinib-insensitive. Overall survival (OS) and progression-free survival (PFS), baseline characteristics, and safety were compared between groups.

The LI group had longer OS (15.9 months vs. 11.9 months, P = 0.001) and PFS (12.6 months vs. 7.3 months, P < 0.001) than the L group. ECOG PS was an independent prognostic factor affecting OS and Up-to-seven was an independent prognostic factor affecting PFS. The frequency of grade ≥ 3 treatment-related adverse events (TRAEs) was not significantly different.

Our study demonstrated that the combination therapy (LI) had longer OS and PFS than the lenvatinib monotherapy (L) in lenvatinib-insensitive patients with uHCC.

Thymic epithelial tumors (TETs) are rare neoplasms typically located in the anterior mediastinum. While immune checkpoint inhibitors (ICIs) show promise for advanced or refractory TETs, their clinical application is hindered by heterogeneous responses across TET subtypes, lack of reliable predictive markers, and the risk of immune-related adverse events (irAEs).

We analyzed TCGA, GEO, and GTEx databases to identify differentially expressed genes (DEGs) among three TET subtypes. Comprehensive enrichment analysis determined gene functions and pathways. CIBERSORT analysis revealed subtype-specific immune infiltration profiles. We assessed immune-related genes using immune/stromal scores, TIDE scores, and immune checkpoint gene correlation analysis. Immunohistochemistry was performed to evaluate FGF17 and PD-L1 protein expression levels and their correlation in TET samples.

Our findings revealed distinctive molecular and immune infiltration patterns across TET subtypes. Pathway analysis showed upregulation of immune-related pathways in type C. CIBERSORT analysis revealed higher fractions of plasma cells and activated CD4 T cells in type C and increased resting dendritic cells in type A or B3. Furthermore, we identified 1,100 DEGs between responders and non-responders to pembrolizumab. FGF17 emerged as a potential predictive marker for immunotherapy response, showing significantly lower expression in type C and a strong negative correlation with PD-L1 expression (P < 0.001). We identified 115 genes potentially linked to irAEs, with CXCL8, IL17A, and CD40LG among the top hub genes in the protein-protein interaction network.

This study provides insights into subtype-specific molecular and immune characteristics of TETs, identifies FGF17 as a potential negative biomarker for immunotherapy response (with lower expression potentially indicating better response), and elucidates mechanisms of irAEs. These findings contribute to the development of targeted immunotherapeutic approaches for managing TETs, particularly in predicting response to immune checkpoint inhibitors.

Newer treatment options offer the promise of improved outcomes for metastatic and unresectable melanoma. This investigation was performed to review these modalities for cutaneous eyelid and orbital disease.

A search for articles that were related to this subject was performed in the PubMed database, and the bibliographies of these manuscripts were reviewed to ensure capture of the appropriate literature. Data was abstracted and analyzed.

Historically, patients who suffer from melanoma of the ocular adnexa have fared poorly. Approaches that employ BRAF and mitogen-associated protein kinase inhibitors, immunotherapy, and novel cellular therapies improve outcomes and survival rates, although the side effect profiles of these agents are problematic. Most of the existing strategies have not explored ocular adnexal disease specifically, and treatment plans are generally adapted from the general cutaneous oncology literature.

Thanks to advances in our comprehension of the cellular biology of the disease, the management of unresectable and metastatic melanoma has evolved considerably over the past several years. Newer modalities will likely continue to improve survival and reduce adverse events.

Standard treatments provide limited benefits for patients with intermediate- or advanced-stage hepatocellular carcinoma (HCC). This retrospective observational study aimed to assess the potential improvements in outcomes associated with systemic therapies in patients receiving transarterial chemoembolization (TACE) for initially unresectable HCC.

Between February 2019 and March 2023, we reviewed patients diagnosed with intermediate-to-advanced HCC who were treated with either TACE or TACE combined with antiangiogenic agents and immune checkpoint inhibitors (combination therapy) as their initial treatment. To address potential confounding biases, patients were further stratified into surgical and non-surgical cohorts, and separate analyses were conducted. The primary endpoints were progression-free survival (PFS) and overall survival (OS), with safety profiles also evaluated.

Among 279 patients with initially unresectable intermediate or advanced HCC, 156 successfully underwent curative-intent liver resection after preoperative treatments (TACE group, n = 69; combination group, n = 87), while 123 patients continued with non-surgical treatments (TACE group, n = 31; combination group, n = 92). After propensity score matching, 26 matched patient pairs were generated within the non-surgical cohort. The combination group exhibited significantly improved PFS in non-surgical patients compared with the TACE group (9.4 vs. 7.2 months, p = 0.043). Cox proportional hazards analysis further confirmed that combination therapy was associated with improved PFS (hazard ratio = 0.476, 95% confidence interval: 0.257-0.883, p = 0.019). For surgical patients exceeding the up-to-seven criteria, the combination group demonstrated superior median PFS (18.0 vs. 14.6 months, p = 0.03) and OS (not reached vs. 50.1 months, p = 0.049) compared with the TACE group. Adverse events were manageable, with no treatment-related fatalities reported.

Combination therapy with TACE demonstrated enhanced survival benefits for patients with intermediate to advanced HCC, particularly in surgical patients with higher tumor burdens.

Fibroblast growth factor receptor 2 (FGFR2) activation is associated with endocrine therapy resistance in luminal breast cancer (BC) in vitro, but clinical evidence remains inconsistent. Given the role of FGFRs in mediating tumour microenvironment (TME) interactions, the prognostic value of FGFR2 may depend on the stromal component. This study aimed to validate the association between FGFR-related profile of the stroma and FGFR2 prognostic value in oestrogen receptor-positive invasive ductal carcinoma (IDC).

An in silico gene expression analysis identified 12 stromal factors (FAP, CXCL12, PDGFRA, COL1A1, HSPG2, CCL2, MMP14, S100A4, MMP9, PDGFA, MCAM, IL6) forming an "FGFR-related profile of the stroma". A cohort of 257 ER+ IDC patients from The Cancer Genome Atlas (TCGA) was analysed. Tumours were clustered using k-means based on stromal gene expression, and Cox proportional hazards regression models were used to assess the association between FGFR2 and overall survival (OS).

Two clusters of ER+ IDC tumours were identified based on the stromal gene expression profile. While both clusters had similar tumour stages and hormone receptor statuses, multivariable analysis adjusted for clinical factors revealed a significant association between FGFR2 expression and cluster assignment. In Cluster I (high expression of stromal genes), high FGFR2 was linked to poor prognosis, whereas in Cluster II (low expression), high FGFR2 indicated favourable prognosis. FGFR1, FGFR3, and FGFR4 showed no significant prognostic value.

Stromal profiles modulate the prognostic significance of FGFR2 in luminal breast carcinoma, highlighting the importance of TME profiling for biomarker assessment and explaining inconsistencies in FGFR2 studies.

In advanced hepatocellular carcinoma (HCC), the triple combination therapy of hepatic arterial infusion chemotherapy (HAIC) with lenvatinib and programmed cell death protein-1 (PD-1) inhibitors has shown promise as a front-line treatment. This study aimed to explore the tumor microenvironment (TME) characteristics of the population benefiting most from this treatment.

The study included 44 patients, with 38 ultimately receiving the HAIC + FOLFOX + lenvatinib + PD-1 inhibitor treatment. Tumor response was evaluated using modified RECIST criteria, classifying patients as responders (complete or partial response) or non-responders (stable or progressive disease). Overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were assessed. Additionally, genetic sequencing and RNA analysis were conducted on biopsy samples to identify TME differences between the two groups.

Among the 38 patients, 22 responded favorably, showing significantly longer median OS (not-reached vs. 8.6 months) and median PFS (15.3 months vs. 2.0 months) compared to non-responders. Common AEs included AST elevation, stomachache, nausea, and hypertension, with limited severe AEs. Genetic analysis revealed no significant differences in DNA features between the groups. However, RNA analysis indicated that responders had a more robust immune status, better drug sensitivity, and increased immune cell infiltration. Notably, higher levels of tumor-infiltrating T lymphocytes were linked to better responses, longer PFS, and OS.

The differences in the initial TME of patients, especially in tumor-infiltrating T lymphocytes, may be potential biomarkers for predicting response and prognosis. This finding provides clues to search for biomarkers for this triple combination therapy in advanced HCC.

Hepatocellular Carcinoma (HCC) is the most common form of primary liver cancer, with cirrhosis being its strongest risk factor. Interestingly, an increasing number of HCC cases is also observed without cirrhosis. We developed an HCC model via intrasplenic injection of highly tumorigenic HCC cells, which, due to cellular tropism, invade the liver and allow for a controllable disease progression. Specifically, C57BL/6JRj mice were intrasplenically inoculated with Dt81Hepa1-6 HCC cells, with a subgroup pre-treated with CCl4 to induce cirrhosis (C-HCC). At four weeks post-inoculation, mice were sacrificed, and diseased livers were analyzed via histology, flow cytometry, and RT-qPCR to profile the extracellular matrix (ECM), angiogenesis, and immune cells. In addition, tumor-bearing mice were treated with the first-line therapy, AtezoBev, to assess therapeutic responsiveness of the model. Dt81Hepa1-6 cells displayed similar gene expression as human HCC. After intrasplenic injection, all mice developed multifocal disease. C-HCC mice had a significantly higher tumor load than non-cirrhotic HCC mice. Both HCC and C-HCC models displayed extensive ECM formation, increased levels of vascularization, and immune cell infiltration compared to healthy and non-cancerous cirrhotic livers. AtezoBev treatment produced robust antitumor efficacy, validating the model's suitability for therapy testing. In conclusion, we established a rapidly developing and high-yield HCC model through a simple intrasplenic injection, with or without cirrhotic damage. The model overexpressed key human HCC genes and showed high responsiveness to first-line treatment. Our model uniquely combines all the above-mentioned features, promoting its use towards HCC therapy testing.

The response rates to immunotherapy vary widely depending on the type of cancer and the specific treatment used and can be disappointingly low for many solid tumors. Fortunately, due to their complementary mechanisms of action, immunotherapy and anti-angiogenic therapy have synergistic effects in cancer treatment. By normalizing the tumor vasculature, anti-angiogenic therapy can improve blood flow and oxygenation to facilitate better immune cell infiltration into the tumor and enhance the effectiveness of immunotherapy. It also reduces immunosuppressive factors and enhances immune activation, to create a more favorable environment for immune cells to attack the tumor. Their combination leverages the strengths of both therapies to enhance anti-tumor effects and improve patient outcomes. This review discusses the vasculature-immunity crosstalk in the tumor microenvironment and summarizes the latest advances in combining anti-angiogenic therapy and immune checkpoint inhibitors to treat digestive system tumors.

Durvalumab plus tremelimumab (Durva/Treme) has recently been approved as a first-line or later-line treatment for patients with unresectable hepatocellular carcinoma (u-HCC) in Japan. We assessed the real-world outcomes of Durva/Treme for u-HCC, with a focus on treatment efficacy and safety.

We retrospectively evaluated 22 patients with u-HCC treated with Durva/Treme at Iwate Medical University during the period from 2023 to 2024, with a comparison of the clinical outcomes between patients who received Durva/Treme as first-line and later-line treatments. We further evaluated changes in the modified albumin-bilirubin (mALBI) grade during treatment.

There were 10 patients in the first-line group and 12 patients in the later-line treatment group. During the follow-up with a median duration of 7.6 months, the median progression-free survival (first-line versus later-line: 4.7 months versus 2.9 months, p = 0.85), the objective response rate (0.0% versus 16.7%, p = 0.48), the disease control rate (60.0% versus 58.4%, p = 1.00), and the incidence of any adverse event (50.0% versus 75.0%, p = 0.38) were not statistically different between the two groups. The changes in the mALBI scores were not statistically significant (p = 0.75).

Durva/Treme may be effective and safe for patients with u-HCC, even in patients who receive Durva/Treme as a later-line treatment.

This study aims to evaluate the efficacy and safety of lenvatinib radiofrequency ablation (RFA) sequential therapy for certain hepatocellular carcinoma (HCC) patients.

One hundred and nineteen patients with unresectable HCC in the intermediate stage with Child-Pugh A were retrospectively recruited in a multicenter setting. Those in the lenvatinib RFA sequential therapy group received lenvatinib initially, followed by RFA and the retreatment with lenvatinib. The study compared overall survival (OS), progression-free survival (PFS), tumor response, and adverse events (AEs) between patients undergoing sequential therapy and lenvatinib monotherapy.

After propensity score matching, 25 patients on sequential therapy and 50 on monotherapy were evaluated. Independent factors influencing OS were identified as sequential therapy, modified albumin-bilirubin (mALBI) grade, and relative dose intensity (%) with hazard ratios (HRs) of 0.381 (95% confidence interval [CI], 0.186-0.782), 2.220 (95% CI, 1.410-3.493), and 0.982 (95% CI, 0.966-0.999), respectively. Stratified analysis based on mALBI grades confirmed the independent influence of treatment strategy across all mALBI grades for OS (HR, 0.376; 95% CI, 0.176-0.804). Furthermore, sequential therapy was identified as an independent factor of PFS (HR, 0.382; 95% CI, 0.215-0.678). Sequential therapy significantly outperformed monotherapy on survival benefits (OS: 38.27 vs. 18.96 months for sequential therapy and monotherapy, respectively, p = 0.004; PFS: 13.80 vs. 5.32 months for sequential therapy and monotherapy, respectively, p < 0.001). Sequential therapy was significantly associated with complete response by modified Response Evaluation Criteria in Solid Tumors (odds ratio, 63.089). Ten of 119 patients experienced grade 3 AEs, with no AE beyond grade 3 observed.

Lenvatinib RFA sequential therapy might offer favorable tolerability and potential prognostic improvement compared to lenvatinib monotherapy.

Bevacizumab and sintilimab combined interventional treatment (BeSiIT) and L envatinib and sintilimab combined interventional treatment (LeSiIT) are two commonly used therapeutic regimens for intermediate-advanced hepatocellular carcinoma (HCC) in clinical practice.

To compare the clinical efficacy and safety of BeSiIT and LeSiIT for the treatment of intermediate and advanced HCC.

Patients diagnosed with intermediate-advanced HCC and initially treated with BeSiIT or LeSiIT in the Tianjin Medical University Cancer Institute and Hospital between February 2020 and July 2021 were included. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), conversion rate, and treatment-related adverse events.

Total 127 patients met the inclusion criteria and were divided into BeSiIT and LeSiIT groups. Twenty-eight and fifty patients in the BeSiIT and LeSiIT groups, respectively, were assessed after 1:2 propensity score matching. PFS and OS rates were not significantly different between the two groups. No significant variations were noted in ORRs or DCRs according to the Response Evaluation Criteria in Solid Tumors (RECIST), and modified RECIST. BeSiIT group showed a better conversion rate than the LeSiIT group (P = 0.043). Both groups showed manageable toxicity profiles. Multivariate analysis showed that the independent factors associated with PFS were alpha-fetoprotein levels and carcinoembryonic antigen score.

In intermediate-to-advanced HCC, the BeSiIT and LeSiIT groups exhibited acceptable toxicities and comparable PFS, OS, and ORR.

Programmed cell death 1 receptor (PD-1) inhibition as monotherapy followed by Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibition in case of progression or as upfront double co-inhibition has drastically improved the survival outcomes of metastatic melanoma. Still, many patients develop primary or acquired resistance to both agents, relapse soon, and survive less. For these patients, the therapeutic options are very limited, and for many years, conventional chemotherapy (CC) was the standard of care. Recently, the phase II LEAP-004 trial supported that pembrolizumab/lenvatinib could potentially overcome anti-PD-1/anti-CTLA-4 immunotherapy refractoriness.

In the absence of any prospective comparative study and to evaluate in a real-world context the clinical benefit of re-administering a PD-1 inhibitor (pembrolizumab 200 mg i.v. every 3 weeks, Q3W) with a multi-kinase inhibitor (lenvatinib, but at a reduced dose 10 mg p.o. daily due to its known toxicity) in this frail population of unmet need, we conducted here a retrospective comparison of LEAP-004-proposed combination with CC (carboplatin 4 AUC and dacarbazine 850 mg/m2 i.v. Q3W) in melanoma patients who relapsed to both checkpoint inhibitors, either in combinatorial or in sequential setting, between July 2022 and January 2024. Baseline demographics, disease characteristics, and treatment outcomes (objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)) were recorded. Survival analyses were performed using the Kaplan-Meier method. All patients were also considered for safety analysis.

A total of 84 patients were included in the effectiveness and safety analysis (pembrolizumab/lenvatinib, n=39 and CC, n=45). The median age was 67 (45-87) years and 64 (34-87) years, and men were 33.3% and 46.7%, respectively. The distribution of their metastatic sites was comparable, including 12.8% and 20% with brain involvement. Most patients had a good PS<2 (69.9% and 56.5%), increased lactate dehydrogenase (LDH) (71.8% and 84.4%), BRAF-wild status (82.1% and 84.8%), and received ≥2 previous systemic therapies (61.5% and 53.3%). The median follow-up was 18 months. The ORR was 23.1% and 11.1% (p<0.0001), the median PFS was 4.8 months and 3.8 months [HR (95%CI), 0.57 (0.36-0.92); p=0.017], and the median OS was 14.2 months and 7.8 months [HR (95%CI), 0.39 (0.22-0.69), p=0.0009] in pembrolizumab/lenvatinib and CC arms, respectively. Grade 3-5 treatment-related adverse events were documented in 48.7% (pembrolizumab/lenvatinib) and 75.6% (CC) of patients (p=0.034), which led to treatment discontinuation in 10.3% and 17.8% of cases, respectively.

This is the first comparative study in patients with metastatic melanoma refractory to PD-1/CTLA-4 inhibition and showed significantly longer outcomes in cases treated with pembrolizumab/lenvatinib versus CC.

Currently, treatment options for patients with advanced melanoma who experience failed immunotherapy or targeted therapy are lacking. Recent studies suggest the antitumor activity of combined pembrolizumab and lenvatinib in patients with advanced melanoma progressing on immunotherapy. Herein, we report the clinical outcomes of combined lenvatinib and a programmed cell death protein-1 inhibitor (PD-1) in this population.

This French multicenter real-world study was conducted between September 2020 and July 2023. The primary endpoint was the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumours (version 1.1). Secondary variables were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS), and duration of response (DOR).

Of the 67 patients included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV-M1c or M1d disease. The overall ORR was 28.4% (95% CI, 18%-41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. Median DOR was 3.1 (interquartile range, 1.3-4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5-3.7) and 9.8 (95% CI, 5.6-13.9) months, respectively. Grades 3-5 TRAEs occurred in 16 (24%) patients; common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). No treatment-related deaths occurred.

Our real-world study demonstrates an interesting response rate and acceptable safety profile in a population with poor prognostic factors. Our data support this treatment option for refractory melanoma, as it is not approved by the Food and Drug Administration or European Medicines Agency, and highlight the need for new strategies.

Though atezolizumab plus bevacizumab (A+B) offer promise for unresectable hepatocellular carcinoma (uHCC) treatment, the response rate remains suboptimal. Our previous studies highlighted the potential of transarterial chemoembolization (TACE) when combined with FOLFOX-based hepatic arterial infusion chemotherapy (HAIC) in HCC treatment. This study aims to evaluate the safety and efficacy of A+B plus TACE-HAIC for high tumor burden uHCC (HTB-uHCC).

This three-center retrospective study involved 82 HTB-uHCC patients administered with TACE-HAIC followed by A+B. We characterized HTB-uHCC patients as those surpassing the up-to-11 criteria, exhibiting VP 3-4, or presenting extrahepatic metastases. The primary outcomes were the objective response rate (ORR) and progression-free survival (PFS). Secondary outcomes encompassed the incidence of treatment-related adverse events (TRAEs) and overall survival (OS).

Employing the mRECIST criteria, the ORR was 62.2 %, wherein 18 (22.0 %) patients achieved complete response, 33 (40.2 %) demonstrated partial response, 21 (25.6 %) maintained stable disease, and 10 (12.2 %) exhibited disease progression. Impressively, 11 (13.4 %) patients were converted to resectable HCC and underwent curative hepatectomy. The median PFS was 10.1 months (95 % CI, 8.4 to NA), and the median OS was still pending. At the one-year mark, the OS and PFS rates were 92.8 % (95 % CI, 86.1 to 100.0) and 42.9 % (95 % CI, 31.3 to 58.7), respectively. 79 (96.3 %) experienced TRAEs, and 39 (47.6 %) had grade 3-4 TRAEs, though no treatment-related death was recorded.

The findings underscore the potential of the A+B and TACE-HAIC combined treatment for HTB-uHCC patients, marking it as a viable therapeutic option, given its potent efficacy and tolerable safety profile.

The vascular endothelium, a specialized monolayer of endothelial cells (ECs), is crucial for maintaining vascular homeostasis by controlling the passage of substances and cells. In the tumor microenvironment, Vascular Endothelial Growth Factor A (VEGF-A) drives tumor angiogenesis, leading to endothelial anergy and vascular immunosuppression-a state where ECs resist cytotoxic CD8+ T cell infiltration, hindering immune surveillance. Immunotherapies have shown clinical promise. However, their effectiveness is significantly reduced by tumor EC anergy. Anti-angiogenic treatments aim to normalize tumor vessels and improve immune cell infiltration. Despite their potential, these therapies often cause significant systemic toxicities, necessitating new treatments. The small GTPase Rap1B emerges as a critical regulator of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) signaling in ECs. Our studies using EC-specific Rap1B knockout mice show that the absence of Rap1B impairs tumor growth, alters vessel morphology, and increases CD8+ T cell infiltration and activation. This indicates that Rap1B mediates VEGF-A's immunosuppressive effects, making it a promising target for overcoming vascular immunosuppression in cancer. Rap1B shares structural and functional similarities with RAS oncogenes. We propose that targeting Rap1B could enhance therapies' efficacy while minimizing adverse effects by reversing endothelial anergy. We briefly discuss strategies successfully developed for targeting RAS as a model for developing anti-Rap1 therapies.

CD8+ T cells are the workhorses executing adaptive anti-tumour response, and targets of various cancer immunotherapies. Latest advances have unearthed the sheer heterogeneity of CD8+ tumour infiltrating lymphocytes, and made it increasingly clear that the bulk of the endogenous and therapeutically induced tumour-suppressive momentum hinges on a particular selection of CD8+ T cells with advantageous attributes, namely the memory and stem-like exhausted subsets. A scrutiny of the contemporary perception of CD8+ T cells in cancer and the subgroups of interest along with the factors arbitrating their infiltration contextures, presented herein, may serve as the groundwork for future endeavours to probe further into the regulatory networks underlying their differentiation and migration, and optimise T cell-based immunotherapies accordingly.

We showed previously that the autocrine activation of the FGFR-mediated pathway in GIST lacking secondary KIT mutations was a result of the inhibition of KIT signaling. We show here that the FGF2/FGFR pathway regulates VEGF-A/VEGFR signaling in IM-resistant GIST cells. Indeed, recombinant FGF2 increased the production of VEGF-A by IM-naive and resistant GIST cells. VEGF-A production was also increased in KIT-inhibited GIST, whereas the neutralization of FGF2 by anti-FGF2 mAb attenuated VEGFR signaling. Of note, BGJ 398, pan FGFR inhibitor, effectively and time-dependently inhibited VEGFR signaling in IM-resistant GIST T-1R cells, thereby revealing the regulatory role of the FGFR pathway in VEGFR signaling for this particular GIST cell line. This also resulted in significant synergy between BGJ 398 and VEGFR inhibitors (i.e., sunitinib and regorafenib) by enhancing their pro-apoptotic and anti-proliferative activities. The high potency of the combined use of VEGFR and FGFR inhibitors in IM-resistant GISTs was revealed by the impressive synergy scores observed for regorafenib or sunitinib and BGJ 398. Moreover, FGFR1/2 and VEGFR1/2 were co-localized in IM-resistant GIST T-1R cells, and the direct interaction between the aforementioned RTKs was confirmed by co-immunoprecipitation. In contrast, IM-resistant GIST 430 cells expressed lower basal levels of FGF2 and VEGF-A. Despite the increased expression VEGFR1 and FGFR1/2 in GIST 430 cells, these RTKs were not co-localized and co-immunoprecipitated. Moreover, no synergy between FGFR and VEGFR inhibitors was observed for the IM-resistant GIST 430 cell line. Collectively, the dual targeting of FGFR and VEGFR pathways in IM-resistant GISTs is not limited to the synergistic anti-angiogenic treatment effects. The dual inhibition of FGFR and VEGFR pathways in IM-resistant GISTs potentiates the proapoptotic and anti-proliferative activities of the corresponding RTKi. Mechanistically, the FGF2-induced activation of the FGFR pathway turns on VEGFR signaling via the overproduction of VEGF-A, induces the interaction between FGFR1/2 and VEGFR1, and thereby renders cancer cells highly sensitive to the dual inhibition of the aforementioned RTKs. Thus, our data uncovers the novel mechanism of the cross-talk between the aforementioned RTKs in IM-resistant GISTs lacking secondary KIT mutations and suggests that the dual blockade of FGFR and VEGFR signaling might be an effective treatment strategy for patients with GIST-acquired IM resistance via KIT-independent mechanisms.

Hepatocellular carcinoma (HCC) is a major fatal cancer that is known for its high recurrence and metastasis. An increasing number of studies have shown that the tumor microenvironment is closely related to the metastasis and invasion of HCC. The HCC microenvironment is a complex integrated system composed of cellular components, the extracellular matrix (ECM), and signaling molecules such as chemokines, growth factors, and cytokines, which are generally regarded as crucial molecules that regulate a series of important processes, such as the migration and invasion of HCC cells. Considering the crucial role of signaling molecules, this review aims to elucidate the regulatory effects of chemokines, growth factors, and cytokines on HCC cells in their microenvironment to provide important references for clarifying the development of HCC and exploring effective therapeutic targets.

Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with high incidence, recurrence, and metastasis rates. The emergence of immunotherapy has improved the treatment of advanced HCC, but problems such as drug resistance and immune-related adverse events still exist in clinical practice. The immunosuppressive tumor microenvironment (TME) of HCC restricts the efficacy of immunotherapy and is essential for HCC progression and metastasis. Therefore, it is necessary to elucidate the mechanisms behind immunosuppressive TME to develop and apply immunotherapy. This review systematically summarizes the pathogenesis of HCC, the formation of the highly heterogeneous TME, and the mechanisms by which the immunosuppressive TME accelerates HCC progression and metastasis. We also review the status of HCC immunotherapy and further discuss the existing challenges and potential therapeutic strategies targeting immunosuppressive TME. We hope to inspire optimizing and innovating immunotherapeutic strategies by comprehensively understanding the structure and function of immunosuppressive TME in HCC.

Lenvatinib is a multikinase inhibitor that suppresses vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor α (PDGFRα), as well as the proto-oncogenes RET and KIT. Lenvatinib has been approved by the US Food and Drug Administration (FDA) for the first-line treatment of hepatocellular carcinoma (HCC) due to its superior efficacy when compared to sorafenib. Unfortunately, the development of drug resistance to lenvatinib is becoming increasingly common. Thus, there is an urgent need to identify the factors that lead to drug resistance and ways to mitigate it. We summarize the molecular mechanisms that lead to lenvatinib resistance (LR) in HCC, which involve programmed cell death (PCD), translocation processes, and changes in the tumor microenvironment (TME), and provide strategies to reverse resistance.

Hepatocellular carcinoma (HCC), one of the most prevalent and destructive causes of cancer-related deaths worldwide, approximately 70% of patients with HCC exhibit advanced disease at diagnosis, limiting the potential for radical treatment. For such patients, lenvatinib, a long-awaited alternative to sorafenib for first-line targeted therapy, has become a key treatment. Unfortunately, despite some progress, the prognosis for advanced HCC remains poor because of drug resistance development. However, the molecular mechanisms underlying lenvatinib resistance and ways to relief drug resistance in HCC are largely unknown and lack of systematic summary; thus, this review not only aims to explore factors contributing to lenvatinib resistance in HCC, but more importantly, summary potential methods to conquer or mitigate the resistance. The results suggest that abnormal activation of pathways, drug transport, epigenetics, tumour microenvironment, cancer stem cells, regulated cell death, epithelial-mesenchymal transition, and other mechanisms are involved in the development of lenvatinib resistance in HCC and subsequent HCC progression. To improve the therapeutic outcomes of lenvatinib, inhibiting acquired resistance, combined therapies, and nano-delivery carriers may be possible approaches.

Intermediate-stage (BCLC-B) hepatocellular carcinoma (HCC) beyond the up-to-11 criteria represent a significant therapeutic challenge due to high and heterogeneous tumor burden. This study evaluated the effectiveness and safety of transarterial chemoembolization (TACE) in combination with lenvatinib and tislelizumab for these patients.

In this retrospective cohort study, patients with unresectable intermediate-stage HCC beyond the up-to-11 criteria were enrolled and divided into TACE monotherapy (T), TACE combined with lenvatinib (TL), or TACE plus lenvatinib and tislelizumab (TLT) group based on the first-line treatment, respectively. The primary endpoint was overall survival (OS). The secondary outcomes included progression-free survival (PFS), tumor response according to RESIST1.1 and modified RECIST, and adverse events (AEs).

There were 38, 45, and 66 patients in the T, TL, and TLT groups, respectively. The TLT group exhibited significantly higher ORR and DCR than the other two groups, as assessed by either mRECIST or RECIST 1.1 (all P<0.05). Median PFS and OS were significantly longer in the TLT group compared with the T group (PFS: 8.5 vs. 4.4 months; OS: 31.5 vs. 18.5 months; all P<0.001) and TL group (PFS: 8.5 vs. 5.5 months; OS: 31.5 vs. 20.5 months; all P<0.05). The incidence of TRAEs was slightly higher in the TLT and TL groups than in the T group, while all the toxicities were tolerable. No treatment-related death occurred in all groups.

TACE combined with lenvatinib and tislelizumab significantly improved the survival benefit compared with TACE monotherapy and TACE plus lenvatinib in patients with intermediate-stage HCC beyond the up-to-11 criteria, with an acceptable safety profile.

A meta-analysis of the clinical survival indicators, adverse reactions and safety of lenvatinib combined with programmed death-1 (PD-1) inhibitors in treating liver cancer was conducted, providing objective and effective evidence for clinical use. The present study is anticipated to guide the clinical application of lenvatinib. In the current meta-analysis, the PubMed, Embase and Cochrane Library databases were searched from inception to September 2023. Randomized controlled trials (RCTs), non-RCTs and single-arm trial studies related to the combined treatment of lenvatinib and PD-1/PD-ligand 1 (L1) inhibitors for hepatocellular carcinoma (HCC) were included, while published and unpublished literature on other study types, literature with incomplete or inadequate information, animal experiments, literature reviews and systematic studies were excluded. Data were processed using STATA 15.1. The pooled results showed that the objective response rate [ORR; odds ratio (OR), 3.36; 95% confidence interval (CI), 2.13-5.30; P<0.001], disease control rate (DCR; OR, 1.62; 95% CI, 1.03-2.57; P=0.038) and partial response (PR; OR, 3.81; 95% CI, 2.17-6.70; P<0.001) of combined lenvatinib and PD-1/PD-L1 inhibitor therapy were significantly higher than those of lenvatinib monotherapy. Additionally, subgroup analysis results showed that the DCR of combination therapy using lenvatinib and nivolumab was significantly higher than that of lenvatinib monotherapy (OR, 2.20; 95% CI; 1.07-4.51; P=0.032). The difference between combination therapy using lenvatinib and camrelizumab, and lenvatinib monotherapy was not significant. However, the complete response, stable disease, progression disease and incidence rate of adverse events between combination therapy and lenvatinib monotherapy were not significantly different. Compared with lenvatinib alone, lenvatinib combined with PD-1/PD-L1 inhibitors significantly improved ORR, mainly PR, and DCR in patients with HCC. At present, lenvatinib is mainly combined with nivolumab to increase the DCR of lenvatinib monotherapy for HCC. In addition, the incidence rate of adverse reactions between combination therapy and lenvatinib monotherapy was not significantly different for HCC.

Both atezolizumab (a PD-L1 inhibitor) plus bevacizumab (A+B) and sintilimab (a PD-1 inhibitor) plus bevacizumab (S+B) are recommended as the first-line regimen for advanced hepatocellular carcinoma (HCC) in China. Different efficacy between the two regimens combined with transvascular intervention for unresectable HCC (uHCC) remain unknown. We retrospectively analyzed uHCC patients treated in three centers by simultaneous combination of A+B or S+B with transarterial chemoembolization (TACE) and FOLFOX-based hepatic arterial infusion chemotherapy (HAIC). Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events (TRAEs) were compared. Totally 188 patients were included, with 92 and 96 administered A+B+TACE-HAIC (ABTH) and S+B+TACE-HAIC (SBTH), respectively. ORRs (62.0 vs. 70.8%, respectively; P = 0.257) and disease control rates (88.0 vs. 93.8%, P = 0.267) were similar between groups by the mRECIST criteria. ABTH showed no survival advantage over SBTH, with median PFS times of 11.7 months and 13.0 months, respectively (HR = 0.81, 95% CI, 0.52-1.26, P = 0.35) and similar OS times (HR = 1.19, 95% CI, 0.32-4.39, P = 0.8). No significant differences were observed in grade 3-4 TRAEs between groups. Either PD-L1 or PD-1 inhibitor plus bevacizumab combined with TACE-HAIC have similarly excellent therapeutic efficacy with manageable adverse events, representing promising treatment options for uHCC.

Limited treatment options exist for unresectable intrahepatic cholangiocarcinoma (ICC), with systemic chemotherapy (SC) serving as the primary approach. This study aimed to assess the effectiveness of first-line hepatic arterial infusion chemotherapy (HAIC) in combination with lenvatinib and PD-(L)1 inhibitors (HLP) compared to SC combined with PD-(L)1 inhibitors (SCP) or SC alone in treating unresectable ICC.

Patient with unresectable ICC who underwent first-line treatment with HLP, SCP or SC from January 2016 to December 2022 were retrospectively analyzed. The study evaluated and compared efficacy and safety outcomes across the three treatment groups.

The study comprised 42, 49, and 50 patients in the HLP, SCP, and SC groups, respectively. Median progression-free survival (PFS) times were 30.0, 10.2, and 6.5 months for HLP, SCP, and SC groups. While the SC group had a median overall survival (OS) time of 21.8 months, the HLP and SCP groups hadn't reached median OS. The HLP group demonstrated significantly superior PFS (p < 0.001) and OS (p = 0.014) compared to the others. Moreover, the HLP group exhibited the highest objective response rate (ORR) at 50.0% and the highest disease control rate (DCR) at 88.1%, surpassing the SC group (ORR, 6.0%; DCR, 52.0%) and SCP group (ORR, 18.4%; DCR, 73.5%) (p < 0.05). Generally, the HLP group reported fewer grades 3-4 adverse events (AEs) compared with others.

In contrast to systemic chemotherapy with or without PD-(L)1 inhibitors, the triple combination therapy incorporating HAIC, lenvatinib, and PD-(L)1 inhibitors showcased favorable survival benefits and manageable adverse events for unresectable ICC.

The FGFR signaling pathway is integral to cellular activities, including proliferation, differentiation, and survival. Dysregulation of this pathway is implicated in numerous human cancers, positioning FGFR as a prominent therapeutic target. Here, we conduct a comprehensive review of the function, signaling pathways and abnormal alterations of FGFR, as well as its role in tumorigenesis and development. Additionally, we provide an in-depth analysis of pivotal phase 2 and 3 clinical trials evaluating the performance and safety of FGFR inhibitors in oncology, thereby shedding light on the current state of clinical research in this field. Then, we highlight four drugs that have been approved for marketing by the FDA, offering insights into their molecular mechanisms and clinical achievements. Our discussion encompasses the intricate landscape of FGFR-driven tumorigenesis, current techniques for pinpointing FGFR anomalies, and clinical experiences with FGFR inhibitor regimens. Furthermore, we discuss the inherent challenges of targeting the FGFR pathway, encompassing resistance mechanisms such as activation by gatekeeper mutations, alternative pathways, and potential adverse reactions. By synthesizing the current evidence, we underscore the potential of FGFR-centric therapies to enhance patient prognosis, while emphasizing the imperative need for continued research to surmount resistance and optimize treatment modalities.

The basigin (BSG) gene, also known as CD147, has been implicated in the progression and prognosis of various cancers, including liver cancer. This study aimed to comprehensively evaluate the prognostic value of total BSG expression and its specific transcript variants, ENST00000353555 and ENST00000545507, in a large cohort of patients with primary liver cancer.

The prognostic values of total BSG, ENST00000353555, and ENST00000545507 expression in overall survival (OS) and progression-free interval (PFI) of patients with primary liver cancer were assessed using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset. Survival analysis, receiver operating characteristic (ROC) analysis, and validation of an extracellular matrix (ECM)-related prognostic signature were performed.

In univariate and multivariate analyses, total BSG, ENST00000353555, and ENST00000545507 expression were associated with poor OS in liver cancer patients. ENST00000353555 showed the highest hazard ratio among the three prognostic indicators. ROC analysis revealed that ENST00000353555 had better prognostic performance than total BSG expression. Replacing total BSG with ENST00000353555 in an existing ECM-related prognostic signature marginally increased the area under the curve values for one year from 0.79 to 0.80, and five-year OS from 0.72 to 0.73. ENST00000353555 showed isoform-specific positive correlations with EDNRB, IL10, C10orf54, and VEGFA.

ENST00000353555 serves as a better prognostic biomarker than total BSG expression in liver cancer, either as an individual marker or as a component of an ECM-related gene signature. Additionally, ENST00000353555 exhibited isoform-specific positive correlations with several immunosuppressive genes, suggesting a potential role in regulating the tumor microenvironment.

Hepatocellular carcinoma (HCC) is a malignancy associated with high morbidity and mortality rates. Conversion therapy provides patients with unresectable HCC (uHCC) the opportunity to undergo radical treatment and achieve long-term survival. Despite accumulating evidence regarding the efficacy of conversion therapy, the optimal treatment approach for such therapy remains uncertain. Lenvatinib (LEN) has shown efficacy and tolerable rates of adverse events (AEs) when applied in combination with immune checkpoint inhibitors (ICIs) or locoregional therapy (LRT) over the past decade. Therefore, the present meta-analysis was performed to systematically assess the safety and efficacy of LEN-based treatment regimens in conversion therapies for uHCC. Data on outcomes, including the conversion rate, objective response rate (ORR), disease control rate (DCR) and AE incidence in patients with uHCC, were collected. A systematic literature search was performed using MEDLINE, Embase, Web of Science and Cochrane Library databases, up to the date of September 1, 2023. In total, 16 studies, encompassing a total of 1,650 cases of uHCC, were included in the final meta-analysis. The pooled conversion rates for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were calculated to be 0.04 (95% CI, 0.00-0.07; I2=77%), 0.23 (95% CI, 0.16-0.30; I2=66%), 0.14 (95% CI, 0.10-0.18; I2=0%) and 0.35 (95% CI, 0.23-0.47; I2=88%), respectively. The pooled ORRs for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were found to be 0.45 (95% CI, 0.23-0.67; I2=96%), 0.49 (95% CI, 0.39-0.60; I2=78%), 0.43 (95% CI, 0.24-0.62; I2=88%) and 0.69 (95% CI, 0.56-0.82; I2=92%), respectively. The pooled DCRs for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were observed to be 0.77 (95% CI, 0.73-0.81; I2=23%), 0.82 (95% CI, 0.69-0.95; I2=90%), 0.67 (95% CI, 0.39-0.94; I2=94%) and 0.87 (95% CI, 0.82-0.93; I2=67%), respectively. The pooled grade ≥3 AEs for LEN alone, LEN + ICI, LEN + LRT and LEN + ICI + LRT were 0.25 (95% CI, 0.14-0.36; I2=89%), 0.43 (95% CI, 0.34-0.53; I2=23%), 0.42 (95% CI, 0.19-0.66; I2=81%) and 0.35 (95% CI, 0.17-0.54; I2=94%), respectively. These findings suggested that LEN-based combination strategies may confer efficacy and acceptable tolerability for patients with uHCC. In particular, LEN + ICI, with or without LRT, appears to represent a highly effective conversion regimen, with an acceptable conversion rate and well-characterized safety profile.

Hepatic arterial infusion chemotherapy (HAIC) has demonstrated remarkable local therapeutic efficacy in treating patients with large unresectable hepatocellular carcinoma (HCC). Additionally, the combination of lenvatinib and programmed cell death protein-1 (PD-1) inhibitors has demonstrated promising antitumor effects in unresectable HCC. Therefore, we conducted a retrospective analysis to evaluate the efficacy and safety of combining HAIC with lenvatinib and PD-1 inhibitors as a first-line therapeutic approach in high-burden HCC patients.

We conducted a retrospective analysis on patients diagnosed with high-burden HCC who had major portal vein tumor thrombosis (Vp3 and Vp4) or tumor occupancy exceeding 50% of the liver. These patients received a first-line treatment consisting of HAIC with a combination of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX), along with lenvatinib and PD-1 inhibitors between November 2020 and June 2023. The primary endpoints of this study included progression-free survival (PFS) and overall survival (OS), while the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs).

Ninety-one patients were enrolled in this study, with a median PFS of 8.8 months (95% confidence interval [CI]: 5.75-11.78) and a median OS of 14.3 months (95% CI: 11.23-17.31). According to RECIST 1.1 criteria, the ORR was 52.7%, and DCR was 95.6%. According to the mRECIST criteria, the ORR was 72.5%, and the DCR was 96.5%. Among all patients, 86 (94.5%) experienced TRAEs, and there were no instances of treatment-related deaths.

The combination of HAIC-FOLFOX with lenvatinib and PD-1 inhibitors as a first-line therapy has exhibited notable therapeutic efficacy and well-tolerated adverse events among patients with high-burden HCC.