Hepatocellular carcinoma (HCC) remains one of the most prevalent and lethal cancers globally. While surgical resection and liver transplantation offer potential cures for early-stage HCC, the majority of patients are diagnosed at advanced stages where such interventions are not viable. Sorafenib, a multi-target kinase inhibitor, has been a cornerstone in the treatment of advanced HCC since its approval in 2007. Despite its significant clinical impact, less than half of the treated patients derive long-term benefits due to the emergence of resistance and associated side effects. This review focuses on the role of sorafenib, an FDA-approved multi-target kinase inhibitor, in treating advanced HCC, discusses the mechanisms underlying its therapeutic effects and associated resistance, and explores additional therapeutic strategies being investigated to improve patient outcomes.

The incorporation of immunotherapy has transformed the treatment landscape for advanced, unresectable, or metastatic gastroesophageal cancers (GECs), with improved survival outcomes. These improvements in outcomes for advanced GECs have led to clinical trials evaluating the role of immunotherapy in patients with resectable early-stage GECs. However, there remains a high burden of morbidity and mortality, and ongoing trials utilizing novel immunotherapy agents and combinations are underway. This review summarizes the findings of previous and ongoing clinical trials related to immunotherapy for patients with early- and late-stage GECs.

Immune checkpoint inhibitors have become a mainstay of treatment in many solid organ malignancies. Alongside this has been the rapid development in the identification and targeting of oncogenic drivers. The presence of alterations in oncogenic drivers not only predicts response to target therapy but can modulate the immune microenvironment and influence response to immunotherapy. Combining immune checkpoint inhibitors with targeted agents is an attractive therapeutic option but overlapping toxicity profiles may limit the clinical use of some combinations. In addition, there is growing evidence of shared resistance mechanisms that alter the response to immunotherapy when it is used after targeted therapy. Understanding this complex interaction between oncogenic drivers, targeted therapy and response to immune checkpoint inhibitors is vital for selecting the right treatment, at the right time for the right patient. In this review, we summarise the preclinical and clinical evidence of the influence of four common oncogenic alterations on immune checkpoint inhibitor response, combination therapies, and the presence of shared resistance mechanisms. We highlight the common resistance mechanisms and the need for more randomised trials investigating both combination and sequential therapy.

Hepatocellular carcinoma (HCC) is a commonly diagnosed malignancy, with the treatment for transplant-ineligible localized disease traditionally relying on locoregional therapies, such as surgical resection, transarterial chemoembolization (TACE), and transarterial radioembolization (TARE). Systemic therapy has historically been reserved for advanced, unresectable HCC. However, lenvatinib, an oral multikinase inhibitor, has recently gained traction as part of a multimodal approach for localized HCC in combination with locoregional treatments. An upfront TACE or TARE can induce tumor hypoxia, leading to the upregulation of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF), which promotes tumor angiogenesis and progression. The rationale for combining lenvatinib with a locoregional therapy is to enhance tumor shrinkage while preserving liver function before a definitive intervention. Clinical trials, such as TACTICS and LAUNCH, have demonstrated improved outcomes with this approach. Additionally, retrospective studies, including those incorporating immune checkpoint inhibitors, have reported further benefits. This review explores the combination of lenvatinib with various locoregional modalities, including TARE, microwave ablation (MWA), and radiofrequency ablation (RFA), highlighting their indications and clinical outcomes. Furthermore, we discuss the ongoing and upcoming clinical trials investigating the integration of systemic agents with locoregional therapies for intermediate-stage HCC, including EMERALD-1, EMERALD-3, LEAP-012, and CheckMate 74W.

Patients with unresectable hepatocellular carcinoma (uHCC) and Child-Pugh grade B face limited treatment options and poor outcomes. This study aims to evaluate whether the effect and safety of combining tyrosine kinase inhibitors (TKIs) with progressive disease (PD)-1 inhibitors in uHCC patients with Child-Pugh B7 (CP7) and B8/9 (CP8/9) differ.

This multicenter retrospective study included 179 uHCC patients with Child-Pugh B (CP7 group: n = 106; CP8/9 group: n = 73), receiving a combination of lenvatinib/sorafenib/other TKIs and PD-1 inhibitors between December 2020 and March 2023. Progression-free survival (PFS) and overall survival (OS) were defined as the primary endpoint. Secondary endpoints included the objective response rate (ORR) and safety.

The median PFS and OS for the entire cohort were 7.3 months (95% confidence intervals [CI]: 6.3-8.3) and 16.0 months (95% CI: 12.9-19.1), respectively. No statistically significant differences were observed between CP7 and CP8/9 groups in PFS (7.8 vs. 6.3 months, p = 0.28), OS (17.8 vs. 14.0 months, p = 0.20), ORR (33.0% vs. 27.4%, p = 0.42), or safety profiles. However, the CP8/9 group had significantly higher rates of TKI dose reductions (46.6% vs. 31.1%, p = 0.04) and discontinuations (57.5% vs. 24.5%, p < 0.001). Notably, 30.2% of patients maintained sustained radiographic responses despite advanced liver dysfunction.

Combining TKIs with PD-1 inhibitors is an effective and well-tolerated option for HCC patients with Child-Pugh B, including those with CP8/9.

Fibroblast growth factor receptor (FGFR) 4 is overexpressed in gastric cancer (GC) and is a potential therapeutic target for GC. Since the FGF/FGFR signaling is involved in tumor microenvironment inducing the formation of an immunosuppression, lenvatinib is expected to inhibit FGFR4 leading to reduced tumor PD-L1 levels and regulatory T cell (Treg) infiltration, improving pembrolizumab efficacy. This study explored the background of the molecular mechanisms underlying the therapeutic efficacy of lenvatinib plus pembrolizumab.

Expression of FGFR4 and its specific ligand FGF19 was assessed by immunohistochemical staining and clinicopathological relevance was also examined. The effect of lenvatinib on FGF19-FGFR4 signaling was evaluated using cellular experiments. Lastly, the expression of FGFR4 on Treg cells was evaluated by immunostaining and flow cytometry. The Cancer Genome Atlas cBioPortal and Gene Expression Omnibus microarray databases were accessed to support these results.

High FGFR4 expression was associated with histological type and venous invasion and predominantly detected in human epidermal growth factor receptor 2 and Epstein-Barr virus-positive GC. Bioinformatics data suggested that FGF19-FGFR4 signaling was activated in GC, and cellular experiments showed that lenvatinib reduced FGFR4 and PD-L1 expression in GC cells. Results of integrating various analyses suggested that FGFR4 did not seem to be enough expressed on Treg cells in GC.

The FGF19-FGFR4 signaling has a pivotal role in gastric tumorigenesis and may be involved in immunosuppression through PD-L1 modification. But, lenvatinib may not regulate immune editing by directly inhibiting FGFR4 on Treg cells.

NCT06203600.

Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. While early-stage HCC can be effectively managed with surgical resection and other interventions, treatment options for advanced HCC are limited. Current systemic treatments for advanced HCC include VEGF-targeted tyrosine kinase inhibitors (Sorafenib, Lenvatinib), and the combination therapy of anti PD-1/PD-L1 and anti VEGF (Atezolizumab plus Bevacizumab, Camrelizumab plus Rivoceranib). However, the lack of response to these drugs and the emergence of acquired drug resistance significantly impairs their efficacy. Numerous studies have demonstrated that the tumor immune microenvironment (TIME) plays a crucial role in modulating the response to these therapies. Various immune cells and their secreted factors within the TIME play a pivotal role in the emergence of secondary drug resistance in HCC. This article reviews the mechanism of TIME promoting drug resistance, discusses the influence of current systemic HCC treatment drugs on TIME, and evaluates how these TIME changes affect the efficacy of treatment. A deeper understanding of the interaction between TIME and systemic treatment drugs may be beneficial to enhance the treatment effect, mitigate drug resistance of advanced HCC, and ultimately improve the prognosis of patients.

Lenvatinib is an orally available multi-tyrosine kinase inhibitor that mainly targets vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling. These inhibitory activities of lenvatinib exhibit antitumor efficacy, mainly due to their repressive effects on angiogenesis. In addition, a recent non-clinical evaluation using mouse tumor models revealed that lenvatinib causes immunomodulatory effects, including activation of effector T-cells and regulation of tumor-associated macrophages (TAMs). Combined treatment with lenvatinib and anti-programmed cell death-1 antibody (anti-PD-1) resulted in enhanced antitumor activity relative to monotreatment with anti-PD-1 or lenvatinib. This review summarizes the antitumor mechanisms of lenvatinib and of lenvatinib plus anti-PD-1 combination therapy.

The process of tumor development involves tumor cells eluding detection and suppression of immune responses, which can cause decreased tumor cell antigenicity, expression of immunosuppressive molecules, and immunosuppressive cell recruitment to the tumor microenvironment (TME). Immunologically and genomically integrated analysis (immunogenomic analysis) of patient specimens has revealed that oncogenic aberrant signaling is involved in both carcinogenesis and immune evasion. In noninflamed cancers such as epidermal growth factor receptor (EGFR)-mutated lung cancers, genetic abnormalities in cancer cells contribute to the formation of an immunosuppressive TME by recruiting immunosuppressive cells, which cannot be fully explained by the cancer immunoediting hypothesis. This review summarizes the latest findings regarding the links between cancer genetic abnormalities and immunosuppression causing clinical resistance to immunotherapy. We propose the concepts of immunogenomic cancer evolution, in which cancer cell genomic evolution shapes the immunosuppressive TME, and immunogenomic precision medicine, in which cancer immunotherapy can be combined with molecularly targeted reagents that modulate the immunosuppressive TME.

Despite remarkable advances in cancer treatment, most solid cancers remain difficult to cure. We recently developed an antibody-drug conjugate (ADC; 84-EBET) for pancreatic cancer by using the carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) antibody #84.7 and the bromodomain and extra-terminal (BET) protein degrader EBET. In this study, we showed the overexpression of CEACAM6 in colorectal, lung, and breast cancers and the broad-spectrum efficacy of 84-EBET in mouse models of these cancers. In vitro assays using cancer organoids and cell lines of colorectal, lung, and breast cancers revealed that 84-EBET was more potent than ADCs with known approved payloads-DXd, SN38, and monomethyl auristatin E-or standard chemotherapies. In mouse studies, a single injection of 84-EBET induced marked regression of colorectal-, lung-, and breast cancer patient-derived xenograft tumors and cell line-derived xenograft tumors. Moreover, in mouse syngeneic colorectal cancer, lung cancer, and breast cancer models resistant to PD-1 antibody, the combination of 84-EBET and PD-1 antibody induced complete regression of most tumors. Mechanistically, 84-EBET degraded bromodomain-containing protein 4 in both cancer and stromal cells via bystander efficacy. It decreased stromal inflammatory phenotypes and increased activated T-cell numbers in tumors. These results demonstrate that delivering BET protein degraders to tumors and their microenvironments via a CEACAM6-targeted ADC may be effective against a wide range of solid cancers.

This study aimed to evaluate the prognostic significance of changes in inflammatory markers in patients with Hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) treated with first-line lenvatinib plus a programmed cell death protein 1 (PD-1) inhibitor.

This study retrospectively included 117 HBV-HCC patients treated with first-line lenvatinib in combination with a PD-1 inhibitor. Independent factors affecting progression-free survival (PFS) and overall survival (OS) were explored based on baseline indicators and inflammatory markers changes after one treatment cycle.

Multivariate analysis revealed that an alpha-fetoprotein (AFP) level ⩾ 400 ng/mL [hazard ratio (HR), 1.69; 95% confidence interval (CI), 1.11-2.58; P = 0.01] was identified as an independent risk factor, platelet-to-neutrophil ratio (PNR) ⩽ 65.43 (HR 0.50; 95% CI 0.30-0.84; P < 0.01 ) and SII ⩽ 539.47 (HR 0.54; 95% CI 0.30-0.96; P = 0.03) were identified as independent protective factors for PFS. Additionally, multivariate analysis demonstrated that AFP ⩾ 400 ng/mL, HBV-HCC patients with diabetes mellitus (DM), and SII > 303.66 were independent risk factors of OS. The patients whose SII had increased after one cycle of treatment showed a poorer PFS (HR 1.61; 95 %CI 1.10-2.37; P = 0.015) and OS (HR 1.76; 95 % CI 1.15-2.70; P = 0.009) than patients whose SII had decreased. The objective response rate (ORR) was higher in the SII-decreased patients (47.5% vs 32.5%, P = 0.11). Mann-Whitney test found a significant difference in therapeutic response between the SII-increased patients and the SII-decreased patients (P = 0.04).

SII can be associated with outcomes in patients with HBV-HCC treated with first-line lenvatinib plus PD-1 inhibitors.

A novel gene signature for MVD was developed. This MVD gene score enables the estimation of MVD, reflecting the sensitivity to antiangiogenic inhibitors, in transcriptomic datasets. We demonstrated the utility of the MVD gene score together with a T cell-inflamed gene signature for potential future use as a clinical biomarker.

Cervical cancer is the third most common malignant tumor in women worldwide in terms of both incidence and mortality. The field of cervical cancer treatment is rapidly evolving, and various combination therapies are being explored to enhance the efficacy of immune checkpoint inhibitors (ICI) and provide new treatment options for patients at different disease stages. Clinical trials involving immune checkpoint inhibitors are now being conducted following a phase 3 trial with cemiplimab, an ICI, which demonstrated a significant improvement in prognosis in advanced or metastatic cervical cancer patients. These trials include monotherapy and combination therapy with other immune therapies, chemotherapy, or radiation therapy. Furthermore, other approaches for controlling tumors via the immune system, such as therapeutic vaccination for specific tumor antigens or immune cell therapy including chimeric antigen receptor (CAR)-T cell therapy and tumor-infiltrating lymphocytes are being investigated. Ongoing trials will continue to illuminate the optimal strategies for combining these therapies and addressing challenges associated with immune checkpoint failure in cervical cancer. Herein, we conducted a review of articles related to immunotherapy for cervical cancer and describe current treatment strategies for cervical cancer via immunotherapy.

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.

Colorectal cancer, ranking as the third most prevalent malignancy globally, substantially benefits from both immunotherapy and VEGF/VEGFR inhibitors. Nevertheless, the use of monotherapy proves inadequate in effectively tackling the heterogeneity of tumors and the intricacies of their microenvironment, frequently leading to drug resistance and immune evasion. This situation underscores the pressing need for innovative strategies aimed at augmenting the effectiveness and durability of treatments. Clinical research demonstrates that the combination of VEGF/VEGFR inhibitors (primarily including VEGF/VEGFR-targeted drugs and multi-kinase inhibitors) with immune checkpoint inhibitors creates a synergistic effect in the treatment of colorectal cancer. Our analysis explores how VEGF/VEGFR inhibitors recalibrate the tumor microenvironment, modulate immune cell functions, and influence the expression of immune checkpoints and cytokines. Furthermore, we critically evaluate the preclinical and clinical feasibility of these combined therapeutic approaches. Despite the potential for toxicity, the significant benefits and prospective applications of these strategies warrant thorough exploration. Exploring the synergistic mechanisms of these combined treatments has the potential to inaugurate a new paradigm in oncology, enabling more personalized and efficacious treatment modalities. Additionally, the synergy between VEGF/VEGFR inhibitors and nascent immunotherapies emerges as a promising field of inquiry.

To explore the efficacy and safety of lenvatinib, either as a monotherapy or in combination with programmed death-1 (PD-1) blockades, as re-challenging treatment in patients with metastatic osteosarcoma following treatment failure with previous tyrosine kinase inhibitors (TKIs).

We retrospectively reviewed the data of 26 patients with metastatic osteosarcoma who received rechallenge treatment with lenvatinib monotherapy or lenvatinib plus PD-1 blockades after failure of the initial TKI treatment from January 2020 to June 2024 in our center. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), and safety.

Of the 26 patients, ORR and CBR were 11.5% and 61.5%, respectively. The median duration of follow-up was 15 months (range, 4.3-25.6) with a median PFS of 7.2 months (95% CI: 1.9-12.5). A total of 14 patients received lenvatinib as a monotherapy, and 12 received a combination therapy of lenvatinib and PD-1 blockade. No significant differences were observed in ORR (0 vs 25%) and CBR (57.1 vs 66.7%) between the two groups. Additionally, the combination cohort exhibited a significantly longer PFS compared to the monotherapy cohort (8.6 [95% CI: 5.0-12.1] vs 4.0 months [95% CI: 1.0-7.0], p = 0.022). 96.2% of patients experienced grade 1 or more adverse events (AEs). Grade 3 adverse events occurred in 6 (23.1%) patients. The safety profiles of the lenvatinib and PD-1 blockade combination group were found to be comparable to those of the lenvatinib monotherapy group.

Our data indicated that patients with metastatic osteosarcoma could potentially benefit from lenvatinib rechallenge after progress with initial TKI treatment. The combination of lenvatinib and PD-1 blockade therapy demonstrated promising survival outcomes in patients with metastatic osteosarcoma, accompanied by a manageable toxicity profile.

Therapeutic options for patients with platinum-resistant ovarian cancer (PROC) remain a major unmet need. PROC patients with multiple recurrences are unable to continue highly toxic treatment after prior multiple lines of systemic therapy. Chemotherapy-free option lenvatinib plus anti-programmed cell death protein-1 (PD-1) combination therapy has shown promising results in several malignancies including ovarian cancer, but the toxicity of a high starting dose of lenvatinib is also notable and needs to be improved. Our previous pilot study indicated that a reduced starting dose of lenvatinib may maintain comparable anti-tumor activity with favorable safety in heavily pre-treated ovarian cancer. This study is designed to further validate the efficacy and safety of the combination therapy of low-dose lenvatinib and PD-1 inhibitor toripalimab in patients with recurrent PROC.

The study is designed as a multicenter, open-label, single-arm, prospective phase II study. Patients with recurrent epithelial ovarian cancer who have disease progression either during or within 6 months after completion of platinum-based therapy will be included. A total of 69 participants will receive low-dose lenvatinib (8 mg or 12 mg, daily, orally, based on patient's body weight) and toripalimab (240 mg, every 21 days, intravenously). Treatment will continue until the development of unacceptable toxicity or disease progression. The primary endpoint is the progression-free survival. The secondary endpoints include objective response rate, duration of response, disease control rate, overall survival, toxicity and patients' quality of life. Exploratory objectives aim to identify biomarkers and molecular signatures for predicting response or prognosis.

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.

Atezolizumab/bevacizumab (A/B) is now a standard first-line treatment for advanced hepatocellular carcinoma (HCC), but the optimal second-line regimen is not known. We evaluated real-world treatment patterns and outcomes to investigate factors associated with post-progression survival (PPS).

In this multicenter, international, retrospective study, we examined clinical characteristics and outcomes of patients with advanced HCC who progressed on first-line A/B. The primary outcome of PPS was defined as time from first radiographic progression on A/B to death.

A total of 406 patients alive after progression on first-line A/B were included in the final analysis, of whom 45.3% (n = 184) received best supportive treatment (BST) and 54.7% (n = 222) continued active systemic treatment. In the second line, 155 patients were treated with tyrosine kinase inhibitors (TKIs), 45 with immune checkpoint inhibitor (IO)-based regimens, and 3 had missing data. Median PPS of the whole cohort (mPPS) was 6.0 months (95% CI 5.2-7.2). On multivariate Cox regression analysis, absence of portal vein tumor thrombus, ECOG <2, and continued active treatment were predictors of better PPS. mPPS was significantly longer for patients who continued active treatment vs. BST (9.7 vs. 2.6 months; HR 0.41, p <0.001). In the second-line setting, patients treated with TKIs had a numerically shorter mPPS compared to those treated with IO (8.4 vs. 14.9 months; HR 1.37, p = 0.256).

Continuation of active therapy after A/B progression was independently associated with better survival even after adjusting for baseline disease characteristics. mPPS with IO-based therapy exceeded a year, suggesting that IO continuation post-progression may retain benefit. The precise sequencing of TKI and IO regimens warrants further investigation.

There is currently a lack of level 1 data on second-line treatment options for patients with advanced hepatocellular carcinoma who progress after frontline atezolizumab plus bevacizumab, as all second-line approvals were established during the frontline sorafenib era. Our study aims to fill in some of the knowledge gap by investigating real-world patient outcomes in the second-line treatment setting. Findings from this study show that patients who continued active treatment had improved post-progression survival compared to those who received best supportive care, and medication regimens incorporating tyrosine kinase inhibitors as well as immunotherapy agents were active. These results can help inform clinicians of possible treatment options for patients who progress after frontline atezolizumab plus bevacizumab while we await maturing data from randomized-controlled trials.

Currently, therapeutic combinations of immune checkpoint inhibitors (ICIs) with anti-angiogenic agents have shown promising outcomes and have the potential to establish a new standard of care. The efficacy and safety of the first-line combination of envafolimab (an ICI) and lenvatinib (an anti-tumor angiogenesis drug) for the treatment of patients with inoperable hepatocellular carcinoma (HCC) have not been demonstrated. Unresectable HCC patients with an Eastern Cooperative Oncology Group (ECOG) physical status score ≤ 1 and a Child-Pugh score ≤ 7 who had not received systemic therapy were included in this single-arm, exploratory, multicentre phase II clinical study. All patients were required to meet the criteria of being at least 18 years of age, having no history of other malignancies, and existing at least one measurable lesion. The patients were treated with envafolimab (150 mg, QW, subcutaneous) in combination with lenvatinib (12 mg for patients weighing over 60 kg, 8 mg for patients weighing under 60 kg). The co-primary endpoint of the study was overall survival (OS), while surrogate endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Between March 2022 and April 2023, 36 patients were enrolled, 30 of whom were treated with envafolimab plus lenvatinib. At data cutoff, the median follow-up duration was 20 months (95% CI 18.9-21.1). Among the 30 assessable patients (patients treated according to the trial protocol), the median overall survival (mOS) and median progression-free survival (mPFS) for the therapy comprising envafolimab alongside lenvatinib were 18.5 months (95% CI 13.2-23.8) and 9.4 months (95% CI 1.6-15.6), respectively. The ORR and the DCR (evaluated according to mRECIST criteria) reached 40% and 80%, respectively. In terms of safety, 23 patients (76.7%) experienced at least one treatment-related adverse event (TRAE), of which the most common was elevated aspartate aminotransferase (AST, 23.3%). Furthermore, grade 3 and higher TRAEs occurred in 30%. This study demonstrates that envafolimab in combination with lenvatinib exhibits favourable anti-cancer activity and a manageable safety profile for the first-line treatment of patients with unresectable HCC.

Infiltrative hepatocellular carcinoma (HCC) remains a therapeutic challenge due to its aggressive course and poor prognosis. Hepatic arterial infusion chemotherapy (HAIC) plus immune checkpoint inhibitors (ICIs) and molecular targeted therapies (MTTs) has shown early promise for advanced HCC, but its role in advanced infiltrative HCC is unclear. This study aims to investigate the efficacy and safety of HAIC combined with ICIs and MTTs in the treatment of advanced infiltrative HCC.

Patients with infiltrative HCC initially treated with HAIC plus ICIs and MTTs were consecutively included at our institution from November 2021 to June 2023. The efficacy evaluation included tumor response, time to response (TTR), duration of response (DOR), progression-free survival (PFS) per RECIST 1.1, and patient survival. Adverse events (AEs) were recorded for safety evaluation.

A total of 27 patients were included and the median follow-up was 15.8 months (range, 4.3-25.9). The best objective response rate (ORR) and disease control rate (DCR) were 70.4% and 88.9%, respectively. The median TTR was 2.8 months (95% confidence interval [CI], 2.6-3.0) and the median DOR was 7.9 months (95% CI, 3.2-12.5). The median PFS was 7.5 months (95% CI, 4.2-10.7), and the median overall survival (OS) was 16.8 months (95% CI, 14.0-19.6), with a 1-year OS rate of 74.1%. No cases of grade 4 or 5 treatment-related adverse events (TRAEs) were observed in this study. Grade 3 TRAEs occurred in 17/27 (63.0%) patients, and the predominant grade 3 treatment-related adverse events were lymphocyte count decreased (18.5%) and neutrophil count decreased (14.8%).

The combination of HAIC plus ICIs and MTTs demonstrated encouraging outcomes and manageable safety concerns for infiltrative HCC.

Digestive system neoplasms are highly heterogeneous and exhibit complex resistance mechanisms that render anti-programmed cell death protein (PD) therapies poorly effective. The tumor microenvironment (TME) plays a pivotal role in tumor development, apart from supplying energy for tumor proliferation and impeding the body's anti-tumor immune response, the TME actively facilitates tumor progression and immune escape via diverse pathways, which include the modulation of heritable gene expression alterations and the intricate interplay with the gut microbiota. In this review, we aim to elucidate the mechanisms underlying drug resistance in digestive tumors, focusing on immune-mediated resistance, microbial crosstalk, metabolism, and epigenetics. We will highlight the unique characteristics of each digestive tumor and emphasize the significance of the tumor immune microenvironment (TIME). Furthermore, we will discuss the current therapeutic strategies that hold promise for combination with cancer immune normalization therapies. This review aims to provide a thorough understanding of the resistance mechanisms in digestive tumors and offer insights into potential therapeutic interventions.

Immunotherapy is one of the research hotspots in colorectal cancer field in recent years. The colorectal cancer patients with mismatch repair-deficient (dMMR) or high microsatellite instability (MSI-H) are the primary beneficiaries of immunotherapy. However, the vast majority of colorectal cancers are mismatch repair proficient (pMMR) or microsatellite stability (MSS), and their immune microenvironment is characterized by "cold tumors" that are generally insensitive to single immunotherapy based on immune checkpoint inhibitors (ICIs). Studies have shown that some pMMR/MSS colorectal cancer patients regulate the immune microenvironment by combining other treatments, such as multi-target tyrosine kinase inhibitors, anti-vascular endothelial growth factor (VEGF) monoclonal antibodies, chemotherapy, radiotherapy, anti-epithelial growth factor receptor (EGFR) monoclonal antibodies, and mitogen-activated protein kinase (MAPK) signaling pathway inhibitors and oncolytic viruses, etc. to transform "cold tumor" into "hot tumor", thereby improving the response to immunotherapy. In addition, screening for potential prognostic biomarkers can also enrich the population benefiting from immunotherapy for microsatellite stable colorectal cancer. Therefore, in pMMR or MSS metastatic colorectal cancer (mCRC), the optimization of immunotherapy regimens and the search for effective efficacy prediction biomarkers are currently important research directions. In this paper, we review the progress of efficacy of immunotherapy (mainly ICIs) in pMMR /MSS mCRC, challenges and potential markers, in order to provide research ideas for the development of immunotherapy for mCRC.

Systemic therapy for unresectable hepatocellular carcinoma (HCC) has progressed with the development of multiple kinases, such as vascular endothelial growth factor (VEGF) signaling, targeting cancer growth and angiogenesis. Additionally, the efficacy of sorafenib, regorafenib, lenvatinib, ramucirumab, and cabozantinib has been demonstrated in various clinical trials, and they are now widely used in clinical practice. Furthermore, the development of effective immune checkpoint inhibitors has progressed in systemic therapy for unresectable HCC, and atezolizumab + bevacizumab (atezo/bev) therapy and durvalumab + tremelimumab therapy are now recommended as first-line treatment. Atezo/bev therapy, which combines an anti-programmed cell death 1 ligand 1 antibody with an anti-VEGF antibody, is the first cancer immunotherapy to demonstrate efficacy against unresectable HCC. With the increasing popularity of these treatments, VEGF inhibition is attracting attention from the perspective of its anti-angiogenic effects and impact on the cancer-immune cycle. In this review, we outline the role of VEGF in the tumor immune microenvironment and cancer immune cycle in HCC and outline the potential immune regulatory mechanisms of VEGF. Furthermore, we consider the potential significance of the dual inhibition of angiogenesis and immune-related molecules by VEGF, and ultimately aim to clarify the latest treatment strategies that maximizes efficacy.

Survival of patients with metastatic sarcoma remains poor, and there is a pressing need for new therapies. Most sarcoma subtypes are not responsive to immune checkpoint inhibition alone. Lenvatinib, a multireceptor tyrosine kinase inhibitor targeting tumor vasculature, has an immunomodulatory activity that contributes to its antitumor effects. Therefore, we hypothesized that a combination of lenvatinib and pembrolizumab would lead to improved clinical outcomes in patients with sarcoma.

This was an open-label, single-arm study of lenvatinib and pembrolizumab in the following cohorts: (A) leiomyosarcoma, (B) undifferentiated pleomorphic sarcoma (UPS), (C) vascular sarcomas (angiosarcoma and epithelioid hemangioendothelioma), (D) synovial sarcoma or malignant peripheral nerve sheath tumor (MPNST), and (E) bone sarcomas (osteosarcoma and chondrosarcoma). The primary endpoint was the best overall response (BOR) rate documented by RECIST v1.1 by 27 weeks in each cohort, with a threshold of ≥2 responses among 10 patients. Secondary endpoints included progression-free survival, overall survival, duration of response, and safety.

Forty-six patients were evaluable for the primary endpoint, which was met in the UPS and MPNST/synovial cohorts (BOR rates by 27 weeks of 25% and 30%, respectively). There were seven partial responses overall with additional responses noted in angiosarcoma and osteosarcoma. Treatment-related adverse events of any grade and grade 3 or higher occurred in 50/51 (98%) and 29/51 (57%) of patients, respectively.

We observed durable responses in MPNST, synovial sarcoma, and osteosarcoma. Patients with UPS and angiosarcoma also responded. Further exploration of this approach is warranted to confirm activity and determine optimal dosing schedules.

We have previously demonstrated that RRP15 (Ribosomal RNA Processing 15 Homolog) was significantly elevated in hepatocellular carcinoma (HCC) and correlated directly with poor prognosis. RRP15 suppression curtails HCC progression through induction of cellular senescence and apoptosis. However, the impact of RRP15 on the precise therapeutic potential of lenvatinib has remained underexplored.

To investigate the relationship between RRP15 expression and sensitivity of lenvatinib in HCC treatment, and also explore the potential of targeting RRP15 by lenvatinib to inhibit HCC progression.

RRP15 and KBTBD8 (Kelch Repeat and BTB Domain Containing 8) expression was examined using western blot and immunohistochemistry. Cell viability, proliferation, migration and invasion as well as apoptosis were assessed using CCK-8, clonogenic assays, transwell, TUNEL (Terminal Deoxynucleotidyl Transferase mediated dUTP Nick-End Labeling) and Annexin V staining assays. The interaction between RRP15 and KBTBD8 was identified through pull-down and mass spectrometry analysis and further validated by immunofluorescence and co-immunoprecipitation assays. RRP15 ubiquitination and degradation were assessed using cycloheximide treatment, plasmid transfection and co-immunoprecipitation, followed by western blot analysis. Tail vein injection lung metastasis model was performed to determine tumor metastasis in vivo.

We reveled a correlation between RRP15 downregulation and enhanced sensitivity to lenvatinib, presenting marked suppression of metastasis and invasiveness. Proteomic analyses and subsequent validation disclosed the pivotal role of the E3 ubiquitin ligase KBTBD8 in mediating the ubiquitination and subsequent degradation of RRP15 protein post-lenvatinib treatment in HCC cells. KBTBD8 inhibition stalled RRP15 ubiquitination and degradation, while its overexpression accelerated these processes. Moreover, RRP15 overexpression fosters HCC cell proliferation and metastasis, a pathological effect mitigated by KBTBD8 overexpression. In vivo experiments further validate the role of lenvatinib in promoting RRP15 degradation via KBTBD8 upregulation.

Our study elucidated a previously unidentified mechanism of lenvatinib action and identified the RRP15-KBTBD8 axis as a novel therapeutic target in HCC, offering new avenues for treatment strategies in combating HCC.

Acral melanoma (AM) is an aggressive melanoma variant that arises from palmar, plantar, and nail unit melanocytes. Compared to non-acral cutaneous melanoma (CM), AM is biologically distinct, has an equal incidence across genetic ancestries, typically presents in advanced stage disease, is less responsive to therapy, and has an overall worse prognosis.

An independent analysis of published sequencing data was performed to evaluate the frequency of receptor tyrosine kinase (RTK) ligands and adapter protein gene variants and expression. To target these genetic variants, a zebrafish acral melanoma model and preclinical patient-derived xenograft (PDX) mouse models were treated with a panel of RTK inhibitors. Residual PDX tumors were evaluated for changes in proliferation, vasculature, necrosis, and ferroptosis by histology and immunohistochemistry.

RTK ligands and adapter proteins are frequently amplified, translocated, and/or overexpressed in AM. Dual FGFR/VEGFR inhibitors decrease acral-analogous melanocyte proliferation and migration in zebrafish, and the potent pan-FGFR/VEGFR inhibitor, Lenvatinib, uniformly induces tumor regression in AM PDX tumors but only slows tumor growth in CM models. Unlike other multi-RTK inhibitors, Lenvatinib is not directly cytotoxic to dissociated AM PDX tumor cells and instead disrupts tumor architecture and vascular networks.

Considering the great difficulty in establishing AM cell culture lines, these findings suggest that AM may be more sensitive to microenvironment perturbations than CM. In conclusion, dual FGFR/VEGFR inhibition may be a viable therapeutic strategy that targets the unique biology of AM.

We aimed to explore the curative effects of hepatic arterial infusion chemotherapy (HAIC) combined with Tislelizumab and Lenvatinib on unresectable hepatocellular carcinoma (HCC).

From September 2021 to September 2023, 42 patients with unresectable HCC who were treated in the First Affiliated Hospital of Chongqing Medical University were enrolled in this retrospective single-arm study. They received HAIC combined with Tislelizumab and lenvatinib. Baseline characteristics, laboratory indicators before and after treatment, and imaging findings were collected from medical records. The primary endpoint was objective response rate (ORR), and the secondary endpoints included disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and safety indicators.

A total of 199 HAIC treatments were performed, with a median of 5.5 times (3.75-6.0 times). Based on the mRECIST and RECIST1.1 criterion, the ORR was 71.4% and 57.1%, the DCR was 92.9% and 92.9%. Up to the follow-up date of October 1, 2024, the median PFS was 14.0 months (95% CI, 11.6-16.4 months), and the median OS was 26.0 months.The incidence of any grade of adverse events was 97.6%. The most commonly reported treatment-related grade 3-4 adverse events included thrombocytopenia (28.6%), elevated total bilirubin (19%), and abdominal pain (16.7%). There was no treatment-related death.

For unresectable HCC, HAIC combined with tirelizumab and lenvatinib has good anti-tumor efficacy and acceptable adverse reactions.

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.

Endometrial cancer is one of the most common gynecological malignancies, and while early-stage cases are highly treatable, recurrent or advanced EC remains challenging to manage. Immunotherapy, particularly immune checkpoint inhibitors, has revolutionized treatment approaches in oncology, and its application in EC has shown promising results. Key to immunotherapy efficacy in EC is the tumor's mismatch repair status, with MMR-deficient tumors demonstrating a higher tumor mutational burden and increased PD-L1 expression, making them more susceptible to immune checkpoint inhibitors (ICIs) such as pembrolizumab, durvalumab, and dostarlimab. However, not all mismatch repair-deficient (MMRd) tumors respond to ICIs, particularly those with a "cold" tumor microenvironment (TME) characterized by poor immune infiltration. In contrast, some MMR-proficient tumors with a "hot" TME respond well to ICIs, underscoring the complex interplay between MMR status, tumor mutational burden (TMB), and TME. To overcome resistance in cold tumors, novel therapies, including Chimeric Antigen Receptor (CAR) T cells and tumor-infiltrating lymphocytes are being explored, offering targeted immune-based strategies to enhance treatment efficacy. This review discusses the current understanding of immunotherapy in EC, emphasizing the prognostic and therapeutic implications of MMR status, TME composition, and emerging cell-based therapies.

The integration of transarterial chemoembolization (TACE) with systemic therapy has demonstrated improved survival outcomes in patients with unresectable hepatocellular carcinoma (HCC). However, there is limited evidence evaluating the combination of TACE with the systemic regimen of anti-PD-1/L1 inhibitor plus lenvatinib. This study aims to assess the efficacy and safety of TACE combined with lenvatinib and sintilimab in unresectable HCC patients.

Unresectable HCC patients who received TACE in combination with sintilimab plus Lenvatinib as first-line treatment from 1 January 2020 to 31 March 2023 were included for the analysis. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were evaluated by modified Response Evaluation Criteria in Solid Tumors criteria. Exploratory biomarker analysis was conducted.

The study included 70 patients with unresectable HCC, predominantly male and infected with Hepatitis B. The median follow-up duration for the whole cohort was 13.8 months (95% CI 11.08-16.7). The ORR was 61.4% (95% CI, 49.0%-72.8%) and the DCR was 68.6% (95%CI, 56.4%-79.2%). The median PFS was 13.2 months (95% CI 11.0-NA), with a corresponding 1-year PFS rate of 50.3% (95% CI 39.7%-65.5%). The median OS was not reached, and the 1-year OS rate was 89.3% (95% CI 81.4%-97.9%). The most common treatment-related adverse events (TRAEs) were fatigue 38.6% (27/70), hypertension 32.9% (23/70), and hand-foot syndrome 31.4% (22/70). Most TRAEs were mild-to-moderate and manageable. In addition, significant predictive value was found in alpha-fetoprotein levels (AFP), with patients showing a level of decrease post-treatment having better PFS.

The combination regimen demonstrated promising efficacy in treating unresectable HCC, accompanied by manageable safety profiles. Furthermore, the results of this investigation suggest that AFP holds promise as predictive biomarkers for this treatment strategy.