Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, primary resistance and acquired resistance continue to limit their efficacy for many patients. To address resistance and enhance the anti-tumor activity within the tumor immune microenvironment (TIME), numerous therapeutic strategies targeting both innate and adaptive immune cells have emerged. These include combination therapies with ICIs, chimeric antigen receptor T-cell (CAR-T), chimeric antigen receptor macrophages (CAR-Ms) or chimeric antigen receptor natural killer cell (CAR-NK) therapy, colony stimulating factor 1 receptor (CSF1R) inhibitors, dendritic cell (DC) vaccines, toll-like receptor (TLR) agonists, cytokine therapies, and chemokine inhibition. These approaches underscore the significant potential of the TIME in cancer treatment. This article provides a comprehensive and up-to-date review of the mechanisms of action of various innate and adaptive immune cells within the TIME, as well as the therapeutic strategies targeting each immune cell type, aiming to deepen the understanding of their therapeutic potential.

Angiogenesis plays an important role in tumour growth and metastasis. Targeting tumour vascular endothelial cells to inhibit tumour angiogenesis and thus block tumour blood and nutrition supply is the current research focus on anti-tumour growth and metastasis. Vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR-2) signal pathway regulates the proliferation, migration, survival and angiogenesis of vascular endothelial cells, which is abnormally activated in different tumours. Studies have confirmed that inhibiting VEGF/VEGFR-2 signalling pathway can produce anti-tumour effect. Nowadays, anti-angiogenesis therapy targeting VEGF/VEGFR-2 inhibition has become the most effective clinical strategy for cancer treatment. Therefore, a variety of VEGF/VEGFR-2 inhibitors with different structures have been developed. A few selectively inhibit VEGF to block the activation of VEGFR-2 pathway, while the majority selectively inhibit VEGFR-2 as multi-target inhibitors. Based on the classification of dominant skeletons, this paper briefly analyzes the biological activity, clinical research process and structure-activity relationship of the representative small molecule inhibitors of VEGF/VEGFR-2.

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.

The tumor microenvironment (TME) plays a pivotal role in cancer progression and metastasis, with vascular endothelial growth factor (VEGF) signaling serving as a key regulator of tumor angiogenesis and immune evasion. VEGF induces abnormal blood vessel formation, promoting tumor growth, immune suppression, and metastasis through epithelialmesenchymal transition (EMT). As a result, VEGF signaling has become a critical therapeutic target in cancer treatment. This review examines the molecular mechanisms driving VEGF-mediated tumor growth and angiogenesis, with a focus on the interaction between tumor and endothelial cells and the dual role of VEGF in fostering vascularization and immune suppression. Current anti-VEGF therapies, including monoclonal antibodies (e.g., bevacizumab) and tyrosine kinase inhibitors (TKIs), have demonstrated efficacy and have received FDA approval for various cancers; however, therapeutic resistance remains a significant challenge. Strategies to overcome resistance, such as novel VEGF inhibitors, vascular normalization approaches, and combination therapies with immune checkpoint inhibitors, have been explored. Additionally, future directions emphasize the need for personalized approaches to improve treatment efficacy and reduce metastasis. A comprehensive understanding of VEGF signaling in the TME may pave the way for more effective cancer therapies.

Lung cancer is one of the most common malignant tumors, of which non-small cell lung cancer (NSCLC) accounts for about 85 %. Although immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 inhibitors, have significantly improved the prognosis of patients with NSCLC. There are still many patients do not benefit from ICIs. Primary resistance remains a major challenge in advanced NSCLC. The cancer-immunity cycle describes the process from antigen release to T cell recognition and killing of the tumor, which provides a framework for understanding anti-tumor immunity. The classical cycle consists of seven steps, and alterations at each stage can result in resistance. This review examines the current status of PD-1/PD-L1 blockade in the treatment of advanced NSCLC and explores potential mechanisms of resistance. We summarize the latest clinical trials of PD-1/PD-L1 inhibitors combined with other therapies and explore potential targets for overcoming primary resistance to PD-1/PD-L1 inhibitors.

Pembrolizumab monotherapy is approved for patients with platinum-ineligible metastatic urothelial carcinoma (mUC). Cabozantinib is a multireceptor tyrosine kinase inhibitor with activity against MET and VEGFR2 and is approved as monotherapy or in combination with a PD-1 inhibitor for other malignancies. The objective was to determine the safety and efficacy of pembrolizumab + cabozantinib as first-line treatment for patients with mUC.

In this open-label, single-arm, multicenter, phase 2 study, patients received pembrolizumab 200 mg every 3 wk + cabozantinib 40 mg daily. Key inclusion criteria were locally advanced UC or mUC, Eastern Cooperative Oncology Group performance status 0-2, ineligible for or refused cisplatin, and no prior PD-1/L1 inhibitor. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). According to the statistical plan, in a cohort of 35 evaluable participants, the lower bound of the 95% confidence interval (CI) would extend no more than 26% from the ORR observed, and in a scenario with ≥17 objective responses, the CI would exclude 32%.

Responses were observed in 16 of 35 evaluable patients, with an ORR of 46% (95% CI 31-62%). Median PFS and OS were 8 mo (95% CI 5-13) and 17 mo (95% CI 13-not reached), respectively. The most common treatment-emergent adverse events (any grade) were diarrhea (58%), fatigue (56%), pruritus (39%), nausea (36%), palmar-plantar erythrodysesthesia (36%), and a decrease in appetite (33%).

This phase 2 trial of pembrolizumab + cabozantinib demonstrated a manageable toxicity profile and promising efficacy as a first-line therapy combination for cisplatin-ineligible patients with mUC.

HNSCC remains a substantial health issue, with treatment options including surgery, radiation, and platinum-based chemotherapy. Unfortunately, despite progress in research, only modest gains have been made in disease control, with existing treatments resulting in significant functional and quality-of-life issues. The introduction of immunotherapy in the treatment of HNSCC has resulted in some improvements in outlook for patients and is now standard of care for populations with both recurrent and metastatic disease. However, despite the early successes, responses to immune checkpoint inhibition (ICI) remain modest to low, approaching 14%-22% objective response rates. Challenges to the effectiveness of ICI and other immunotherapies are complex, including the diverse and dynamic molecular plasticity and heterogeneity of HNSCCs; lack of immunogenic antigens; accumulated suppressive immune populations such as myeloid cells and dysfunctional T cells; nutrient depletion; and metabolic dysregulation in the HNSCC tumor microenvironment. In this Review, we explore the mechanisms responsible for immunotherapy resistance, dissect these challenges, and discuss potential opportunities for overcoming hurdles to the development of successful immunotherapy for HNSCC.

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 multi-kinase inhibitor sorafenib has shown potential to inhibit tumor cell growth and intra-tumoral angiogenesis by targeting several kinases, including VEGFR2 and RAF. Abnormal activation of the Ras/Raf/MAPK/ERK kinase cascade and the VEGF pathway is a common feature in breast cancer. However, the efficacy of sorafenib in breast cancer treatment remains limited. Recently, fasting has emerged as a promising non-pharmacological approach to modulate cancer metabolism and enhance the effectiveness of cancer therapies. In this study, we found that fasting significantly enhances the anti-cancer effects of sorafenib monotherapy and its combination with immunotherapy in breast cancer models without causing obvious side effects. This combined treatment effectively inhibits tumor cell proliferation and intra-tumoral angiogenesis. The fasting-induced reduction in peripheral blood glucose levels strongly correlated with enhanced sensitivity to sorafenib. Mechanistically, the combined treatment induced mitophagy, characterized by mitochondrial dysfunction and activation of the PINK1-Parkin pathway. Consequently, increased mitochondrial ROS levels promoted p53 expression, amplifying cell cycle arrest and apoptosis in breast cancer cells. Furthermore, fasting reduced lactate levels within the tumor, and the consequent glucose limitation synergized with sorafenib to activate AMPK, which in turn elevated PD-L1 expression in tumor cells, potentially enhancing their sensitivity to immunotherapy. In summary, our findings demonstrate that fasting and sorafenib, as a rational combination therapy, induce mitophagy, thereby enhancing sorafenib's efficacy in treating breast cancer through the ROS-driven p53 pathway. This study underscores the potential of fasting in breast cancer therapy and provides a foundation for optimizing the clinical application of sorafenib.

This paper aims to explore the research hot spot and development trend in osteosarcoma treatment using a bibliometric method based upon Web of Science Core Collection (WoSCC) platform over the last decade.

The literature related to osteosarcoma and cure which were published from January 2014 to December 2023 were retrieved from the database of WoSCC and made an overall analysis for the papers published including number of articles, distribution of countries and institutions, author information, and keywords, with the CiteSpace 6.2.R5.

A total of 3131 papers were retrieved, including 2601 articles and 530 reviews, and the number of papers published has been increasing year by year in the last decade. There were 415 countries and 10,719 research institutions participating into the study. China's output of literature was the highest relying on its 1490 papers published, followed by The United States (548 papers). Shanghai Jiaotong university had the largest number of papers published (121 papers) and Central South University ranked second (82 papers). A total of 16,816 authors participated in the study. The number of the paper published by Massimo Serra of the Rizzoli Orthopaedics Institute was the largest (27 papers), followed by Dominique Heymann of the University of Sheffield (20 papers). The visualization analysis of keywords by CiteSpace software showed that the drug resistance, drug delivery, tumor tissue engineering and gene expression have become hotspots in the field of osteosarcoma treatment. Drug resistance significantly limits the effectiveness of current cancer treatments. Drug delivery technology not only enhances the targeting and efficacy of drugs but also helps to overcome drug resistance. The stem cells, targeted therapy, and tumor microenvironment represent the new research trends. In particular, the tumor microenvironment plays a key role in tumor development, progression, and drug resistance, and it offers numerous potential therapeutic targets.

Our investigation has identified key research foci and hotspots in osteosarcoma treatment, including drug resistance mechanisms, innovations in drug delivery technology, stem cell development, tumor microenvironment analysis, the development of novel therapies, and the clinical translation of tumor tissue engineering.

Cancer remains a leading global health challenge, placing immense burdens on individuals and healthcare systems. Despite advancements in traditional treatments, significant limitations persist, including treatment resistance, severe side effects, and disease recurrence. Immunotherapy has emerged as a promising alternative, leveraging the immune system to target and eliminate tumour cells. However, challenges such as immunotherapy resistance, patient response variability, and the need for improved biomarkers limit its widespread success. This review provides a comprehensive analysis of the current landscape of cancer immunotherapy, highlighting both FDA-approved therapies and novel approaches in clinical development. It explores immune checkpoint inhibitors, cell and gene therapies, monoclonal antibodies, and nanotechnology-driven strategies, offering insights into their mechanisms, efficacy, and limitations. By integrating emerging research and clinical advancements, this review underscores the need for continued innovation to optimise cancer immunotherapy and overcome existing treatment barriers.

To evaluate the efficacy and safety of programmed cell death protein 1 or its ligand (PD-1/L1) inhibitors as first-line therapy in advanced or metastatic urothelial carcinoma (mUC) who are ineligible for platinum-based chemotherapy.

A systematic search was conducted in four databases (Pubmed, Embase, Web of Science, and the Cochrane Library) to find articles that evaluate the effectiveness of first-line PD-1/L1 inhibitors for mUC, from the establishment of the databases to 22 November 2023. Meta-analyses were performed to evaluate the frequencies of progression-free survival (PFS), overall survival (OS), complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rate (ORR), disease control rate (DCR), and grade ≥ 3 treatment-related adverse events (trAEs).

Totally six studies were included for meta-analysis. The CR, PR, SD, PD, ORR, DCR, and grade ≥ 3 trAEs rate were 0.06 [95% confidence interval (CI), 0.04 to 0.07], 0.22 (95% CI, 0.16 to 0.30), 0.27 (95% CI, 0.23 to 0.31), 0.31 (95% CI, 0.20 to 0.44), 0.28 (95% CI, 0.21 to 0.37), 0.57 (95% CI, 0.47 to 0.67) and 0.26 (95% CI, 0.14 to 0.40), respectively. The median PFS and OS were 4.5 months and 13.7 months, respectively. Subgroup analysis showed that PD-1/L1 inhibitors monotherapy had an ORR rate of 0.25 (95% CI, 0.21 to 0.29) and a DCR rate of 0.50(95% CI, 0.44 to 0.56), while PD-1/L1 dual immunotherapy had a better ORR rate of 0.33 (95% CI, 0.15 to 0.52) and a DCR rate of 0.65 (95% CI, 0.49 to 0.80). However, there was no significant difference in PFS and OS between the two groups.

The findings indicated that PD-1/L1 inhibitors could be used as a safe and viable first-line treatment option for patients with advanced or metastatic urothelial carcinoma who were not suitable candidates for platinum-based chemotherapy. Specifically, the combination of Enfortumab vedotin (EV) and pembrolizumab (Pembro) showed more effectiveness in treating patients compared to trials using the current standard treatment, suggesting that it could be a promising alternative treatment option.

https://www.crd.york.ac.uk/prospero/, identifier CRD42024510152.

The interaction between programmed death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) constitutes a critical immune checkpoint pathway that leads to immune tolerance in cancer cells and impacts antitumor treatment. Monoclonal antibody blockade of the PD-L1 immunoinhibitory pathway has demonstrated significant and lasting clinical antitumor responses. Furthermore, PD-L1 serves as an important biomarker for predicting the effectiveness of immune checkpoint inhibitors (ICIs). To date, numerous studies based on monoclonal antibodies have been carried out to detect the expression levels of PD-L1 and predict the antitumor effectiveness of PD-L1 ICIs. However, due to the deficiencies of monoclonal antibodies, researches of PD-L1 peptides have received increasing attention. PD-L1 peptides present promising candidates due to their advantages, including reduced manufacturing costs, enhanced stability, decreased immunogenicity, faster clearance and improved tumor or organ penetration, thereby offering broad application prospects in cancer immunoimaging and immunotherapy. In this review, we analyze the existing evidence on PD-L1 peptides in cancer immunoimaging and immunotherapy. First, the design techniques of different types of PD-L1 targeting peptides and their strengths and weaknesses are briefly introduced. Second, the recent advancements in immunoimaging and the development trends in immunotherapy are summarized. Finally, the existing challenges and future directions in this field are comprehensively deliberated.

Combining the programmed death-1 inhibitor toripalimab and the angio-immuno kinase inhibitor surufatinib showed preliminary antitumor activity in patients with advanced solid tumors in a phase I study. Here, we report the efficacy and safety of this combination regimen in treatment-naive advanced or metastatic non-small-cell lung cancer (NSCLC) patients with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of 1% or greater (PD-L1-positive) and patients with previously treated small-cell lung cancer (SCLC).

This open-label, single-arm phase II study included patients with treatment-naive advanced or metastatic PD-L1-positive NSCLC or previously treated SCLC in China. Patients received surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every 3 weeks). Primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included duration of response (DoR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety.

Forty-three patients were treated (NSCLC cohort, n = 23; SCLC cohort, n = 20). ORRs (95% CIs) were 57.1% (34.0-78.2) in the NSCLC cohort and 15.8% (3.4-39.6) in the SCLC cohort. Median duration of response was not reached (NR) in both cohorts. Median PFS was 9.6 (5.5-NR) and 3.0 months (2.8-4.1), respectively, and median OS was 24.3 (10.8-NR) and 11.0 months (5.0-15.7), respectively. Grade ≥ 3 treatment-related adverse events were reported in 24 patients (55.8%) overall.

Surufatinib plus toripalimab showed encouraging antitumor activity and a tolerable safety profile in patients with treatment-naive advanced or metastatic PD-L1-positive NSCLC and previously treated SCLC.

This meta-analysis evaluates the efficacy and safety of lenvatinib, both as monotherapy and in combination with other (tyrosine kinase inhibitors) TKIs, compared with other TKIs in metastatic renal cell carcinoma (RCC) treatment.

We searched for relevant studies from inception to February 2024 using PubMed, Web of Science, Cochrane Library, and Scopus. Eligible studies reported on the efficacy and safety of lenvatinib alone or in combination with other TKIs versus other TKIs for metastatic RCC. Primary outcomes included progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate (ORR), adverse events (AEs), and health-related quality of life (HRQOL).

Seventeen studies met the inclusion criteria. Lenvatinib, especially in combination therapies, significantly improved PFS (HR: 0.46, 95% CI: 0.38-0.54, P <0.001) and OS (HR: 0.80, 95% CI: 0.70-0.91, P <0.001) compared with other TKIs. Quality of life analyses showed mixed results, with EQ-5D demonstrating significant improvement (HR: 1.21, 95% CI: 0.90-1.53, P <0.001), while EORTC QLQ-C30 was not statistically significant. ORR analysis indicated a higher likelihood of achieving a complete or partial response with lenvatinib (OR: 2.04, 95% CI: 1.15-2.93, P =0.00). The analysis of total AEs above grade 3 showed no significant difference between lenvatinib and other TKIs (OR: -0.08, 95% CI: -0.21 to 0.06, P =0.26).

Lenvatinib significantly enhances survival outcomes in metastatic RCC patients compared with other TKIs. While associated with various adverse events, its safety profile is comparable to other TKIs.

Recently, due to its promising efficacy against advanced renal cell carcinoma (RCC), the combination therapy with lenvatinib and pembrolizumab or everolimus has been approved as a first-line treatment for patients with advanced RCC in China and the United States. However, the high costs of combination therapies, especially of those new drugs, may limit their viability as clinical treatment options. Thus, our study aimed to evaluate the cost-effectiveness of using lenvatinib plus pembrolizumab or everolimus as a first-line treatment for patients with advanced RCC from the perspective of the Chinese healthcare system and US third-party payers.

We established a Markov model using TreeAge Pro 2022 software to estimate and compare the cost and effectiveness of the therapy with lenvatinib plus pembrolizumab or everolimus with those of sunitinib therapy for treating advanced RCC based on the clinical data derived from a phase III randomized controlled trial (CLEAR, ClinicalTrials.gov number NCT02811861). Transition probabilities and other data were calculated and obtained by using parametric survival modeling. The direct medical costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were used as economic indicators in this analysis. The robustness of the model was assessed by performing one-way and probability sensitivity analyses (PSA).

Among the 3 treatment strategies, the sunitinib 1 was the least expensive option. All ICERs were far higher than the thresholds of $38,024 and $100,000 selected for China and the United States, respectively. The ICERs of the therapy with lenvatinib plus pembrolizumab versus sunitinib therapy were 106,749.06 US$/QALY and $414,672.19 US$/QALY in China and the United States, respectively. Thus, among these 2, the former strategy was less cost-effective than the latter. In addition, the ICERs of the lenvatinib plus everolimus treatment vs. sunitinib treatment were $44,353.18 US$/QALY and $292,653.10 US$/QALY in China and the United States, respectively. Thus, among these 2 strategies, the former was less cost-effective than the latter. The total cost of the lenvatinib plus everolimus treatment strategy was lower than that of lenvatinib plus pembrolizumab; however, the former treatment was less effective than the latter.

The treatment with lenvatinib plus pembrolizumab or everolimus is less cost-effective than the sunitinib treatment for patients with advanced RCC in China and the United States.

The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood.

In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA sequencing, reverse-phase protein array analyses were performed on pre- and post-chemotherapy samples.

Thirty-one eligible patients were enrolled. Median PFS and OS was 14.88 (95% CI 12.39-23.00) and 57.43 months (95% CI 30.88-not reached), respectively. Among those with PD-L1 combined positive score (CPS) ≥10, the median PFS and OS were not reached compared to those with CPS <10 (10.50 and 30.90 months, respectively). Feasibility was met, with all patients completing their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-β, and β-catenin signaling.

Pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. Patients with CPS ≥10 may benefit more from this regimen, and future studies should investigate this potential biomarker.

This investigator-initiated trial was funded by Merck.

To investigate whether blocking both programmed cell death protein and vascular endothelial growth factor receptor could offer superior anticancer activity in these patients without compromising safety. In this study, patients were administered oral anlotinib (12 mg/day) on days 1-14 and intravenous sintilimab (200 mg) on day 1 of a 3-weekly cycle. The primary endpoints included the objective response rate and disease control rate. The secondary endpoints included overall survival (OS) and safety. Ten eligible patients were enrolled between June 2019 and May 2022, and eight patients underwent radiographic assessments. The results showed an objective response rate of 50% (partial and complete response in four and zero patients, respectively) and a disease control rate of 100%; four patients demonstrated stable disease for at least 8 weeks. The median OS was 4.37 (in our study, the score was 7), and the OS rate at 12 months was 37.5%. The Kaplan-Meier survival curve showed that the group with high blood glucose levels had a significantly shorter duration of survival than those with normal blood glucose levels. Adverse events of grade 3 and higher occurred in 50% of patients, and the most common severe adverse events included tumor pain (50%), hypertension (37.5%), tumor hemorrhage (25%), and decreased appetite (25%). The combination of anlotinib and sintilimab showed promising efficacy in controlling tumor size. However, the disappointing OS rate suggests that anti-vascular endothelial growth factor receptor agents should be used cautiously after radical radiation therapy. The combination used in this study demonstrated a toxicity profile comparable to that of other agents used in this setting. These findings warrant further investigation into the potential clinical utility of this combination.

For non-small-cell lung cancer (NSCLC) patients who progressed after first-line chemotherapy, immunotherapy targeting programmed cell death (ligand) 1 has shown promising activity. However, the activity is relatively limited in patients harboring epidermal growth factor receptor (EGFR) mutations.

This study aimed to evaluate the efficacy and safety of camrelizumab plus famitinib in previously treated patients with locally advanced and metastatic NSCLC.

A single-center, single-arm, phase II study.

Previously treated patients with locally advanced and metastatic NSCLC were enrolled to receive camrelizumab (200 mg, administered intravenously every 3 weeks) and famitinib (20 mg, administered orally once daily). Patients harboring EGFR mutation genes had received at least one EGFR tyrosine kinase inhibitor and no more than two lines of chemotherapy regimen before the enrollment. The other patients had progressed on first-line chemotherapy with or without immunotherapy before the enrollment. The primary endpoint was the objective response rate (ORR) per RECIST v1.1 by the investigator.

Our study encompassed 23 NSCLC patients between October 2019 and October 2022. For all patients, the confirmed ORR was 30.4%, and the disease control rate was 95.7%. The median progression-free survival (PFS) was 6.9 months (95% CI: 4.9 months-not reached). The median overall survival (OS) was not reached. 1- and 2-year OS rates were 85.6% (95% CI: 71.8%-100.0%) and 56.8% (95% CI: 37.7%-85.7%). Especially, for the 6 patients with EGFR genetic aberrations, the confirmed ORR was 33.3%, the median PFS was 10.3 months (95% CI: 1.8-18.8 months), and the median OS was 20.3 months (95% CI: 0.8-39.8 months). The most common grade 3 and above treatment-related adverse events were platelet count decreased, white blood cell count decreased, and hypertension. No unexpected adverse events were reported.

Camrelizumab plus famitinib demonstrated encouraging clinical activity with a manageable safety profile in previously treated patients with locally advanced and metastatic NSCLC. The results warranted further validation.

Chinese Clinical Trial Registry identifier: ChiCTR1900026641.

BackgroundExtensive-stage small cell lung cancer (ES-SCLC) is a highly aggressive malignancy with poor prognosis. This study aimed to assess the efficacy of combining immunotherapy (IT) with Anlotinib in ES-SCLC patients.MethodsThis study was a multicenter retrospective cohort analysis. Survival outcomes were evaluated using Kaplan-Meier curves and Cox proportional hazards regression models.ResultsA total of 147 patients were included in the analysis. The median overall survival (mOS) for the cohort was 15.5 months (95% CI: 13.9-17.1). Patients in the chemotherapy(CT) plus IT group had an mOS of 17.8 months, compared to 12.6 months in the CT-alone group (p = 0.055). When stratified into CT + IT + Anlotinib, CT + IT, and CT-alone groups, the mOS were 18.5, 16.3, and 12.6 months, respectively, with the CT + IT + Anlotinib group demonstrating significantly improved OS compared to CT-alone (p = 0.044). The ORR and DCR for the entire cohort were 71.4% and 85.7%, respectively. Subgroup analysis revealed ORRs of 74.1% (CT + IT + Anlotinib), 73.9% (CT + IT), and 70.1% (CT-alone), with corresponding DCRs of 92.6%, 91.3%, and 82.5%. Multivariate analysis revealed that radiotherapy (RT, p = 0.003) and IT (p = 0.021) were independent prognostic factors for OS, while liver metastasis (p = 0.023) and RT (p = 0.018) were associated with PFS. Patients receiving RT in combination with CT showed markedly improved OS (17.5 vs 12.5 months; p = 0.002) and PFS (7.3 vs 6.3 months; p = 0.004). The incidence of adverse events was comparable across all groups (p = 0.721).ConclusionThe combined application of Anlotinib with IT and the combination of CT with RT both significantly improved survival outcomes in patients with ES-SCLC while maintaining a favorable safety profile. These findings warrant further investigation in future studies.

Preclinical data indicate that fianlimab (antilymphocyte activation gene-3) plus cemiplimab (anti-PD-1) enhances antitumor activity. Here, we report prespecified final analyses of the dose-escalation part of a first-in-human, phase 1 study (NCT03005782) of fianlimab as monotherapy and in combination with cemiplimab in patients with advanced malignancies.

Adult patients received 1 to 40 mg/kg of fianlimab plus 350 mg of cemiplimab every 3 weeks (Q3W) across various dose-escalation schedules. Primary objectives were the rate of dose-limiting toxicities, adverse events (including immune mediated), deaths, laboratory abnormalities, and pharmacokinetics. Secondary outcomes were objective response rate, best overall response, duration of response, and antidrug antibody variables.

Seventy-eight patients were enrolled (fianlimab + cemiplimab, n = 47; fianlimab monotherapy, n = 31). One patient treated with 3 mg/kg fianlimab + cemiplimab experienced dose-limiting toxicities, including increased blood creatine phosphokinase and myasthenic syndrome. No maximum tolerated dose was reached. Any-grade treatment-emergent adverse events occurred in 90% of patients with fianlimab monotherapy, in 87% of patients with fianlimab + cemiplimab, and in 87% of patients who transitioned from monotherapy to combination therapy. Fianlimab pharmacokinetics were dose proportional and similar in monotherapy and combination therapy. Across patients who received fianlimab + cemiplimab, five achieved a partial response, three of whom experienced a response after transitioning from monotherapy to combination therapy. Fianlimab 1,600 mg Q3W (20 mg/kg in an 80-kg individual) is the selected dose for phase 2 and phase 3 studies.

Fianlimab as monotherapy and in combination with cemiplimab demonstrated acceptable safety and preliminary antitumor activity, which is generally consistent with previous reports of cemiplimab.

Combined treatment with lenvatinib and pembrolizumab is currently regarded as one of the standard first-line therapies for advanced renal cell carcinoma (aRCC) patients. The objective of this study was to assess the efficacy and safety of this combined regimen in treatment-naïve Japanese aRCC patients.

This study included a total of 50 consecutive aRCC patients receiving combined lenvatinib plus pembrolizumab in routine clinical practice in Japan, and comprehensively analyzed clinical outcomes of this treatment.

Of these 50, 7 (14.0%), 23 (46.0%) and 20 (40.0%) were classified into favorable, intermediate and poor risk groups, respectively, according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) system. Responses to this combined therapy in the 50 patients were as follows: complete response, 7 (14.0%); partial response, 26 (52.0%); stable disease, 15 (30%) and progressive disease, 2 (4%); thus, the objective response rate (ORR) was 66%. ORRs in favorable, intermediate and poor risk groups were 57.1, 69.6 and 65.0%, respectively. During the observation period, disease progression and death occurred in 14 (28.0%) and 6 (12.0%) patients, respectively, and neither the median PFS nor OS was reached. Adverse events and those corresponding to grade ≥ 3 were observed in all (100%) and 33 (66.0%) patients, respectively.

To our knowledge, this is the first study focusing on real-world outcomes of lenvatinib and pembrolizumab for treatment-naïve aRCC patients, showing that the efficacy and safety of this combined regimen are similar to those noted in randomized clinical trial.

In the past decade, the treatment of metastatic urothelial cancer (mUC), including bladder cancer (BC), has transformed significantly with the introduction of diverse therapies, such as immune checkpoint inhibitors, targeted therapies, and antibody-drug conjugates. This change is partly due to advancements in genomic understanding, particularly next-generation sequencing, which has identified numerous mutations in UC. Among these therapies, erdafitinib, a pan-fibroblast growth factor receptor (FGFR) inhibitor for specific FGFR2 and FGFR3 alterations, is the only targeted therapy approved till now. In 2019, erdafitinib became pivotal for the treatment of mUC, particularly in patients with specific FGFR alterations. Recent studies have highlighted the benefits of combining erdafitinib with immunotherapy, thereby broadening the treatment options. Ongoing investigations exist on its use in non-muscle-invasive BC and in combination with drugs such as enfortumab vedotin in mUC. Other FGFR-targeted agents are under development; however, overcoming FGFR resistance and ensuring the safety of combination therapies remain major hurdles. FGFR3 mutations are particularly prevalent in BC, a heterogeneous form of UC, and account for a considerable proportion of new cancer diagnoses annually. Approximately half of these cancers have FGFR3 mutations, with gene rearrangements being a common feature. These FGFR3 genomic alterations often occur independently of mutations in other BC oncogenes, such as TP53 and RB1. This review emphasizes the importance of FGFR inhibition in UC and the optimization of its use in clinical practice. Moreover, it underscores the ongoing efforts to evaluate combination strategies and early treatment testing to enhance the effectiveness of targeted therapies for UC.

Immunotherapy, remarkably immune checkpoint inhibitors (ICIs), has significantly altered the treatment landscape for non-small cell lung cancer (NSCLC). Despite their success, the discontinuation of ICIs therapy may occur due to factors such as prior treatment completion, disease progression during ICIs treatment, or immune-related adverse events (irAEs). As numerous studies highlight the dynamic nature of immune responses and the sustained benefits of ICIs, ICIs rechallenge has become an attractive and feasible option. However, the decision-making process for ICIs rechallenge in clinical settings is complicated by numerous uncertainties. This review systematically analyses existing clinical research evidence, classifying ICIs rechallenge into distinct clinical scenarios, exploring methods to overcome ICIs resistance in rechallenge instances, and identifying biomarkers to select patients likely to benefit from rechallenge. By integrating recent studies and new technologies, we offer crucial recommendations for future clinical trial design and provide a practical guideline to maximize the therapeutic benefits of immunotherapy for NSCLC patients.

Head and neck squamous cell carcinoma present challenges in effective treatment, with 50%-60% of cases exhibiting recurrence or metastasis, often resistant to surgery alone. Immunotherapy, a promising approach, does not guarantee benefits for all patients. Thus, the imperative lies in identifying reliable biomarkers for predicting immunotherapy efficacy. FAM3D, a protein-coding gene known for its potent chemotactic activity in human peripheral blood monocytes and neutrophils, plays a crucial role in regulating tumour immune responses and holds promise as an immune biomarker.

We employed comprehensive database analysis to scrutinise FAM3D, evaluating its gene expression, mutation profiles and prognostic implications in head and neck squamous cell carcinoma, along with its associations with clinical characteristics and immune cell infiltration. Complementary functional experiments were conducted to delve into the potential mechanisms governed by FAM3D.

Our findings establish a significant correlation between low FAM3D expression and the invasiveness and metastatic potential of head and neck squamous cell carcinoma. FAM3D likely exerts its influence through the regulation of epithelial-mesenchymal transition.

FAM3D emerges as a valuable biomarker for predicting the responsiveness of patients with head and neck squamous cell carcinoma to immunotherapy, holding substantial clinical diagnostic and therapeutic relevance.

Head and neck squamous cell carcinoma (HNSCC) is a complex cancer requiring a multidisciplinary approach. For patients with locally or regionally advanced disease, surgery and/or radiation are the cornerstones of definitive treatment. Medical therapy plays an important adjunct role in this setting, typically consisting of a platinum-based regimen given as induction, concurrent, or adjuvant treatment. While relapsed/metastatic HNSCC has historically been a difficult-to-treat disease with poor outcomes, options have considerably improved with the incorporation of biologics and immune checkpoint inhibitors. Clinical trials are ongoing to investigate novel approaches, including new and combination immunotherapies, targeted therapies, therapeutic vaccines, antibody-drug conjugates, and cellular therapies. The results thus far have been mixed, highlighting the knowledge gaps that continue to challenge the medical oncologist treating HNSCC. Here, we present the most updated and broad review of the current treatment landscape in both locoregional and metastatic HNSCC and discuss the expansive future medical therapies under investigation.

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.

Novel treatments are needed for patients with advanced, triple-negative breast cancer (TNBC) that progresses or recurs after first-line treatment with chemotherapy. The authors report results from the TNBC cohort of the multicohort, open-label, single-arm, phase 2 LEAP-005 study of lenvatinib plus pembrolizumab in patients with advanced solid tumors (ClinicalTrials.gov identifier NCT03797326).

Eligible patients had metastatic or unresectable TNBC with disease progression after one or two lines of therapy. Patients received lenvatinib (20 mg daily) plus pembrolizumab (200 mg every 3 weeks; up to 35 cycles). The primary end points were the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1, and safety (adverse events graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0). Duration of response, progression-free survival, and overall survival were secondary end points.

Thirty-one patients were enrolled. The objective response rate by investigator assessment was 23% (95% confidence interval [CI], 10%-41%). Overall, the objective response rate by blinded independent central review (BICR) was 32% (95% CI, 17%-51%); and, in patients who had programmed cell death ligand 1 combined positive scores ≥10 (n = 8) and <10 (n = 22), the objective response rate was 50% (95% CI, 16%-84%) and 27% (95% CI, 11%-50%), respectively. The median duration of response by BICR was 12.1 months (range, from 3.0+ to 37.9+ months). The median progression-free survival by BICR was 5.1 months (95% CI, 1.9-11.8 months) and the median overall survival was 11.4 months (95% CI, 4.1-21.7 months). Treatment-related adverse events occurred in 94% of patients (grade 3, 52%; grade 4, 0%). One patient died due to a treatment-related adverse event of subarachnoid hemorrhage.

The combination of lenvatinib plus pembrolizumab demonstrated antitumor activity with a manageable safety profile in patients with previously treated, advanced TNBC.

The use of immunotherapy in head and neck squamous cell carcinoma (HNSCC)has increased treatment options for patients who may not be candidates for traditional cytotoxic chemotherapy. Recent studies have resulted in the approval of immunotherapy in the first and second line setting for recurrent/metastatic disease. Various combinations of immunotherapy with targeted therapies, monoclonal antibodies, or human papilloma virus vaccines are also being studied in recurrent/metastatic disease. Currently, programmed death-ligand 1 status is the main marker utilized to assess potential response to immunotherapy. Studies are focused on identifying additional markers, which may help better predict response to immunotherapy for HNSCC patients.

Advanced intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by limited response to standard therapeutic modalities, such as radiotherapy, chemotherapy, and targeted therapy. The prognosis for patients with advanced ICC is exceedingly bleak, with an overall survival of less than 1 year. In recent years, personalized neoantigen vaccines have emerged as a promising approach to augment the immune response against tumors. Clinical investigations are currently underway to evaluate the efficacy of neoantigen-based peptide, DNA, and dendritic cell vaccines. Herein, we present a noteworthy case of advanced ICC patients who experienced disease progression following relapse and subsequently received immunotherapy with a personalized neoantigen nanovaccine. This innovative treatment strategy involved the administration of a custom-designed neoantigen-based peptide nanovaccine tailored to the patient's specific gene mutation profile subsequent to failure of first-line therapy. The clinical efficacy and anti-tumor immune responses were evaluated using various methods, including imaging, interferon-γ ELISPOT assay, and intracellular cytokine staining. Notably, the neoantigen nanovaccine elicited a robust and specific tumor-killing effect mediated by T cells, resulting in a durable response lasting up to 25 months. These findings highlight the potential of neoantigen-based immunotherapy as a novel therapeutic avenue for the management of advanced ICC.

Drug combinations are increasingly utilized in cancer treatment to enhance drug effectiveness through synergistic therapeutic effects. However, determining the optimal biological dose combination (OBDC) in small-scale drug combination trials presents challenges due to the increased complexity of the dose space. To effectively optimize the dose combination of combined drugs, we propose a model-assisted design by extending the single-agent Bayesian optimal interval phase I/II (BOIN12) design. Our approach incorporates a utility function to balance the trade-off between risk and benefit and directly models the utility of each dose by constructing a quasi-beta-binomial model. A key advantage of our design is the simplification of decision-making during interim periods by considering all possible outcomes and pre-including the decision rule in the protocol. Additionally, we present a time-to-event (TITE) version of our design, employing an approximate likelihood approach to mitigate potential late-onset effects. We demonstrate that our proposed design exhibits robust and desirable operating characteristics across various scenarios through extensive simulation studies.

Patients with recurrent or metastatic head and neck cancers (R/M HNCs) are prone to developing resistance after immunotherapy. This retrospective real-world study aims to investigate whether the addition of anlotinib can reverse resistance to PD-1 inhibitors (PD-1i) and evaluate the efficacy and safety of this combination in R/M HNCs. Main outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Potential biomarkers included PD-L1 expression, lipid index, and genomic profiling. Twenty-one patients with R/M HNCs were included, including 11 nasopharyngeal carcinoma (NPC), five head and neck squamous cell carcinoma (HNSCC), three salivary gland cancers (SGC), and two nasal cavity or paranasal sinus cancers (NC/PNC). Among all patients, ORR was 47.6% (95% CI: 28.6-66.7), with 2 (9.5%) complete response; DCR was 100%. At the median follow-up of 17.1 months, the median PFS and OS were 14.3 months (95% CI: 5.9-NR) and 16.7 months (95% CI:8.4-NR), respectively. The median DOR was 11.2 months (95% CI: 10.1-NR). As per different diseases, the ORR was 45.5% for NPC, 60.0% for HNSCC, 66.7% for SGC, and 50.0% for NC/PNC. Most treatment-related adverse events (TRAEs) were grade 1 or 2 (88.9%). The most common grades 3-4 TRAE was hypertension (28.6%), and two treatment-related deaths occurred due to bleeding. Therefore, adding anlotinib to the original PD-1i could reverse PD-1 blockade resistance, with a favorable response rate, prolonged survival, and acceptable toxicity, indicating the potential as a second-line and subsequent therapy choice in R/M HNCs.

A number of conditions and factors can cause the transformation of normal cells in the body into malignant tissue by changing the normal functions of a wide range of regulatory, apoptotic, and signal transduction pathways. Despite the current deficiency in fully understanding the mechanism of cancer action accurately and clearly, numerous genes and proteins that are causally involved in the initiation, progression, and metastasis of cancer have been identified. But due to the lack of space and the abundance of details on this complex topic, we have emphasized here more recent advances in our understanding of the principles implied tumor cell transformation, development, invasion, angiogenesis, and metastasis. Inhibition of angiogenesis is a significant strategy for the treatment of various solid tumors, that essentially depend on cutting or at least limiting the supply of blood to micro-regions of tumors, leading to pan-hypoxia and pan-necrosis inside solid tumor tissues. Researchers have continued to enhance the efficiency of anti-angiogenic drugs over the past two decades, to identify their potential in the drug interaction, and to discover reasonable interpretations for possible resistance to treatment. In this review, we have discussed an overview of cancer history and recent methods use in cancer therapy, focusing on anti-angiogenic inhibitors targeting angiogenesis formation. Further, this review has explained the molecular mechanism of action of these anti-angiogenic inhibitors in various tumor types and their limitations use. In addition, we described the synergistic mechanisms of immunotherapy and anti-angiogenic therapy and summarizes current clinical trials of these combinations. Many phase III trials found that combining immunotherapy and anti-angiogenic therapy improved survival. Therefore, targeting the source supply of cancer cells to grow and spread with new anti-angiogenic agents in combination with different conventional therapy is a novel method to reduce cancer progression. The aim of this paper is to overview the varying concepts of cancer focusing on mechanisms involved in tumor angiogenesis and provide an overview of the recent trends in anti-angiogenic strategies for cancer therapy.