UNASSIGNED: Development of novel vascular networks is a fundamental requirement for tumor growth and progression. In the last decade, biomarkers and underlying molecular pathways of angiogenesis have been intensely investigated to disrupt the initiation and progression of tumor angiogenesis. However, the clinical applications of anti-angiogenic agents are constrained due to toxic side effects, acquired drug resistance, and unavailability of validated biomarkers.
UNASSIGNED: This review discusses the development of dendrimeric nanocarriers that could be a promising domain to explore for the eradication of current challenges associated with angiogenesis-based cancer therapy. Novel drug-delivery approaches with subtle readouts and better understanding of molecular mechanisms have revealed that dendrimers comprise innate anti-angiogenic activity and incorporation of anti-angiogenic agents or gene-silencing RNA could lead to synergistic anti-angiogenic and anticancer effects with reduced side effects.
UNASSIGNED: Dendrimer-mediated targeting of angiogenic biomarkers has efficiently led to the vascular normalization, and rational linking of dendrimers with anti-angiogenic agent or siRNA or both might be a potential area to eradicate the current challenges of angiogenesis-based cancer therapy. However, drawbacks associated with the dendrimers-mediated targeting of angiogenic biomarkers, such as poor stability or small expression of these biomarkers on the normal cells, limit their application at market scale.

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UNASSIGNED: Most predictive biomarkers approved for clinical use measure single analytes such as genetic alteration or protein overexpression. We developed and validated a novel biomarker with the aim of achieving broad clinical utility. The Xerna™ TME Panel is a pan-tumor, RNA expression-based classifier, designed to predict response to multiple tumor microenvironment (TME)-targeted therapies, including immunotherapies and anti-angiogenic agents.
UNASSIGNED: The Panel algorithm is an artificial neural network (ANN) trained with an input signature of 124 genes that was optimized across various solid tumors. From the 298-patient training data, the model learned to discriminate four TME subtypes: Angiogenic (A), Immune Active (IA), Immune Desert (ID), and Immune Suppressed (IS). The final classifier was evaluated in four independent clinical cohorts to test whether TME subtype could predict response to anti-angiogenic agents and immunotherapies across gastric, ovarian, and melanoma datasets.
UNASSIGNED: The TME subtypes represent stromal phenotypes defined by angiogenesis and immune biological axes. The model yields clear boundaries between biomarker-positive and -negative and showed 1.6-to-7-fold enrichment of clinical benefit for multiple therapeutic hypotheses. The Panel performed better across all criteria compared to a null model for gastric and ovarian anti-angiogenic datasets. It also outperformed PD-L1 combined positive score (>1) in accuracy, specificity, and positive predictive value (PPV), and microsatellite-instability high (MSI-H) in sensitivity and negative predictive value (NPV) for the gastric immunotherapy cohort.
UNASSIGNED: The TME Panel\'s strong performance on diverse datasets suggests it may be amenable for use as a clinical diagnostic for varied cancer types and therapeutic modalities.

OBJECTIVE: Central nervous system (CNS) metastases including brain metastases (BM) and leptomeningeal metastases (LM) are frequent in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), and are correlated with poor outcomes. In this study, we evaluated the efficacy of single-agent furmonertinib 160 mg or combining with anti-angiogenic agent in NSCLC patients who had developed BM/LM progression from previous tyrosine kinase inhibior (TKI) treatment.
METHODS: EGFR-mutated NSCLC patients who developed BM (the BM cohort) or LM progression (the LM cohort) were included, having received furmonertinib 160 mg daily as second-line or later treatment, with or without anti-angiogenic agents. The intracranial efficacy was evaluated by intracranial progression-free survival (iPFS).
RESULTS: Totally 12 patients in the BM cohort and 16 patients in the LM cohort were included. Almost one half of patients in the BM cohort and a majority in the LM cohort had a poor physical status, with a Eastern Cooperative Oncology Group performance status (ECOG-PS) ≥2. The administration of single-agent furmonertinib or combination treatment achieved a median iPFS of 3.6 months (95%CI 1.435-5.705) in the BM cohort, and 4.3 months (95%CI 2.094-6.486) in the LM cohort. Subgroup and univariate analysis has shown that a good ECOG-PS correlated with a favorable efficacy of furmonertinib in the BM cohort (median iPFS = 2.1 with ECOG-PS ≥ 2 vs. 14.6 months with ECOG-PS < 2, P < 0.05). Overall, any grade of adverse events (AEs) occured in 46.4% of patients (13/28). Among them, 14.3% of patients (4 of 28) had grade 3 or higher AEs, and were all under control, led to no dose reductions or suspension.
CONCLUSIONS: Single-agent furmonertinib 160 mg or in combination of anti-angiogenic agent is an optional salvage therapy for advanced NSCLC patients who developed BM/LM progression from prior EGFR-TKI treatment, with a promising efficacy and an acceptable safety profile, and is worth of further exploration.

OBJECTIVE: Ramucirumab (RAM) and docetaxel (DOC) are commonly used after first-line therapy for advanced non-small cell lung cancer (NSCLC). Therefore, we aimed to elucidate sequencing strategies of RAM and DOC following prior treatments, including immune checkpoint inhibitor (ICI), cytotoxic agent (CTx) alone, bevacizumab (BEV), and tyrosine kinase inhibitor (TKI).
METHODS: We recruited patients with NSCLC who received RAM and DOC and compared the groups with and without prior ICI, CTx alone, BEV, and TKI, respectively. By tumor response to such treatments, the patients were further classified into \"complete response (CR) + partial response (PR),\" \"stable disease,\" and \"progressive disease\" groups, respectively. We compared RAM and DOC efficacy among these groups.
RESULTS: In total, 237 patients were registered. In the group with prior ICI, the objective response rate and disease control rate were significantly higher than those without prior ICI (p = 0.012 and 0.028, respectively), and the median progression-free survival (PFS) was also significantly longer (p = 0.027). There were no significant differences in PFS between the groups with and without CTx alone, BEV, and TKI. Multivariate analysis revealed that prior ICI was an independent factor associated with better PFS. Furthermore, the prior ICI group with CR + PR significantly prolonged PFS compared to the group without prior ICI (p = 0.013).
CONCLUSIONS: RAM and DOC may be preferably administered after ICI, rather than after CTx alone, BEV, or TKI, and, furthermore, enhanced if the prior ICI has a favorable tumor response.

The therapeutic armamentarium of metastatic Renal Cell Carcinoma (mRCC) has consistently expanded in recent years, with the introduction of VEGF/VEGFR (Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor Receptor) inhibitors, mTOR (mammalian Target Of Rapamycin) inhibitors and Immune Checkpoint (IC) inhibitors. Currently, for the first-tline treatment of mRCC it is possible to choose between a VEGFR-TKI (VEGFR-Tyrosine Kinase Inhibitor) monotherapy, an ICI-ICI (Immune Checkpoint Inhibitor) combination and an ICI-VEGFRTKI combination. However, a consistent part of patients does not derive benefit from first-line therapy with ICIs; moreover, the use of combination regimens exposes patients to significant toxicities. Therefore, there is a critical need to develop prognostic and predictive biomarkers of response to VEGFR-TKIs and ICIs, and measurement of serum IL-8 is emerging as a potential candidate in this field. Recent retrospective analyses of large phase II and phase III trials found that elevated baseline serum IL-8 correlated with higher levels of tumor and circulating immunosuppressive myeloid cells, decreased T cell activation and poor response to treatment. These findings must be confirmed in prospective clinical trials; however, they provide evidence for a potential use of serum IL-8 as biomarker of resistance to VEGFR-TKIs and ICIs. Considering the amount of new agents and treatment regimens which are transforming the management of metastatic renal cell carcinoma, serum IL-8 could become a precious resource in tailoring the best therapy for each individual patient with the disease.

The types of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) patients who could obtain significant clinical benefit from the dual inhibition of EGFR/vascular EGFR (VEGFR) pathways remain unclear. No consensus has been reached on the significance of smoking habits in clinical benefit obtained from EGFR-TKI plus anti-angiogenic agents.
PubMed, EMBASE, and Cochrane databases for all phase II/III randomized clinical trials (RCTs) investigating the efficacy of EGFR-TKI combined with anti-angiogenic agents stratified by smoking habits (updated October 2021) were searched systematically. The primary outcomes were the pooled HRs for PFS/OS in smokers and non-smokers, and differences in efficacy of EGFR-TKI plus anti-angiogenic treatment between smokers and non-smokers, measured by difference in PFS and OS.
Seven phase II/III RCTs involving 1452 patients were identified. The pooled analysis demonstrated that EGFR-TKI plus anti-angiogenic agent could decrease the risk of progression by 40% (HR, 0.60; 95%CI 0.48-0.75) in smokers when compared with EGFR-TKI alone, but not in non-smokers (HR, 0.92; 95%CI 0.68-1.25). The comparison analysis further demonstrated that EGFR-mutated NSCLC patients who smoked obtained greater progression-free survival (PFS) benefit from treatment with EGFR-TKI plus anti-angiogenic agents (HR, 0.68; 95%CI 0.51-0.91). Consistent with the results for PFS, smokers receiving EGFR-TKI plus anti-angiogenic agents appeared to exhibit better overall survival (OS) than non-smokers but not to a statistically significant degree (HR, 0.60; 95%CI 0.23-1.52). Meta-regression analysis revealed no significant effect of the line of treatment (P = 0.52), trial phase (P = 0.52), EGFR-TKI type (P = 0.13), or anti-angiogenic agent type (P = 0.50) on PFS effect sizes under multivariate models.
Comprehensive analysis suggested that EGFR-TKI plus anti-angiogenic agents led to favorable PFS among smoking EGFR-mutant patients, comparable to nonsmokers, which might provide a useful guide for clinicians.

PD-1/PD-L1 inhibitor immunotherapy has showed impressive activity in various cancers, especially relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). However, acquired resistance is inevitable for most patients. Sometimes severe side effects also lead to treatment termination. When immunotherapy failed, alternative treatment options are limited. In the past few years, we have used the anti-angiogenic agent apatinib and PD-1 inhibitor camrelizumab to treat cHL patients who failed prior immunotherapy. In this study, we analyzed the data of these patients.
Patients with r/r cHL who had failed immunotherapy and subsequently received apatinib-camrelizumab (AC) combination therapy were included in this study. Patient data were collected from medical records and follow-up system. The efficacy and safety of AC therapy were analyzed.
Seven patients who failed immunotherapy were identified in our database, of which five patients acquired immunotherapy resistance and two patients experienced severe side effects. They received a combination of camrelizumab (200 mg every four weeks) and apatinib (425 mg or 250 mg per day). As of the cut-off date, these patients had received a median of 4 cycles (range, 2 - 31) of treatment. Two (2/7) patients achieved complete response, four (4/7) partial response, and one (1/7) stable disease. The median progression-free survival was 10.0 months (range, 2.0 - 27.8). Low-dose apatinib (250 mg) plus camrelizumab was well tolerated and had no unexpected side effects. Besides, no reactive cutaneous capillary endothelial proliferation was observed in AC-treated patients.
Low dose apatinib plus camrelizumab might be a promising treatment option for r/r cHL patients who have failed immunotherapy. This combination treatment is worthy of further investigation in more patients including solid cancer patients who have failed immunotherapy.

Aim: Advanced esophageal squamous cell carcinoma (ESCC) is a lethal disease with poor response to conventional chemotherapy. Immunotherapy showed better activity than chemotherapy in late-line treatment. However, the rate and duration of response are far from satisfactory. The efficacy of an anti-angiogenic agent combined with immunotherapy for ESCC is unknown. Results: A patient with ESCC experienced disease relapse after chemo-radiotherapy. The disease progressed after combined chemotherapy. A combination regimen of the PD-1 inhibitor camrelizumab and the anti-angiogenic agent apatinib was administered. The patient achieved a PET/CT-confirmed durable complete response with mild toxicity. Conclusion: The PD-1 inhibitor combined with the anti-angiogenic agent is effective and safe for the treatment of ESCC. This regimen is worth investigation in clinical trials.