To summarize the research status of lung cancer immunotherapy using bibliometrics. CiteSpace software was used to analyze all literature on lung cancer immunotherapy collected from the Web of Science (WOS) database from 2004 to 2024. A total of 1702 publications on lung cancer immunotherapy were searched, and the number of articles increased more rapidly after 2014. Two areas intensively studied by the discipline are tumor microenvironment and dendritic cells. He, Jie, Chinese Academy of Medical Sciences - Peking Union Medical College, and China of America were the authors, institutions, and countries with the most. The research trajectory in the use of immunotherapy for lung cancer is thoroughly examined in this article. With tumor microenvironment, blockade, nivolumab, resistance, and chemotherapy being the primary research hotspots. Future studies might concentrate on melanoma, antibody, dendritic cells, non-small cell lung cancer, and ctla 4 blockade.

Effectiveness and safety of second-line tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC) for whom first-line immuno-oncology (I-O) combination therapy was discontinued because of adverse events (AEs) remain to be determined.

Clinicopathological data were retrospectively collected from 34 institutions between August 2018 and January 2022 for 243 patients with mRCC who received second-line TKIs after first-line I-O combination therapy. Two patients who requested discontinuation of first-line I-O combination therapy were excluded. Oncological outcomes and safety were compared between patients who discontinued first-line I-O combination therapy because of progressive disease (Group PD) and AEs (Group AE). First- and second-line overall survival (OS) were defined as the time from the start of first- and second-line therapy to death, respectively. Propensity score matching was applied to adjust prognostic factors between the 2 groups.

There were 179 patients in Group PD and 62 patients in Group AE. Objective response rate and disease control rate were similar between the 2 groups. Progression-free survival (PFS), second-line OS, and first-line OS were significantly longer in Group AE than in Group PD (median 13.6 months vs. 8.5 months, P = 0.005; median not reached [NR] vs. 19.5 months, P = .005; median NR vs. 30.8 months, P = .012, respectively). After propensity score matching, PFS and second-line OS were still significantly longer and first-line OS tended to be longer in Group AE than in Group PD. There were no significant differences in the occurrence of AEs of any grade, including severe grades of 3 or greater, between the 2 groups.

Second-line TKIs are safe and at least as effective in patients with mRCC who discontinued first-line I-O combination therapy because of AEs as they are in patients who discontinued because of PD.

Immune checkpoint plus tyrosine kinase inhibition (IO + TKI) has emerged as the first-line therapy in metastatic renal cell carcinoma (RCC), but no biomarker can predict its efficacy. Thymidine kinase 1 (TK1) is closely associated with immune evasion in tumors.

Metastatic RCC patients treated by IO + TKI were enrolled from two cohorts (ZS-MRCC, n = 45; Javelin-101, n = 726). High-risk localized RCC were also enrolled (ZS-HRRCC, n = 40). TK1 was assessed by RNA-sequencing in all cohorts, and the immune contexture was assessed by flow cytometry and immunohistochemistry.

Higher TK1 expression was found in patients resistant to IO + TKI therapy (p = 0.025). High-TK1 group showed poor progression-free survival (PFS) in both the ZS-MRCC cohort (P = 0.008) and the Javelin-101 cohort (P = 0.036). By multivariate Cox regression, high-TK1 was determined as an independent factor for poor PFS (hazard ratio (HR) = 3.855, P = 0.002). High-TK1 expression was associated with decreased granzyme B+ CD8+ T cells (ρ=-0.22, P = 0.18), increased PD1+ CD4+ T cells (ρ = 0.33, P = 0.04), increased PDL1+ macrophages (ρ = 0.45, P < 0.001), and increased regulatory T cells (ρ = 0.35, P = 0.03). A novel random forest (RF) risk score was built by machine learning based on TK1 and immunologic parameters. Combined IO + TKI therapy surpassed sunitinib monotherapy in the low RF risk score group (HR = 0.158, P < 0.001), but was inferior to sunitinib in the high RF risk score group (HR, 2.195, P < 0.001).

High-TK1 expression could be a potential indicator for therapeutic resistance, poor PFS and immune evasion in metastatic RCC under IO + TKI therapy. The novel RF risk score may help stratify patients for IO + TKI therapy.

Post-marketing surveillance focusing on hepatic function disorder was requested owing to its higher incidence in the pembrolizumab plus axitinib group than in the sunitinib group in KEYNOTE-426. We aimed to evaluate the prevalence and risk factors of adverse events (AEs) of hepatic function disorder in patients with unresectable/metastatic renal cell carcinoma (RCC) treated with pembrolizumab plus axitinib in real-world clinical practice in Japan.

Patients were observed for 9 months after starting treatment with pembrolizumab plus axitinib.

In total, 193 patients were included in the safety analysis set (median age, 70 years). Most patients did not have a history of hepatic function disorder before starting treatment (96.4%, 186/193). The median treatment period was 27.1 weeks. At the 9-month data cut-off, 62.2% (120/193) of patients discontinued treatment, the most common reason being any AE in 31.1% (60/193). The incidence of AEs of hepatic function disorder was 30.1% (58/193) for any grade and 15.0% (29/193) for grade ≥ 3. Most AEs of hepatic function disorder occurred within 3 months from starting treatment. AEs of hepatic function disorder were the reason for discontinuation of pembrolizumab in 9.3% (18/193) of patients; axitinib, 7.3% (14/193); and both pembrolizumab and axitinib, 5.2% (10/193). No background factors were identified as being associated with the occurrence of AEs of hepatic function disorder.

There were no new safety signals for AEs of hepatic function disorder, and the incidence was consistent with that reported in KEYNOTE-426, in Japanese patients with radically unresectable/metastatic RCC treated with pembrolizumab plus axitinib.

Immune checkpoint inhibitor (ICI)-based combination therapies are first-line treatments for locally advanced or metastatic renal cell carcinoma (mRCC). However, second-line treatment efficacy remains uncertain due to limited large randomized trials. This study evaluated real-world oncological outcomes after second-line treatments in patients who received combination ICIs as first-line treatment.

Among 467 patients who received ICI combination therapy as first-line treatment for mRCC between January 2018 and January 2024, those who received cabozantinib (Cabo) or axitinib (Axi) as second-line treatment were included in this study. The patient characteristics at the initiation of second-line treatment, progression-free survival (PFS), and overall survival (OS) were compared between the two groups. Prognostic factors associated with OS after the initiation of second-line treatment were evaluated.

The Cabo and Axi groups included 87 and 45 patients, respectively. Median OS and PFS after the initiation of secondary treatment were 32 and 9 months in the Cabo group (p = 0.269), and 33 and 12 months in the Axi group (p = 0.399). Multivariable analysis identified serum C-reactive protein (CRP) ≥ 0.6 mg/dL and estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2 at the start of secondary treatment as independent predictors of OS. Stratification by these factors revealed a significant OS difference (p < 0.001).

Oncological outcomes after the initiation of secondary treatment did not differ significantly between the Cabo and Axi groups. An eGFR < 40 mL/min/1.73 m2 and CRP ≥ 0.6 mg/dL at the start of Cabo or Axi treatment were independent OS predictors after secondary treatment.

Our previous findings showed that the addition of metformin to nivolumab resulted in remarkable tumor regression and increased the number of tumor-infiltrating T cells in mouse models. Therefore, we conducted a phase Ib study using combination therapy with nivolumab and metformin in patients with refractory/recurrent solid tumors.

This study consisted of two parts: 1, evaluating the maximum tolerated dose (MTD), safety, pharmacokinetics in solid tumors, and 2, principally investigating the safety at the recommended dose limited to thoracic and pancreatic cancers. Metformin and nivolumab were administered orally at doses of 750-2,250 mg/day and biweekly at a fixed intravenous dose of 3 mg/kg, respectively. Dose-limiting toxicity was evaluated within the first 4 weeks. Both metformin and nivolumab were continued until disease progression or discontinued because of toxicity.

In total, 17 and 24 patients were enrolled in parts 1 and 2, respectively. One patient experienced increased pancreatic enzyme levels (grade 4) and lactic acidosis (grade 3). No Grade 5 adverse events were observed. MTD was not reached up to 2,250 mg/day of metformin, 2,250 mg/day was selected for part 2. An objective response was observed in 4 of 41 patients. One-year progression-free and overall survival rates were 9.8% and 56.8%, respectively. Two patients remained alive without disease progression for more than three years.

Nivolumab and metformin combination therapy was well-tolerated and showed preliminary signals of efficacy in a subset of patients. Further verification of the underlying mechanism in cases where treatment is effective is required.

UMIN registration number 000028405 https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000031915 .

The optimal first-line therapy for metastatic renal cell carcinoma (mRCC) remains uncertain, despite recent advancements in immune-based combinations. This retrospective study compares the effectiveness of pembrolizumab plus axitinib (PA) and nivolumab plus cabozantinib (NC) as first-line treatments for mRCC in a real-world setting.

Patient data were collected from 55 centers across 16 countries, encompassing individuals diagnosed with mRCC receiving first-line treatment with PA or NC between January 2016 and October 2023. Clinical and tumor features and treatment responses were recorded. The primary endpoints were overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to second progression. Statistical analyses included Kaplan-Meier survival estimates, Cox proportional hazard models, and chi-square tests.

A total of 760 patients with a median age of 64 years (range, 29-88) were included. Of them, 607 received PA, and only 153 NC. In the overall study population, ORR was 59% for and 49% for PA. Median OS was 55.7 months and not reached (NR) for PA and NC, respectively (P = .51), while median PFS was longer with NC (27.6 months) than for PA (16.2 months, P = .003). Subgroup analysis suggested a PFS benefits for NC in male, younger patients, intermediate risk group, clear cell histology, and lung involvement, as well as ORR favored NC in good risk patients. Multivariate analysis identified first-line therapy as a significant factor associated with PFS.

In this certainly biased retrospective comparison, NC demonstrated superior ORR and longer PFS compared to PA in mRCC. These findings underscore the importance of considering individual patient characteristics and risk profiles when selecting first-line therapy for mRCC.

To evaluate the efficacy of topical dasatinib and axitinib for treating experimentally induced corneal neovascularization (CNV) in a mouse alkali burn model, and to compare these treatments to established therapies like dexamethasone and bevacizumab.

Thirty-six C57BL/6; 129 Sv mice underwent a standardized alkali burn to induce CNV in both eyes by applying a paper disc soaked in 1M NaOH to the cornea for 20 seconds. The mice were randomly assigned to one of 6 treatment groups: saline (0.9% sodium chloride), DMSO (5%), dexamethasone (0.1%), bevacizumab (0.5%), dasatinib (0.5%), or axitinib (0.5%). Treatments were applied topically 3 times daily. After 2 weeks of treatment, the mice were sacrificed. CNV assessments, including corneal neovascularization area (CNA), vessel length index (VLI), and limbus vasculature thickness, were conducted postmortem using corneal flat-mounts stained with a CD31 antibody for immunohistochemistry.

Dexamethasone proved the most effective in inhibiting alkali burn-induced CNA (P < 0.0001), with bevacizumab showing comparable efficacy (P < 0.001). Axitinib also effectively reduced CNA (P < 0.001) and VLI (P < 0.01). In contrast, dasatinib did not significantly reduce CNA (P = 0.74) or VLI (P = 0.98). All eyes in the dexamethasone group developed cataracts compared with 25%-41.7% in the other groups.

Axitinib reduced CNA and VLI, although not as effectively as other established treatment modalities, whereas dasatinib did not demonstrate significant effects.

Manganese ions are known to enhance anti-tumor immunity by activating the cGAS-STING signaling pathway. However, precise modulation of the tumor microenvironment using manganese ions remains a challenge. Dopamine, with its controlled release properties within the tumor microenvironment, offers significant potential for precision drug delivery systems. Metastatic renal cell carcinoma (RCC), being refractory to conventional treatments, necessitates innovative therapeutic approaches. In this study, a multifunctional manganese-polydopamine nano-immunomodulator coated with hyaluronic acid (PDA-Mn-HA NPs) is developed. These nanoparticles selectively bind to CD44 molecules, which are highly expressed in tumor-associated macrophages and RCC cells, and release manganese ions in a tumor microenvironment-responsive manner. Treatment with PDA-Mn-HA NPs effectively induces macrophage M1 polarization, triggers the production of pro-inflammatory cytokines and chemokines. Transcriptomic analysis reveals that PDA-Mn-HA NPs polarize and activate macrophages through the reactive oxygen species(ROS)-STING-p38/MAPK signaling pathway. Additionally, PDA-Mn-HA NPs induce ROS-caspase-3/GSDME-dependent pyroptosis in RCC cells via a Fenton-like reaction. In RCC mouse models, PDA-Mn-HA NPs remodel the macrophage-mediated immune microenvironment, enhance immune cell infiltration, and significantly suppress tumor growth. In conclusion, multifunctional PDA-Mn-HA NPs demonstrate translational potential by addressing the limitations of precision manganese delivery and achieving synergistic targeting of macrophages and tumor cells, offering a promising therapeutic strategy for RCC.

Combinations of immune checkpoint inhibitors (ICIs) and antiangiogenic agents have demonstrated potent clinical activity across multiple tumor types. We hypothesized that the combination of axitinib, a highly potent inhibitor of VEGFR1-3, with the anti-PD-L1 antibody avelumab would be well tolerated and effective in the treatment of recurrent MMRP EC.

We conducted an investigator-initiated, single-arm phase 2 study of avelumab/axitinib in MMRP EC (NCT02912572). Eligible participants had recurrent EC of any histology that was MMRP, measurable disease, no upper limit of prior therapies and no prior ICI treatment. Co-primary endpoints were objective response rate (ORR) and progression-free survival rate at 6 months (PFS6). Targeted next-generation sequencing and multiplexed immunofluorescence were performed.

Thirty-five patients initiated protocol therapy. There were 14 objective responses (ORR 40 %, 95 % CI 23.9 %-57.9 %), including 1 confirmed CR, 1 unconfirmed CR, 8 confirmed PRs, and 4 unconfirmed PRs. Thirteen patients (37.1 %) had stable disease (SD), and 6 (17.1 %) patients had progressive disease (PD). The confirmed objective response rate (ORR) was 25.7 % (95 % CI 12.5 % to 43.3 %), estimated median DOR was 13.8 months, PFS at 6 months was 55.8 %, and the estimated median PFS was 7 months. The most common G3+ treatment-related toxicities were hypertension (37.1 %), ALT increased (5.7 %) and AST increased (5.7 %); 5 (14.3 %) patients discontinued protocol therapy because of toxicity. Objective response rate was 48 % in TP53 mutated tumors and 28.6 % in NSMP tumors.

Avelumab and axitinib had an acceptable safety profile and demonstrated encouraging activity in recurrent MMRP EC.

The tumor microenvironment (TME) in renal cell carcinoma (RCC) frequently exhibits significant immune cell infiltration. However, tumor cells often manage to evade immune surveillance. This study revealed the mechanism by which circular RNA circGRAMD4 regulates NBR1. CircGRAMD4 is markedly elevated in RCC, and its high levels are correlated with a poor prognosis. Notably, the absence of circGRAMD4 has been demonstrated to result in a significant inhibition of renal cancer cell growth. This inhibition has been attributed to an enhanced anti-tumor immunity mediated by CD8+ T cells. Mechanistically, circGRAMD4 interacts with the RBM4 protein, stabilizing the autophagic cargo receptor NBR1 mRNA. This interaction promotes NBR1 expression, which in turn leads to the degradation of MHC-I molecules through macroautophagy/autophagy pathways. Consequently, this process affects renal cancer cell antigen presentation, induces CD8+ T cell dysfunction, and contributes to tumor immune escape. Moreover, by inhibiting circGRAMD4 and using immune checkpoint blockers (ICB), the immunosuppressive TME is altered to prevent tumor immune evasion, ultimately increasing the effectiveness of ICB treatment. The discovery highlights the significant impact of circGRAMD4 on RCC immune escape and proposes that blocking circGRAMD4 could serve as a promising immunotherapy strategy when combined with ICB to enhance patient outcomes.

Adaptive resistance to immunotherapy remains a significant challenge in cancer treatment. The reshaping of the tumor immune microenvironment in response to therapeutic pressures is a crucial factor contributing to this resistance. In this study, by comprehensive metabolic profiling of tumor tissues, we identified elevated itaconate in response to anti-PD-1 therapy as an adaptive resistance mechanism that promoted immune escape and tumor progression. CD8+ T-cell-derived IFNγ induced a significant upregulation of cis-aconitate decarboxylase 1 (ACOD1) in macrophages via the JAK-STAT1 pathway, thereby rewiring the Krebs cycle toward itaconate production. In murine models, macrophage-specific deletion of Acod1 increased the antitumor efficacy of anti-PD-1 therapy and improved survival. Additionally, itaconate and its derivative, 4-octyl itaconate, suppressed the tumor antigen presentation and cross-priming ability of dendritic cells, resulting in the impairment of antigen-specific T-cell antitumor responses. In summary, these findings identify an IFNγ-dependent immunometabolic mechanism of anti-PD-1 resistance, providing a promising strategy for combination therapy. Significance: Elevated itaconate production by macrophages induced by IFNγ is a critical negative feedback immunoregulatory metabolic response to anti-PD-1 immunotherapy that inhibits the cross-priming function of dendritic cells and confers immunotherapy resistance.

Significant advances in the management, in particular the treatment, of renal cell carcinoma (RCC) has have been made over the years. However, it is not clear whether these advances reduce the disease burden of RCC at the population level.

Using data from the Surveillance, Epidemiology, and End Results database, we estimated the temporal trends of RCC incidence, incidence-based mortality (IBM), and survival rates in the United States (US) from 1992 to 2019.

From 2008 to 2019, the incidence increased slowly at 1.1% annually (95% CI: 0.6% to 1.5%). The overall IBM rate of RCC increased by 6.8% per year (95% CI: - 1.1% to 15.3%) between 1994 and 1997, plateaued between 1997 and 2015, and then decreased nonsignificantly after 2015. During the study period, the overall Five year survival rate of RCC continuously increased from 53.69 in 1992 to 72.90% in 2014, with the best improvement observed for RCC patients with distant disease. However, we projected that, given the current trends, the incidence of RCC in the US will continue to increase from 6.92 per 100,000 in 2015-2019 to 9.59 per 100,000 in 2040-2044.

Over the years, the mortality of RCC has been decreased reducing at the US population level mainly because the considerably significantly improved survival of RCC patients at all stages through the advances in treatment. However, the overall incidence of RCC is continuously increasing, indicating that more effective preventive strategies should be developed to reduce the disease burden of RCC.

Modern clinical trials can capture tens of thousands of clinicogenomic measurements per individual. Discovering predictive biomarkers, as opposed to prognostic markers, remains challenging. To address this, we present a neural network framework based on contrastive learning-the Predictive Biomarker Modeling Framework (PBMF)-that explores potential predictive biomarkers in an automated, systematic, and unbiased manner. Applied retrospectively to real clinicogenomic datasets, particularly for immuno-oncology (IO) trials, our algorithm identifies biomarkers of IO-treated individuals who survive longer than those treated with other therapies. We demonstrate how our framework retrospectively contributes to a phase 3 clinical trial by uncovering a predictive, interpretable biomarker based solely on early study data. Patients identified with this predictive biomarker show a 15% improvement in survival risk compared to those in the original trial. The PBMF offers a general-purpose, rapid, and robust approach to inform biomarker strategy, providing actionable outcomes for clinical decision-making.

This study aims to develop a peripheral blood-based model that can predict the response to the combination therapy of camrelizumab and apatinib as a second-line or later-line treatment regimen in patients with recurrent/metastatic nasopharyngeal carcinoma (R/M-NPC).

We collected peripheral blood routine data from 72 patients with R/M-NPC from two clinical trial studies (NCT04547088, NCT04548271). Utilising the least absolute shrinkage and selection operator Cox regression model, we built a peripheral blood signature and developed a prognostic nomogram through multivariable analysis. Spectral flow cytometry analysed peripheral blood mononuclear cell immunophenotyping.

Six indicators (WBC, MCV, HCT, MCHC, P-LCR, MLR) were included to construct the peripheral blood signature. By combining this signature with Epstein-Barr virus DNA, distant lymph node metastasis and previous PD-1 inhibitor treatment, we constructed a peripheral blood-based nomogram that showed favourable performance. High-risk individuals had lower overall survival than low-risk individuals (P < 0.05). Immunophenotyping revealed that the high-risk individuals had increased monocytic myeloid-derived suppressor cells, Tregs and decreased CD8 effector memory cells (P < 0.05).

We established a model that could predict the prognosis of combined therapy. The model could predict outcomes and reflect the systemic immune and inflammatory status, which is beneficial for risk stratification and therapeutic modification.

Pembrolizumab plus lenvatinib is a treatment option for metastatic Renal Cell Carcinoma (mRCC). In the ARON-1 study we investigated we the real-world experiences gained from the use of this combination for mRCC.

We retrospectively investigated real-world clinical outcomes of mRCC patients receiving pembrolizumab plus lenvatinib within the ARON-1 study. Overall survival (OS) was calculated from the start of pembrolizumab plus lenvatinib to death for any cause. Progression-Free Survival (PFS) was defined as the time from the start of pembrolizumab to progression or death from any cause. Duration of response (DoR) was defined as the time from the start of pembrolizumab to disease progression or death, whichever occurred first, in patients who achieved complete remission (CR) or partial response (PR). Overall Response Rate (ORR) was defined as the proportion of patients who achieve a CR or PR per RECIST criteria. Adverse events were retrospectively collected from electronic and paper charts and categorized by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

Overall, we included 202 mRCC patients treated with pembrolizumab plus lenvatinib. The median follow-up time was 15.1 months. The median OS was not reached (NR), with a median PFS of 25.6 months and an Overall Response Rate (ORR) of 59%. The median Duration of Response (DoR) was 26.2 months. G3-G4 adverse events (AEs) were observed in 92 patients (46%), with hypertension being the most common AE (13%).

Pembrolizumab plus lenvatinib is an effective and tolerable treatment for mRCC also in the real-world setting.

In metastatic clear-cell renal cell carcinoma (mccRCC), choosing between immuno-oncology (IO) combinations and IO plus anti-VEGF therapies is uncertain. The BIONIKK trial revealed that ipilimumab plus nivolumab (Ipi/Nivo) achieved a 70% objective response rate in angiogenic cluster1/2 versus 41% in cluster4/5, which featured T-effector/cell-cycle signatures (p = 0.048). Complete responses were exclusively observed in cluster1/2 (p = 0.012), with longer progression-free survival (p = 0.014). Ipi/Nivo may particularly benefit angiogenic mccRCC, supporting molecular subtype-based treatment strategies.

While vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) are a mainstay of treatment for advanced renal cell carcinoma (RCC), mechanisms of resistance to VEGF-TKIs remain under ongoing investigation. To assess transcriptomic changes in clear-cell RCC (ccRCC) and non-ccRCC exposed to a VEGF-TKI, we analyzed differential single-cell gene expression in RCC tumor-organoids exposed to cabozantinib versus control solvent. In ccRCC organoid cells, LRRC75A was notably highly associated with cabozantinib exposure (log2 fold-change 2.18, detected proportion 0.52 vs. 0.23, false-detection rate adjusted p<0.001). Importantly, our findings were independently validated in a recent study of advanced ccRCC patients treated with cabozantinib, which demonstrated that higher LRRC75A expression was significantly associated with decreased tumor response and less robust reduction of VEGF expression. LRRC75A has been shown to mediate VEGF secretion in a separate study and may potentiate compensatory angiogenesis after cabozantinib exposure. Gene expression scores were then developed based on transcriptomic changes associated with cabozantinib exposure and applied to stage IV patients in several independent cohorts. Higher scores were significant predictors of worse overall survival in TCGA non-RCC patients and worse progression-free survival in JAVELIN Renal 101 ccRCC patients. Overall, this experiment represents an incremental step in a larger effort to elucidate resistance mechanisms to VEGF-TKIs.

The real-world incidence of hepatic dysfunction after combination therapy with cabozantinib plus nivolumab (CABO+NIVO) in Japanese patients with metastatic renal cell carcinoma remains undetermined; hence, this study aimed to determine the incidence of hepatotoxicity in these patients.

A total of 48 patients treated with CABO+NIVO were enrolled in this study. Alanine aminotransferase (ALT) levels were used to evaluate liver dysfunction because of its liver specificity.

ALT elevation of any grade was found in 30 patients (63%), and grade 3 elevation was found in eight patients (17%). No grade 4 or 5 elevations were observed. Female gender and a higher body mass index were independent predictive factors for ALT elevation. All patients were managed with dose reduction or interruption of cabozantinib and concomitant use of hepatoprotective agents without high-dose corticosteroids. Of the seven patients that underwent cabozantinib rechallenge after grade 3 ALT elevation, only two (23%) required re-interruption due to repeat grade 3 ALT elevation.

This is the first study to examine hepatic dysfunction caused by CABO+NIVO in Japanese patients. The incidence of hepatic dysfunction was higher in real-world patients than in global patients found in pivotal phase 3 trials. Cabozantinib appeared to be a major cause of hepatic dysfunction since dose reduction or interruption of cabozantinib without the use of corticosteroids resolved hepatotoxicity. In addition, additional care should be taken when treating female or obese patients with CABO+NIVO.

Side effects from tyrosine kinase inhibitors (TKIs) are common and burdensome. Olanzapine is useful for managing symptoms from conventional chemotherapy, but its role in treating TKI-related side effects is unclear.

Examine the efficacy of olanzapine for TKI-induced nausea, vomiting, anorexia, weight loss, and insomnia.

All patients prescribed olanzapine with lenvatinib, cabozantinib, axitinib, or tivozanib at Mayo Clinic between January 2018 and June 2024 were assessed for inclusion. For baseline assessment, clinical notes documenting symptoms and indication(s) for starting olanzapine were reviewed. Notes and portal messages from the first three months after starting olanzapine were then evaluated for qualitative descriptions of change in symptom burden. Data were categorized as "improved," "worsened," "stable," or "missing data," with each symptom domain analyzed independently, when olanzapine was prescribed for multiple interrelated symptoms.

Sixty patients received olanzapine, most commonly 5 mg (n = 37, 61.7%) or 2.5 mg (n = 16, 26.6%). Indications included nausea without vomiting (n = 35), anorexia (n = 25), nausea with vomiting (n = 16), weight loss (n = 16), and insomnia (n = 11). It was given for multiple symptoms in 32 patients. Within the first 3 months, 85% of patients had improvement in nausea without vomiting, 93% in nausea with vomiting, 74% in appetite, and 85% in sleep. Among 34 patients with weight loss prior to olanzapine, 50% gained weight (median: 6.1 kg), 26% stabilized (±1 kg), and 24% continued to lose weight. Only 4 patients discontinued olanzapine due to side effects.

Olanzapine appears effective in treating TKI-induced nausea, vomiting, anorexia, insomnia, and weight loss, warranting further investigation in prospective studies.

We describe a paradigm wherein combined high TLS and low tissue-resident exhausted CD8+ T cells are required for optimal response to PD-1 blockade in RCC. This analysis identifies key determinants of response to PD-1 blockade in advanced RCC and suggests avenues for future immune modulation through rational combination therapy strategies.

The fragility index (FI) has been applied as a supplement to the noncomprehensive P-values to assess the robustness of randomized controlled trials (RCTs). The objective of this study is to evaluate the statistical robustness of RCTs of advanced/metastatic renal cell cancer (a/mRCC) using the FI.

RCTs related to a/mRCC published in the 4 highest-impact general medical journals and the 25 highest-impact urological journals between January 1, 2000, and December 31, 2023, were identified from PubMed database. The FI was calculated by using Fisher's exact test. Spearman's correlation analysis was conducted to assess potential correlates regarding FI.

16 eligible RCTs were screened with a median total sample size of 654.5 (IQR, 461-847) and a median patients lost to follow-up of 14 (IQR, 3-23). The median FI was 12.5 (IQR, 8.5-27), suggesting that a switch in outcomes in only 13 patients would have reversed the significance of the trials. The number of patients lost to follow-up exceeded or equaled to the FI in 7 (44%) RCTs. P-values were negatively associated with the FI, while the number of patients lost to follow-up and patients enrolled were not statistically significant.

Not all RCTs associated with a/mRCC are as statistically robust as previously considered and should therefore be construed carefully. We suggest that additional reporting of FI in urological RCTs as a supplement to the P-value to assist readers in concluding reliably by considering the fragility of the outcomes.

Background/Objectives: The precise role of volumetric body composition (VBC) parameters, visceral adipose tissue index (VATI), subcutaneous adipose tissue index (SATI), and skeletal muscle index (SMI) on the survival of metastatic renal cell carcinoma (mRCC) is not fully elucidated. Herein, the present study investigated the clinical significance of baseline VBC parameters and their changes after 3-4 months from treatment initiation in patients with mRCC treated with first-line targeted therapy. Methods: A total of 108 patients were enrolled. VBC parameters were depicted from computerized tomography (CT) images at the third lumbar vertebra level. Kaplan-Meier curves were used to estimate survival probability, and the differences between prognostic subgroups were compared with the log-rank test. The association of baseline VBC variables and their change values (First CT value minus baseline CT value) with progression-free survival (PFS) and overall survival (OS) was evaluated in univariate and multivariate analyses. Results: The median PFS and OS of the whole patients were 11 and 46 months, respectively. Patients with increased VATI and SATI change values had poorer OS than those with decreased values. However, patients with higher SMI change values had superior OS than those with lower values. Among VBC variables, the independent predictors of worse OS were high VATI change (HR 5.10, p = 0.001) and low SMI change values (HR 2.66, p = 0.007), in addition to International Metastatic Renal Cell Carcinoma Database Consortium prognostic stratification (p = 0.001). Conclusions: Our findings showed that high VATI and low SMI changes were associated with worse OS in mRCC patients treated with first-line targeted therapy.

This review focuses on contemporary research into potential prognostic and therapeutic biomarkers for advanced renal cell carcinoma (RCC) published over the past 18 months. Beyond serum lab values, there is no consensus on the use of specific biomarkers for this purpose. Potential biomarkers being investigated consist of genetic, protein, immunologic, and radiologic candidates.

New insights in genomic biomarkers include a better understanding of VHL mutational heterogeneity, tumor mutational burden, and the importance of genes like PBRM1 and SETD2 . Protein biomarkers such as C-reactive protein (CRP) and PDZK1 have demonstrated utility in predicting disease progression, therapeutic response, and survival, while immunologic biomarkers like PSMD2, cytokines, and Tregs continue to shed light on the tumor microenvironment and immune evasion. Emerging imaging biomarkers, from CAIX-targeted radiotracers to PSMA-based PET-CT, offer noninvasive diagnostic and prognostic tools that may revolutionize RCC management.

There are several promising biomarkers currently under investigation for use in advanced RCC.

Immuno-oncology (IO) is one of the fastest growing therapeutic areas within oncology. IO agents work indirectly via the host's adaptive and innate immune system to recognize and eradicate tumor cells. Despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product category. Current Food and Drug Administration (FDA)-approved classes of IO agents include: immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy (CAR-T), bi-specific T-cell engager (BiTE) antibody therapy, T-cell receptor (TCR) engineered T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, cytokine therapy, cancer vaccine therapy, and oncolytic virus therapy. Cancer immunotherapy has made progress in multiple cancer types including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma; however, several cancers remain refractory to immunotherapy. Future directions of IO include exploration in the neoadjuvant/perioperative setting, combination strategies, and optimizing patient selection through improved biomarkers.

Imiquimod (IQM), an imidazoquinoline derivative, is an immunomodulator that activates an adaptive immune response. IQM is applied topically for genital warts and actinic keratosis. Programmed cell death-1 (PD-1) suppresses activated T cells by binding to programmed cell death-ligand 1 and programmed cell death-ligand 2, braking antitumor immunity. Anti-PD-1 therapy has been used for various malignant neoplasms including renal cell carcinoma (RCC). Whether combination therapy with transcutaneous administration of IQM cream and intraperitoneal administration of anti-PD-1 monoclonal antibody (mAb) suppresses mouse RCC cells growing in subcutaneous tissue was investigated.

Female BALB/c mice were implanted subcutaneously with 2 × 105 RENCA mouse RCC cells and treated with a transcutaneously applied cream containing IQM and intraperitoneal administration of anti-PD-1 mAb beginning 5 days after cell implantation. Tumor burden and survival of the mice were determined. RENCA tumor-specific IgG production and a minor CD8+ T cell subset derived from the spleen of the mice bearing RENCA tumor were detected by flow cytometry. The tumor and spleen weights of mice treated with IQM, anti-PD-1 mAb, and their combination were compared.

Combination therapy with IQM and anti-PD-1 mAb significantly suppressed tumor growth compared to each monotherapy and prolonged the survival of the mice. The combination therapy produced more RENCA tumor-specific IgG than either IQM or anti-PD-1 mAb alone. The percentage of the CD44highCD62Llow CD8+ T cell subset (effector memory T cells) among splenocytes from mice treated with IQM therapy increased. The CD44lowCD62Llow CD8+ T cell subset (pre-effector-like T cells) of mice treated with anti-PD-1 mAb increased. A negative correlation between tumor and spleen weights was suggested in mice treated with therapies containing IQM.

The present results show that combination therapy with IQM and anti-PD-1 mAb might be a promising novel therapeutic strategy for advanced RCC.

The impact of baseline cardiovascular disease (CVD) on survival in patients undergoing immune checkpoint inhibitor (ICI) therapy is not well understood. Therefore, we sought to determine the relationship between baseline CVD on mortality in patients undergoing ICI monotherapy or combination therapy.

Using TriNetX, a global database of over 120 million patients, we identified 27,820 patients with pre-existing cardiovascular disease prior to starting ICI monotherapy and an equal number of corresponding matched controls.

Systolic heart failure (HR: 1.38, 95% CI: 1.29-1.48), diastolic heart failure (HR: 1.34, 95% CI: 1.27-1.42), and atrial fibrillation/flutter (HR: 1.24, 95% CI: 1.19-1.29) had the greatest associations with mortality across ICI monotherapy.

Future trials of patients initiating ICI therapy should capture these baseline values to guide risk assessment, pretreatment optimization, and surveillance strategies prior to treatment initiation.

The purpose of this study was to indirectly compare pembrolizumab + lenvatinib to other treatments of interest for first-line advanced renal cell carcinoma (aRCC).

A systematic literature review searched EMBASE, MEDLINE, and CENTRAL databases for relevant randomized controlled trials of interest up to 30 January 2024, with an updated search conducted on 17 March 2025. A fixed effect Bayesian network meta-analysis (NMA) was conducted to determine the relative treatment effects for overall survival (OS), progression-free survival (PFS), and objective response rate (ORR).

When comparing against other immune checkpoint inhibitors (ICI), a statistically significant improvement in PFS was demonstrated between pembrolizumab + lenvatinib compared with nivolumab + ipilimumab (hazard ratio (HR) = 0.53; 95% credible interval (CrI): 0.40-0.71), avelumab + axitinib (HR = 0.71; 95% Crl: 0.53-0.94), atezolizumab + bevacizumab (HR = 0.54; 95% CrI: 0.40-0.73), and pembrolizumab + axitinib (HR = 0.69; 95% CrI: 0.51-0.91). Treatment with pembrolizumab + lenvatinib resulted in no statistically significant difference between pembrolizumab + lenvatinib and other combination ICI-based therapies for OS. A statistically significant higher ORR was shown for pembrolizumab + lenvatinib compared with nivolumab + ipilimumab (odd ratio (OR) = 3.29; 95% Crl: 2.21-4.93), pembrolizumab + axitinib (OR = 1.92; 95% CrI: 1.27-2.94), atezolizumab + bevacizumab (OR = 4.05; 95% Crl: 2.71-6.05), bempegaldesleukin + nivolumab (OR = 6.20; 95% CrI: 3.69-10.48), and nivolumab (OR = 5.92; 95% CrI: 2.70-13.24).

The overall population analysis indicated that pembrolizumab + lenvatinib improves PFS and ORR compared with other approved ICI combination therapies in first-line aRCC. No significant differences in OS were observed between pembrolizumab + lenvatinib and other combination immune checkpoint inhibitor-based therapies.

Although hypertension is a common side effect of tyrosine kinase inhibitor (TKI) treatment for renal cell carcinoma (RCC), there is limited evidence regarding its occurrence and related risk factors. Preliminary studies suggest that proton pump inhibitors (PPIs) may mitigate the risk of TKI-induced hypertension; however, their clinical effectiveness remains unclear.

In this study, we examined the prevalence of TKI-induced hypertension and the patterns of antihypertensive prescriptions among patients with RCC in Japan. Additionally, we investigated factors associated with TKI-induced hypertension to assess the potential impact of PPIs.

Data from patients diagnosed with RCC who were prescribed TKIs between April 2008 and July 2021 were retrospectively gathered from a Japanese administrative database. TKI-induced hypertension was detected following the diagnosis of hypertension and subsequently the prescription of an antihypertensive agent during TKI therapy. The prescription details for antihypertensive agents were organized in a tabular format. Cox proportional hazards regression analysis was conducted to examine factors contributing to TKI-induced hypertension. Among the 225 patients analyzed, 36.4% experienced hypertension, and calcium channel blockers were the most prescribed antihypertensive agents. Pre-existing hypertension was identified as a risk factor for TKI-induced hypertension, while the concurrent use of PPIs did not show a tendency to reduce the risk of TKI-induced hypertension.

These findings indicate the importance of blood pressure management in patients with elevated baseline blood pressure.

Despite that incorporating antiangiogenic in combination with immune-checkpoint inhibitors as the standard first-line treatment for advanced clear cell renal cell cancer (ccRCC) yields promising outcomes, these regimens often lead to significant toxicity. However, a subgroup of patients has shown responsiveness to VEGFR tyrosine-kinase inhibitors (TKIs) in monotherapy, leading to the question of whether employing combination therapies can significantly enhance overall survival in all patients over monotherapy. Thus, we aim to identify gene expression signatures that can predict TKI response within subpopulations that might benefit from single-agent therapies, to minimize unnecessary exposure to combination therapies and their associated toxicities, as well as to discover new potential therapeutic targets to improve ccRCC treatment. Based on prior data, the androgen receptor (AR) might meet both conditions.

We evaluated the association between AR expression, assessed through NanoString® technology-derived mRNA counts, and the clinical outcomes of 98 ccRCC patients treated with first-line antiangiogenics and determined its association with other genes implicated in ccRCC tumorigenesis.

Higher AR-expression correlates significantly with better prognosis and survival based on the MSKCC risk score, and longer PFS. Furthermore, we have identified a gene set signature associated with AR-overexpression and several genes involved in angiogenesis and transcriptional targets of the hypoxia-inducible factor, a cornerstone of ccRCC.

AR-overexpression and its association with other genes could favor a transcriptomic signature set to aid in identifying patients suitable for TKI in monotherapy, rather than aggressive combinations, enhancing thus, precision and personalized therapeutic decisions.