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.

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.

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.

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.

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.

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.

Ipilimumab with nivolumab (Ipi + Nivo) and immune checkpoint inhibitors with tyrosine kinase inhibitors (ICI + TKI) are the first-line approved treatments for intermediate- and poor-risk metastatic clear cell renal cell carcinoma (mccRCC); however, they have not been compared head-to-head in prospective trials to guide treatment selection. Thereupon, we sought to compare survival outcomes of patients receiving first-line Ipi + Nivo versus ICI + TKI, using a large, real-world database among patients with intermediate- and poor-risk mccRCC. This retrospective cohort study used a nationwide electronic health record-derived deidentified database, where patients with mccRCC with intermediate- or poor-risk who received first-line Ipi + Nivo or ICI + TKI between 20 June, 2016, and 26 January, 2023, were included. Primary outcomes were real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS), summarized via Kaplan-Meier survival estimates with 95% confidence intervals (CIs) and compared in the context of propensity score (PS) matching weighted analysis. Of the 12,707 patients in the dataset, 1,438 with mccRCC met eligibility and were included. After PS matching weighted analysis, no significant difference in rwOS was noted between both groups (HR 1.01, 95% CI 0.86-1.19; p = 0.91); however, rwTTNT was significantly shorter with Ipi + Nivo than with ICI + TKI (HR 0.78, 95% CI 0.68-0.89; p < 0.001). In this large real-world study, there was evidence that rwOS was comparable, while rwTTNT was superior in patients receiving ICI + TKI compared to those receiving Ipi + Nivo. These real-world data offer important guidance for clinicians in choosing between Ipi + Nivo and ICI + TKI as frontline treatment.

Renal cell carcinoma (RCC) is characterized by a high degree of genomic but also functional intratumoral heterogeneity (ITH). Mutations in VHL, chromatin remodeling genes such as SETD2 and genes that regulate the PI3K/AKT/mTOR pathway have been identified as recurrent drivers despite genomic ITH. Whether and to what extent these mutations shape functional ITH including the formation of spatial niches is incompletely understood. Herein, we analyze the correlation between mutational drivers and their functional proxies in a spatially defined manner.

A total of 23 RCCs were analyzed by panel next-generation sequencing followed by immunohistochemistry for five functional proxies for key genetic alterations including the expression of CD31, GLUT1, phospho-mTOR S2448, H3K36me3 and Ki-67. Antibody stainings were scored semiquantitatively in the tumor periphery and the tumor center.

Unexpectedly, the presence of a VHL mutation was not found to correlate with its functional proxies including the expression of CD31/microvessel density or the expression of the glucose transporter GLUT1. Likewise, there was no correlation between the presence of activating mutations in genes of the PI3K/AKT/mTOR pathway and the expression of activated phospho-mTOR S2448. Furthermore, mutations in the methyltransferase gene SETD2 were not found to correlate with the expression level of its downstream target H3K36me3. Lastly, there was no correlation between the expression of the proliferation marker Ki-67 and the number of driver mutations.

This proof-of-concept study adds genotype-phenotype heterogeneity as additional layer of complexity to the known genomic and functional ITH in RCC.

Combination therapy of nivolumab-plus-ipilimumab has been approved for advanced or metastatic renal cell carcinoma in Japan, but large-scale clinical data targeting Japanese patients is limited. To evaluate the early outcomes and factors related to early progression and response.

J-ENCORE is an ongoing multicenter, prospective, observational study of the effectiveness and safety of nivolumab-plus-ipilimumab for patients in Japan with advanced or metastatic renal cell carcinoma. The objective response rate, duration of response, progression-free survival, overall survival, incidence of adverse events, and factors related to early progression within 3 months, and response were assessed.

We included 274 patients (median age: 68 years, 24.8% aged ≥ 75 years, 78.8% male). The median follow-up was 23.4 months. The objective response rate was 36.8%. Among responders, 63.3% had progression-free survival > 12 months. The median progression-free survival was 9.9 months; the 12-month overall survival was 76.3%. Of the patients, 77.0% experienced treatment-related adverse events, 42.3% experienced grade 3-4 events, and 1.1% experienced treatment-related death. Early progression was associated with female sex, poor risk status, liver metastasis, high baseline C-reactive protein levels, and high neutrophil-to-lymphocyte ratios. Responders were less likely to have bone metastases. Limitations include the observational nature of the study and a relatively short follow-up period.

This is the first prospective, real-world study to demonstrate the effectiveness and safety of nivolumab-plus-ipilimumab in Japan, with the results comparable to those of CheckMate 214. These findings support the use of nivolumab-plus-ipilimumab, although further studies with longer follow-up on nivolumab-plus-ipilimumab are needed.

ClinicalTrials.gov identifier: NCT04043975; University Hospital Medical Information Network-Clinical Trial Registration: UMIN000036772.

Genitourinary (GU) cancers, including renal cell carcinoma, prostate cancer, bladder cancer, and testicular cancer, represent a significant health burden and are among the leading causes of cancer-related mortality worldwide. Despite advancements in traditional treatment modalities such as chemotherapy, radiotherapy, and surgery, the complex interplay within the tumor microenvironment (TME) poses substantial hurdles to achieving durable remission and cure. The TME, characterized by its dynamic and multifaceted nature, comprises various cell types, signaling molecules, and the extracellular matrix, all of which are instrumental in cancer progression, metastasis, and therapy resistance. Recent breakthroughs in immunotherapy (IO) have opened a new era in the management of GU cancers, offering renewed hope by leveraging the body's immune system to combat cancer more selectively and effectively. This approach, distinct from conventional therapies, aims to disrupt cancer's ability to evade immune detection through mechanisms such as checkpoint inhibition, therapeutic vaccines, and adoptive cell transfer therapies. These strategies highlight the shift towards personalized medicine, emphasizing the importance of understanding the intricate dynamics within the TME for the development of targeted treatments. This article provides an in-depth overview of the current landscape of treatment strategies for GU cancers, with a focus on IO targeting the specific cell types of TME. By exploring the roles of various cell types within the TME and their impact on cancer progression, this review aims to underscore the transformative potential of IO strategies in TME targeting, offering more effective and personalized treatment options for patients with GU cancers, thereby improving outcomes and quality of life.

Ubiquitin-specific protease 35 (USP35) has gained attention as a regulator in cancer progression. However, its specific role in kidney clear cell carcinoma (KIRC) remains unclear.

USP35 expression in KIRC tumor and normal tissues was evaluated using TCGA data. Correlations between USP35 expression, clinical parameters, and survival outcomes were examined. Functional enrichment analyses were performed to explore the pathways associated with USP35 expression. Immune-related analyses were conducted to assess the effect of USP35 on immune cell recruitment and neoantigen presentation. Drug sensitivity analyses were used to identify potential therapeutic agents targeting USP35.

USP35 was significantly overexpressed in KIRC tumor tissues compared to normal tissues, and its high expression correlated with advanced disease stages and poor survival outcomes. Gene set enrichment analysis revealed that high USP35 expression was associated with oncogenic pathways, including glycerophospholipid and linoleic acid metabolism, while low expression linked to nitrogen and purine metabolism. USP35 also modulated immune responses, affecting immune cell recruitment and neoantigen presentation, suggesting a role in immune evasion. Drug sensitivity analysis showed that high USP35 expression correlated with increased sensitivity to paclitaxel, bosutinib, and lapatinib. In vitro knockdown of USP35 significantly reduced KIRC cell proliferation, migration, and epithelial-mesenchymal transition (EMT), further supporting its role in tumor progression.

USP35 is overexpressed in KIRC and associated with poor prognosis, likely promoting tumor progression through oncogenic pathways and immune modulation. Its correlation with drug sensitivity positions USP35 as a potential therapeutic target, warranting further investigation into its mechanistic functions and therapeutic applications.

The numbers of tumor-infiltrating immune cells (TIICs) expressing programmed death (PD)-1 or PD-ligand 1 (PD-L1) reportedly predict prognosis and resistance to targeted drugs in clear cell renal cell carcinoma (ccRCC). The impact of local tumor microenvironment based on immunosuppressive TIICs on recurrence and prognosis has not been fully investigated in localized ccRCC.

A total of 105 patients with pT1b ccRCC were included. Immunostaining for PD-1 and PD-L1 were performed. PD-1-positive TIICs and PD-L1-positive TIICs were counted in the tumor periphery (TP) and the tumor nest (TN).

Patients with elevated PD-1-positive TIIC scores and those with elevated PD-L1-positive TIIC scores had significantly lower recurrence-free survival (RFS) rates than their counterparts (3-year RFS rates; patients with high vs. low PD-1-positive TIIC score of TN = 73.9% vs. 95.0%, those with high vs. low PD-1-positive TIIC score of TP = 73.8% vs. 93.8%, those with high vs. low PD-L1-positive TIIC score of TN = 70.9% vs. 93.0%, and those with high vs. low PD-L1-positive TIIC score of TP = 80.3% vs. 92.6%). Univariate analysis showed that high PD-1-positive scores, high PD-L1-positive scores, high PD-L1-positive tumor cell score, high-grade tumor, tumor necrosis, and lymphovascular invasion were significantly associated with RFS. Multivariate analysis revealed that tumor necrosis [hazard ratio (HR) = 2.841, P = .0269] and PD-1-positive TIIC score of TN (HR = 6.135, P = .0023) were independent risk factors for RFS. Risk stratification using the two factors efficiently predicts recurrence (3-year RFS rates: 96.4% with 0 factor, 83.8% with 1 factor, and 61.4% with 2 factors).

PD-1-positive TIIC score of TN and tumor necrosis may efficiently predict recurrence in pT1b ccRCC.

Avelumab + axitinib was approved for the treatment of advanced renal cell carcinoma (aRCC) in Japan in December 2019. We report long-term real-world subgroup analyses with first-line avelumab + axitinib in patients with aRCC by International Metastatic RCC Database Consortium (IMDC) risk classification from the J-DART2 study in Japan.

J-DART2 was a multicenter, noninterventional, retrospective study examining characteristics, treatment patterns, and outcomes in patients with aRCC who started first-line avelumab + axitinib in Japan between December 2019 and October 2022.

Data from 150 patients across 19 sites were analyzed. IMDC risk was favorable in 39 patients (26.0%), intermediate (1 risk factor) in 46 (30.7%), intermediate (2 risk factors) in 36 (24.0%), and poor in 29 (19.3%). Baseline characteristics were generally consistent across IMDC risk subgroups. In subgroups with favorable, intermediate (1 risk factor), intermediate (2 risk factors), and poor risk, median progression-free survival was 31.0, 15.3, 16.4, and 8.1 months; median overall survival (OS) was not reached, but 24-month OS rates were 95.2%, 91.3%, 85.3%, and 57.6%, respectively. Objective response rates were 54.5%, 56.8%, 47.1%, and 54.2%, respectively. High-dose corticosteroid treatment for immune-related adverse events was administered in 5.1%, 8.7%, 8.3%, and 6.9% of patients, respectively.

Subgroup analyses from J-DART2 confirm the long-term real-world effectiveness of first-line avelumab + axitinib across IMDC risk groups in patients with aRCC in Japan. Our findings were consistent with previous analyses by IMDC risk and support the favorable benefit-risk profile of avelumab + axitinib in clinical practice in Japan.