Standard first-line treatment for patients with advanced renal cell carcinoma (aRCC) has commonly included combined immune-oncology (IO) agents (IO-IO) or combinations of a tyrosine kinase inhibitor (TKI) and an IO agent (IO-TKI); however, there are few head-to-head comparative real-world studies, especially involving Japanese cohorts. To compare prognoses of patients treated with IO-IO or IO-TKI therapy in routine Japanese clinical practice. This retrospective study included 416 International Metastatic RCC Database Consortium (IMDC) intermediate- and poor-risk patients with aRCC treated with either IO-IO or IO-TKI at four institutions from September 2018 to February 2026. Effectiveness and safety outcomes were comprehensively compared. Overall (OS) and progression-free survival (PFS) rates were estimated with the Kaplan-Meier method. We used propensity-score matching to compare 324 patients (IO-IO: 162; IO-TKI: 162). The IO-TKI cohort showed significantly higher objective response rates than the IO-IO cohort (66 versus 44%, respectively, p < 0.01), longer PFS (17.1 versus 8.4 months, respectively, HR = 0.56, p < 0.01), and longer OS (51.7 versus 31.5 months, respectively, HR = 0.70, p = 0.04), although OS did not reach significance in the IMDC risk-stratified subgroups. While all-grade adverse events (AEs) were more common in the IO-TKI group (94 versus 83%, respectively, p < 0.01), rates of immune-related AEs and corticosteroid administration were significantly higher in the IO-IO cohort. The study limitations include the retrospective design and treatment strategy solely decided by each physician. IO-TKI combinations were associated with higher rates of adverse events but survival benefits in IMDC intermediate- and poor-risk patients with aRCC.

Infusion-related reactions (IRRs) to immune checkpoint inhibitors (ICIs) have been reported in up to 20% of administrations, but the incidence varies among ICIs. We aimed to report and compare the incidence of IRRs among each ICI therapy. We searched PubMed/MEDLINE, Embase, and Web of Science to identify phase 3 randomized controlled trials (RCTs) evaluating ICIs (CTLA-4, PD-1, PD-L1, and LAG-3 inhibitors) in solid tumors. We performed a random-effects model network meta-analysis to compare the odds ratios (ORs) of IRRs by using RCTs comparing dual ICIs, ICI monotherapy, and placebo/observation. A proportional meta-analysis was also performed to pool the incidence of IRRs of ICI monotherapy and dual ICIs. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) registry (CRD42023433659). Overall, 40,872 patients from 61 phase 3 RCTs were included in the analysis. Proportional meta-analyses revealed that the pooled incidence of treatment-related IRRs was 2.31% for PD-1 inhibitors, 8.27% for PD-L1 inhibitors (avelumab: 13.53%, non-avelumab: 1.79%), 5.70% for PD-1 plus LAG-3 inhibitors, 5.55% for PD-1 plus CTLA-4 inhibitors, and 1.79% for CTLA-4 inhibitors. A network meta-analysis of treatment-related IRRs, including 12 RCTs, showed that avelumab (OR 79.26, 95% confidence interval [CI]: 4.84-1297.49) and atezolizumab (OR 43.99, 95% CI 2.65-729.89) had a significantly higher risk of treatment-related IRRs compared with placebo/observation. Network ranking revealed that avelumab, atezolizumab, and relatlimab plus nivolumab had the greatest risk of treatment-related IRRs. Avelumab has the highest risk of IRRs followed by atezolizumab and dual ICIs. This comparative study provides insight into the incidence of IRRs with ICI regimens. These results are useful in assessing which systemic therapies are responsible for IRRs, particularly when ICIs are combined with other agents.

Currently, data concerning the prognostic impact of metastatic sites in biliary tract cancers (BTC) are limited. The aim of the present study is to evaluate the prognostic impact of metastatic sites in patients with BTC treated with cisplatin-gemcitabine-durvalumab (CGD). The study population comprised a large worldwide cohort of patients treated with CGD. The primary objectives were overall survival (OS) and progression-free survival (PFS) based on the location and number of metastatic sites. A total of 666 patients with locally advanced (111) or metastatic (555) BTC treated with CGD were included in the study. None of the metastatic sites were shown to have a prognostic impact on OS at multivariate analysis. Patients with one to two metastatic sites had longer OS (hazard ratio [HR] 0.59; p = 0.005) and PFS (HR 0.73; p = 0.03) compared with those with three to five metastatic sites in the univariate analysis but not in the multivariate analysis. No statistically significant differences were observed in OS or PFS across different metastatic sites limited to a single organ. Patients with progressive disease (PD) on first-line CGD with a change in metastatic sites from baseline showed no statistically significant differences in OS2 (defined as the time from PD on first-line therapy to death for any cause) compared with those without a change in metastatic sites (HR 0.88; p = 0.60). Our study did not show statistically significant differences in outcomes associated with location and number of metastatic sites in a large population of patients with BTC treated with CGD.

Adavosertib is a highly selective, small molecule Wee1 inhibitor that sensitizes tumor cells to cytotoxic agents. We report results from the lead-in cohorts of two phase II studies: carboplatin/pemetrexed plus adavosertib versus carboplatin/pemetrexed in first-line metastatic non-squamous non-small-cell lung cancer (NSCLC) (NCT02087241); and docetaxel plus adavosertib versus docetaxel in recurrent NSCLC (NCT02087176). Both lead-in cohorts assessed early safety and efficacy (objective response rate [ORR]). First-line metastatic treatment was carboplatin (area under the curve to 6 h [AUC6]) plus pemetrexed 500mg/m2 intravenously on day 1, every 21 days; recurrent treatment was docetaxel 75mg/m2 intravenously on day 1 plus prophylactic granulocyte-colony stimulating factor 6mg subcutaneously on day 4 every 21 days. All patients received adavosertib 225mg twice daily orally on days 1-3 (five doses). After a planned safety analysis of the first-line trial, dose and schedule were modified to reduce toxicity. First-line: 14 patients were enrolled in four treatment cohorts. Median time on trial was 17.3 weeks, with an ORR of 29%. The most common adverse events were diarrhea (50%), nausea (50%), vomiting (50%), anemia (43%), neutropenia (43%), decreased appetite (43%), and dehydration (43%). Recurrent: 32 patients were enrolled. The ORR was 9%. The most common adverse events were diarrhea (66%), anemia (50%), nausea (47%), fatigue (47%), vomiting (44%),and thrombocytopenia (41%). Both studies terminated early; the recurrent study after an interim analysis showed increased toxicity and limited efficacy, and the first-line study after a change in first-line standard of care. ClinicalTrials.gov, NCT02087241 and NCT02087176.

Metastatic castration-resistant prostate cancer (mCRPC) presents a challenge for clinicians in determining the optimal treatment sequence because of the lack of direct head-to-head comparisons, which is further complicated by the now-widespread use of androgen receptor pathway inhibitors (ARPIs) in metastatic hormone-sensitive prostate cancer (mHSPC). This study is a Bayesian network meta-analysis (NMA) intended to provide a comprehensive evaluation and comparison of the efficacy of mCRPC treatments across different treatment lines. We performed a systematic search of ClinicalTrials.gov, extracted information, assessed the risk of bias, and reconstructed missing outcomes. We performed an NMA to evaluate treatment efficacy for overall survival (OS) and progression-free survival (PFS) in first and subsequent lines. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) NMA guidelines and was registered with PROSPERO (CRD42024499607). The NMA included 43 trials with 33,494 patients. ARPI-based therapies, particularly in combination with poly(ADP-ribose) polymerase inhibitors, demonstrated the most significant benefits for OS and PFS in first-line mCRPC treatment, followed by chemotherapy regimens. However, ARPI re-treatment showed limited effectiveness in subsequent lines, leading to weaker OS and PFS benefits. This NMA highlights the superiority of ARPI-based therapiesand chemotherapies as first-line options for mCRPC while emphasizing the need for treatment class switching after ARPI failure. To refine treatment sequencing and enable precision care, future research should integrate individual participant data to better address patient-level heterogeneity and identify biomarkers for personalized therapy.

Tinurilimab is a humanized immunoglobulin G subclass 2 antibody that blocks carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), an immune checkpoint regulator that is overexpressed in several tumor types. This phase I study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and tumor response profile of tinurilimab in patients with advanced solid tumors with a described expression of CEACAM6. In this first-in-human, dose-escalation and dose-expansion study, tinurilimab was administered as a 1-h intravenous infusion in 21-day cycles at a starting dose of 2.5mg, with a planned escalation up to 1800mg. Following observation of treatment toxicity (cytokine release syndrome in one patient and neutropenia in all patients treated at 30mg), a premedication regimen was initiated that included dexamethasone 8mg before and after dosing. Thirty patients received treatment across six dosing cohorts (2.5-100 mg with or without dexamethasone). The maximum tolerated dose was not determined, as the study was terminated due to an unfavorable benefit/risk assessment. All 30 patients (100%) treated with tinurilimab experienced at least one treatment-emergent adverse event of any grade, most commonly fatigue (36.7%), infusion-related reaction (30.0%), and neutropenia (26.7%). The most common grade≥3 treatment-related adverse events were neutropenia (23.3%), followed by febrile neutropenia, cytokine release syndrome, increased hepatic enzymes, decreased lymphocyte count, hypophosphatemia, lactic acidosis, and acute kidney injury (3.3% each). No patients reported an objective response. Following study termination, the clinical development program for tinurilimab was discontinued permanently. www. gov , NCT03596372.

Relugolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, has been established as an effective androgen deprivation therapy (ADT) for advanced prostate cancer, offering advantages over traditional GnRH agonists. The combination of relugolix with androgen receptor pathway inhibitors (ARPIs) is increasingly utilized in clinical practice, necessitating an understanding of its pharmacokinetics, efficacy, safety, and drug-drug interactions. This review explores the real-world data and clinical studies evaluating relugolix coadministration with ARPIs, including enzalutamide, abiraterone, apalutamide, and darolutamide. Pharmacokinetic interactions, particularly via the CYP3A4 enzyme system and P-glycoprotein (P-gp) transporter, influence drug exposure and, in theory, necessitate dose adjustments in certain combinations. However, clinical studies and real-world studies suggest that relugolix maintains testosterone suppression when combined with ARPIs even if administered in a standard dose. While these findings support the efficacy and safety of relugolix-based combination therapy, further large-scale prospective trials are needed to refine treatment recommendations and provide information on long-term outcomes.

Metastatic castration-resistant prostate cancer (mCRPC) patients with BRCA1/2 mutations show significant responses to poly-ADP ribose polymerase inhibitors (PARPi), while the efficacy of these agents in patients with homologous recombination repair (HRR) gene alterations other than BRCA remains unclear. This meta-analysis aimed at assessing the efficacy of PARPi in mCRPC harboring alterations in four rare HRR genes (i.e. CDK12, PALB2, ATM, and CHEK2). Five randomised phase III trials (PROfound, PROpel, MAGNITUDE, TALAPRO-2, TRITON3) were selected through searching the Medline/PubMed, Cochrane Library, and ASCO Meeting abstracts. Data extraction followed the PRISMA statement. The primary endpoints, radiographic progression-free survival (rPFS) and overall survival (OS) with the relative 95% CI, were calculated using fixed- or random-effects methods, depending on the studies' heterogeneity. RevMan software for meta-analysis (v.5.2.3) was used. PARPi significantly improved rPFS in mCRPC patients with CDK12 alterations (hazard ratio (HR) = 0.65; p = 0.02) without OS benefit. In patients with ATM, CHEK2, or PALB2 alterations, no significant benefit was observed in rPFS or OS. Due to the low incidence of these rare mutations, we grouped them into gene panels, revealing a significant rPFS advantage when CDK12+PALB2 (HR = 0.63; p = 0.009) were combined, and a similar benefit when including CHEK2 in the gene panel (HR = 0.69; p = 0.01). CDK12 alterations could be considered as a predictive biomarker of rPFS benefit with PARPi. A gene panel grouping CDK12 and PALB2 with or without CHEK2 mutations could also enable prediction of rPFS benefit with PARPi.

The treatment of renal cell carcinoma (RCC), a malignancy that is typically chemoresistant, has drastically evolved with the introduction of vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) and immune checkpoint inhibitors (ICIs). The introduction of ICI-based regimens has significantly improved outcomes for patients with metastatic RCC. Currently, first-line therapy for patients with metastatic RCC involves multiple ICI-based regimens, either dual ICIs (with anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA- 4) and anti-programmed cell death- 1 (PD- 1) therapies) or anti-PD- 1 therapy in combination with VEGFR TKIs. Despite improving patient outcomes with ICI-based regimens, durable responses remain uncommon, highlighting the need for innovative treatment strategies. In this review, we highlight the current standard of care ICI-based regimens followed by ongoing clinical trials with novel combinations of existing FDA-approved agents and targets. We also discuss novel immunotherapies currently in clinical trials, which aim to improve antitumor T cell immunity either by improving T cell activation or T cell navigation to the tumor microenvironment. The incorporation of these novel therapies offers the potential to improve RCC patient outcomes, particularly by enhancing the durability of treatment responses.