Geynisman, Daniel M.

The NCCN Clinical Practice Guidelines (NCCN Guidelines) for Wilms Tumor (WT; nephroblastoma) cover strategies for the screening, diagnosis, and treatment of WT, which is the most frequent primary kidney tumor in children. WT can generally be separated into 2 histology types: favorable histology WT and anaplastic WT. Five-year survival is high for children with favorable histology WT who receive appropriate treatment; however, survival rates are much lower for patients who present with higher stage diffuse anaplastic WT. Treatment of WT can range from surgery alone to surgery plus intensive chemotherapy and radiation depending on whether the tumor is unilateral or bilateral, histology, and local stage. The goal of therapy is to maximize cure while minimizing long-term toxicities. The content featured in this issue covers the NCCN panel’s recommendations for overall management of both favorable histology WT and anaplastic WT.

4568 Background: The 2IR immune response score was initially developed using bulk RNA sequencing of pre-treatment tissue from ImVigor 210 and CheckMate 275 trials, however these trials enrolled patients (pts) with pure urothelial carcinoma (pUC) histology. Patients with hsUC often exhibit worse response to immune checkpoint inibitors (ICI) than patients with pUC. Here, we evaluated the 2IR score as a prognostic or predictive biomarker in real-world pts with hsUC. Methods: Specimens from pts with pUC (n = 1677) and hsUC (n = 417) were profiled at Caris Life Sciences (Phoenix, AZ) using next generation sequencing (NGS) of DNA and RNA. HsUC histologies included majority ( > 50%) squamous (n = 340), sarcomatoid (n = 51), neuroendocrine (n = 20), and micropapillary (n = 6) component. 2IR was calculated by comparative RNA expression of 10 adaptive immune genes and 39 pro-tumorigenic genes. Tumors were classified as 2IR-Low (2IR ≤ -0.5), -Mid (-0.5 < 2IR < 0), and -High (2IR ≥ 0), as previously described (Wang et al., 2022). Spearman correlation analysis was utilized to compare 2IR with tumor mutation burden (TMB), interferon score (IFN) and the tumor microenvironment (TME) cell fractions estimated using quanTIseq. Clinical outcomes included real-world overall survival (rwOS) from ICI start to last contact and time on treatment (ToT) with pembrolizumab, obtained via matched insurance claims data and calculated using Kaplan-Meier methods, while Hazard ratio (HR) was calculated by Cox proportional model. Results: For patients with hsUC, distribution of 2IR score was High 5.76%, Mid 33.3%, and Low 60.9%. Median 2IR score was significantly lower in squamous (-0.60, p < 0.0001) and sarcomatoid UC (-0.82, p < 0.0001) compared to pUC (-0.41) and significantly higher in neuroendocrine UC (-0.15, p = 0.003). Among patients with hsUC, median rwOS was significantly longer for patients with high/mid 2IR score compared to low 2IR score (25.3 [10.9-39.3] months vs. 8.7 [6.2-11.3] months; HR 0.52, 95% CI 0.34 – 0.78, p = 0.0017). ToT with pembrolizumab was also significantly longer for high/mid 2IR score compared to low 2IR score (3.0 [1.4-5.5] months vs. 2.1 [1.4-3.3] months; HR 0.68, 95% CI 0.46-1.00, p = 0.0471). Similar to pUC, 2IR score in patients with squamous UC was positively associated with CD8 T cell infiltration (r = 0.39; p < 0.0001), IFN score (r = 0.41, p < 0.0001), and TMB (r = 0.20, p < 0.001) and negatively associated with M1 macrophage infiltration (r = -0.25, p < 0.0001). 2IR scores in hsUC correlated positively but not significantly with mutations in TP53 (Median: -0.59 vs -0.62, p = 0.067) and PIK3CA (Median: -0.56 vs -0.61, p = 0.172) and negatively with mutations in CDKN2A (Median: -0.67 vs -0.59, p = 0.052). Conclusions: In a real-world cohort of patients with hsUC, we show the 2IR score may be prognostic for rwOS and predictive for pembrolizumab ToT. Prospective studies are needed to further validate this biomarker for use in this population.

The NCCN Guidelines for Testicular Cancer provide recommendations for the multidisciplinary approach to the diagnostic workup, treatment, and follow-up for testicular germ cell tumors, including both seminoma and nonseminoma. These NCCN Guidelines Insights discuss the current treatment recommendations and supporting clinical data for seminomas as presented in Version 2.2025 of the NCCN Guidelines for Testicular Cancer.

4601 Background: Cretostimogene grenadenorepvec is a type-5 oncolytic adenovirus designed to selectively replicate in bladder cancer cells with alterations in the retinoblastoma pathway. Additionally, the virus is engineered to express the GM-CSF transgene, resulting in a potent oncolytic immunotherapy mode of action. Cretostimogene monotherapy recently received Food and Drug Administration (FDA) Fast Track and Breakthrough Therapy Designations (BTD) in the BCG-Unresponsive, High-Risk, non-Muscle Invasive Bladder Cancer with Carcinoma in Situ (BCG-UR HR NMIBC with CIS) indication with a Complete Response (CR) at any time rate of 76%. This phase-2 study assessed the potential synergy between intravesical cretostimogene and pembrolizumab in patients with BCG-UR, HR NMIBC, with CIS, with or without Ta/T1 tumors. This combination has also received BTD from the FDA. Methods: 35 pts were treated with cretostimogene (1x1012 viral particles) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. Cretostimogene induction was given as 6 weekly intravesical instillations followed by 3 weekly maintenance doses at months 3, 6, 9, 12, and 18. Pts with persistent CIS or high-grade Ta tumors at the 3mo assessment were eligible for re-induction. Pembrolizumab was administered for up to 24mo. Response assessments included cystoscopy, urine cytology, cross-sectional imaging, and mandatory bladder mapping biopsies at 12mo. The primary endpoint was CR at 12mo. Secondary endpoints included CR at any time, duration of response (DOR), CR at 24mo, cystectomy-free survival, and safety. Exploratory endpoints included analyses of baseline viral receptor expression, free E2F levels, PD-L1 status, urinary cytokine panels and measures of viral replication. Results: 30/35 pts are evaluable per protocol for the primary endpoint. Five pts discontinued prior to the 12mo time point. The CR rate in the Intention to Treat (ITT) population at 12mo and any time, was 57% (20/35) (95% CI 40-73%) and 83% (29/35) (95% CI 66-93%), respectively. Median DOR has not been reached but exceeds 21mo. The current CR rate in the ITT population at 24mo is 46% (16/35) (95% CI 29-63%). Three pts have yet to reach the 24mo time point. Cystectomy-free survival at 21mo is 80%. Complete data on the ITT and evaluable patient cohorts will be presented. Analyses of treatment-related adverse events (AE) are consistent with the individual agents and demonstrate no synergistic toxicity. Conclusions: The efficacy and safety of cretostimogene plus pembrolizumab for treatment of BCG-UR, HR NMIBC with CIS demonstrates best-in-class CR and DOR compared to current FDA-approved therapies, with an acceptable AE profile. Further investigation of this promising combination therapy is warranted and may serve to address a considerable unmet need. Clinical trial information: NCT04387461 .

LBA531 Background: Muscle-invasive urothelial carcinoma (MIUC) is an aggressive disease with high relapse rates. Neoadjuvant platinum-based chemotherapy (NAC) is the standard of care in patients (pts) who are cisplatin (Cis)-eligible. However, many pts are Cis-ineligible or have persistent muscle-invasive disease after NAC and surgery. We evaluated pembrolizumab (Pembro) as adjuvant therapy in pts with high-risk MIUC following surgical resection. Methods: The AMBASSADOR study is an open-label, randomized, phase III trial that enrolled pts with histologically confirmed MIUC of the bladder, upper tract, or urethra who (1) had ≥ pT2 and/or pN+ or margins+ at surgery (radical cystectomy, nephrectomy, nephroureterectomy, or ureterectomy) following NAC or (2) ≥ pT3 and/or pN+ or margins+ at surgery without NAC and were either Cis-ineligible or declined adjuvant Cis-based therapy. Pts were registered ≥4 to 16 weeks after surgery and randomized 1:1 to receive Pembro 200 mg every 3 weeks for 1 year or observation (Obs). Randomization was stratified by pathologic stage, centrally tested PD-L1 status, and prior NAC. The dual primary endpoints were disease-free survival (DFS) and overall survival (OS) with a target sample size of 739 pts and required 387 DFS and 320 OS events for final analysis. Secondary objectives included evaluation of DFS and OS in PD-L1-positive and -negative pts and assessing safety. Here we present the interim DFS and OS results. Results: Between 09/2017 and 08/2021 a total of 702 pts were randomized prior to early closure due to US FDA approval of nivolumab for MIUC pts: 354 pts to Pembro and 348 pts to Obs; 13.0% vs 21.6% withdrew from study without event in the Pembro vs Obs arms, respectively. 74 pts (21%) in the Obs arm received an immune checkpoint inhibitor. Median follow-up was 22.3 months (mos) for DFS and 36.9 mos for OS. The DFS endpoint (based on 319 events needed for interim analysis) crossed the efficacy boundary. Median DFS was 29.0 months (95% confidence interval (CI) 21.8‒not evaluable (NE)) with Pembro and 14.0 months (95% CI 9.7‒20.20) with Obs (hazard ratio (HR) 0.69 [95% CI 0.55–0.87]; p=0.0013). At the interim analysis (n = 257 events), median OS was 50.9 months (95% CI 43.9‒NE) with Pembro and 55.8 months (95% CI 53.3‒NE) with Obs (HR 0.98 [95% CI 0.76–1.26]; p=0.88). Grade 3+ adverse events occurred in 48.4% and 31.8% of pts in the Pembro and Obs arms, respectively. Conclusions: Adjuvant Pembro demonstrated a statistically significant and clinically meaningful improvement in DFS vs Obs for high-risk MIUC pts after radical surgery. The OS endpoint may have been impacted by pts on the Obs arm receiving a checkpoint inhibitor. Pembro was tolerable with no new safety signals. These results support adjuvant Pembro as a new therapeutic option for pts with MIUC with high risk for recurrence. Additional follow-up is ongoing for the final DFS/OS, PD-L1 subgroups, and ctDNA analyses. Clinical trial information: NCT03244384 .

AbstractBackgroundThe VESPER trial demonstrated improved progression‐free (PFS) and (preliminarily) overall survival (OS) with six cycles of neoadjuvant dose‐dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVACx6) versus four cycles of gemcitabine and cisplatin (GCx4) before radical cystectomy (RC) for muscle‐invasive bladder cancer (MIBC), but with increased toxicity. This study compares the cost‐effectiveness of these regimens.MethodsA cost‐effectiveness analysis of neoadjuvant ddMVACx6 and GCx4 was performed using a decision‐analytic Markov model with 5‐year, 10‐year, and lifetime horizons. Probabilities were derived from reported VESPER data. Utility values were obtained from the literature. Primary outcomes were effectiveness measured in quality‐adjusted life years (QALY) and incremental cost‐effectiveness ratio (ICER) with a willingness to pay threshold of $100,000 per QALY. One‐way and probabilistic sensitivity analyses were performed to evaluate the robustness of the model.ResultsAt 5 years, ddMVACx6 improved QALYs by 0.30 at an additional cost of $16,100, rendering it cost‐effective relative to GCx4 (ICER: $53,284/QALY). Additionally, probabilistic sensitivity analysis found ddMVACx6 to be cost‐effective in 79% and 81% of microsimulations at10‐year and lifetime horizons, respectively. One‐way sensitivity analysis demonstrated a minimum difference in 5‐year progression of 0.9% and progression mortality of 0.7% between ddMVACx6 and GCx4 was necessary for ddMVACx6 to remain cost‐effective.ConclusionsNeoadjuvant ddMVACx6 was more cost‐effective than GCx4 for MIBC. These data, together with the improved PFS and (albeit preliminary) OS noted in VESPER, support use of this regimen in appropriate candidates for neoadjuvant chemotherapy before RC.Lay summary We performed a benefit‐to‐cost analysis using evidence from a randomized controlled trial that compared two different chemotherapy treatments before bladder removal for bladder cancer that had invaded into the bladder muscle. Despite being more expensive and having a greater likelihood of toxicity, six cycles of dose‐dense methotrexate, vinblastine, doxorubicin, and cisplatin was more cost‐effective (or had higher value) than four cycles of gemcitabine and cisplatin.

Testicular cancer is relatively uncommon and accounts for <1% of all male tumors. However, it is the most common solid tumor in men between the ages of 20 and 34 years, and the global incidence has been steadily rising over the past several decades. Several risk factors for testicular cancer have been identified, including personal or family history of testicular cancer and cryptorchidism. Testicular germ cell tumors (GCTs) comprise 95% of malignant tumors arising in the testes and are categorized into 2 main histologic subtypes: seminoma and nonseminoma. Although nonseminoma is the more clinically aggressive tumor subtype, 5-year survival rates exceed 70% with current treatment options, even in patients with advanced or metastatic disease. Radical inguinal orchiectomy is the primary treatment for most patients with testicular GCTs. Postorchiectomy management is dictated by stage, histology, and risk classification; treatment options for nonseminoma include surveillance, systemic therapy, and nerve-sparing retroperitoneal lymph node dissection. Although rarely occurring, prognosis for patients with brain metastases remains poor, with >50% of patients dying within 1 year of diagnosis. This selection from the NCCN Guidelines for Testicular Cancer focuses on recommendations for the management of adult patients with nonseminomatous GCTs.