Survival Outcomes in Patients With Muscle-Invasive Bladder Cancer Receiving Neoadjuvant Chemotherapy Stratified by Number of Cycles.

INTRODUCTION: The ≥3 cycles of neoadjuvant cisplatin-based chemotherapy (NAC) are commonly administered to treat MIBC. However, some patients are unable to complete all planned cycles of NAC. Prognosis of patients receiving <3 cycles of NAC has yet to be elucidated. METHODS: This retrospective single-center study quantifies pathologic complete response (pT0N0), recurrence-free survival (RFS), and 5-year overall survival (OS) in patients treated with <3 cycles of NAC compared to ≥3 cycles. Patients with MIBC between 2004 and 2018 receiving at least 1 cycle of cisplatin-based NAC were included. Exclusion criteria were metastasis before initiation of NAC, progression/death during NAC. Patient characteristics were compared using chi-square tests, Fisher's exact tests, and Wilcoxon rank sum tests. Kaplan Meier curves, log-rank tests, and Cox proportional hazards models compared RFS adjusting for patient age, ECOG status, GFR, stage, node positivity, and NAC regimen. 5-year OS was analyzed via logistic regression with the aforementioned patient characteristics in the cohort of patients with 5 years of follow-up, unless deceased prior. RESULTS: In a cohort of 256 patients, the median RFS was 11.6 months (95% CI 7.79, 28.5) versus 79.5 months (95% CI 62.13, NA) in those receiving ≥3 cycles of NAC. Of 228 patients with documented pathologic stage, complete pathologic response (pT0) was observed in 9.4% of patients receiving <3 cycles, and 27.0% of patients receiving ≥3 cycles of NAC (P = .008). In 195 patients with a minimum of 5 years of follow-up, patients with <3 cycles the 5-year OS was 13.3% with <3 cycles compared to 53.3% with ≥3 cycles of NAC. CONCLUSIONS: In this retrospective, single-center investigation, early cessation of planned NAC was associated with worse pCR rate, RFS, and OS. While further prospective evaluation is required to confirm causality, clinicians should prioritize administering at least 3 cycles of NAC when feasible to optimize outcomes.

Identification and Validation of Prognostic Model for Tumor Microenvironment-Associated Genes in Bladder Cancer Based on Single-Cell RNA Sequencing Data Sets.

PURPOSE: The purpose of this study was to elucidate the relationship between the tumor microenvironment (TME) and cellular diversity in bladder cancer (BLCA) progression, leveraging single-cell RNA sequencing (scRNA-seq) data to identify potential prognostic biomarkers and construct a prognostic model for BLCA. METHODS: We analyzed scRNA-seq data of normal and tumor bladder cells from the Gene Expression Omnibus (GEO) database to uncover crucial markers within the bladder TME. The study compared gene expression in normal versus tumor bladder cells, identifying differentially expressed genes. These genes were subsequently assessed for their prognostic significance using patient follow-up data from The Cancer Genome Atlas. Prognostic models were constructed using Least Absolute Shrinkage and Selection Operator and multivariate Cox regression analyses, focusing on eight genes of interest. The predictive performance of the model was also tested against additional GEO data sets (GSE31684, GSE13507, and GSE32894). RESULTS: The prognostic model demonstrated reliable prediction of patient outcomes. Validation through gene set enrichment analysis and immune cell infiltration assessment supported the model's efficacy. The results from both the univariate and multivariate analyses suggest that the risk score is an independent prognostic factor with a hazard ratio of 2.97 (95% CI, 2.28 to 3.9, P < .001). In the validation cohort, the AUC at 1, 2, and 3 years is 0.74, 0.74, and 0.72, respectively. CONCLUSION: Our findings proposed biomarkers with prognostic potential, laying the groundwork for future in vitro validation and therapeutic exploration. This contributes to a deeper understanding of the genes associated with bladder TME and may improve prognostic precision in BLCA management.

Epacadostat plus pembrolizumab versus placebo plus pembrolizumab for advanced urothelial carcinoma: results from the randomized phase III ECHO-303/KEYNOTE-698 study.

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) levels correlate with poor outcomes in urothelial carcinoma (UC). IDO1 and programmed death-ligand 1 (PD-L1) are often co-expressed. Epacadostat is a potent and highly selective inhibitor of IDO1. In a subgroup analysis of patients with advanced UC participating in a phase I/II study, epacadostat-pembrolizumab treatment produced an objective response rate (ORR) of 35%. METHODS: ECHO-303/KEYNOTE-698 was a double-blinded, randomized phase III study of adults with metastatic or unresectable locally advanced UC with recurrence or progression following first-line platinum-based chemotherapy. Participants were randomized to epacadostat 100 mg twice daily (BID) plus pembrolizumab or placebo plus pembrolizumab until completion of 35 pembrolizumab infusions, disease progression, or unacceptable toxicity. The primary endpoint was investigator-assessed ORR per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Target enrollment was 648 patients; enrollment was halted early based on efficacy results from the phase III ECHO-301/KEYNOTE-252 study in metastatic melanoma. Forty-two patients were randomized to each treatment arm. Median duration of follow-up was 62 days in each arm. The investigator-assessed ORR (unconfirmed) was 26.2% (95% CI 16.35-48.11) for epacadostat plus pembrolizumab and 11.9% (95% CI 4.67-29.50) for placebo plus pembrolizumab. Two complete responses were reported, both in the placebo-plus-pembrolizumab arm. Circulating kynurenine levels increased from C1D1 to C2D1 in the placebo-plus-pembrolizumab arm and numerically decreased in the epacadostat-plus-pembrolizumab arm. The safety profile of epacadostat plus pembrolizumab was similar to that of pembrolizumab monotherapy, although a numerically greater proportion of patients in the combination vs. control arm experienced treatment-related grade ≥ 3 adverse events (16.7% vs. 7.3%). One patient in each arm died due to cardiovascular events, which were not deemed drug-related. No new safety concerns were identified for either agent. CONCLUSIONS: Epacadostat plus pembrolizumab demonstrated anti-tumor activity and was generally tolerable as second-line treatment of patients with unresectable locally advanced or recurrent/progressive metastatic UC. Epacadostat 100 mg BID, when administered with pembrolizumab, did not normalize circulating kynurenine in most patients. Further study of combined IDO1/PD-L1 inhibition in this patient population, particularly with epacadostat doses that result in durable normalization of circulating kynurenine, may be warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03374488. Registered 12/15/2017.

Correlative Analysis of ATM, RB1, ERCC2, and FANCC Mutations and Pathologic Complete Response After Neoadjuvant Chemotherapy in Patients with Muscle-invasive Bladder Cancer: Results from the SWOG S1314 Trial.

We previously reported that tumors harboring any one of four gene mutations (ATM, RB1, FANCC, or ERCC2) were likely to respond to neoadjuvant cisplatin-based chemotherapy (NAC), resulting in cancer-free surgical specimens at the time of cystectomy (pT0). Here, we report our validation of this finding. Using the CARIS 592 Gene Panel (Caris Life Sciences, Phoenix, AZ, USA), we analyzed 105 pre-NAC tumor specimens from a large multicenter trial (S1314) of either neoadjuvant gemcitabine and cisplatin (GC), or dose-dense methotrexate, vinblastine, Adriamycin, and cisplatin (DDMVAC). We found that a mutation in any one of these four genes predicted for pT0 at surgery (odds ratio = 5.36; 95% confidence interval [CI] 2.05, 14.02; two-sided p = 0.0006). The biomarker was better at predicting the presence of disease (negative predictive value for pT0 86%; 95% CI 73%, 94%) than the absence of disease (positive predictive value for pT0 48%; 95% CI 35%, 62%). There was no evidence of an interaction between the treatment arm (DDMVAC vs GC) and the genetic variant in terms of pT0. When combined with clinical assessment, these findings help inform patient selection for bladder preservation after cisplatin-based chemotherapy.

Treatment-free survival and partitioned survival analysis of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib: 5-year update of CheckMate 214.

BACKGROUND: Immunotherapy can be associated with prolonged disease control even after cessation of treatment without the need for further cancer-directed therapy. Treatment-related adverse events (TRAEs) can also persist after discontinuation of therapy. Treatment-free survival (TFS) with and without toxicity as a component of a partitioned survival model can characterize patient survival time, which is not captured by standard outcome measures. METHODS: Data from 1096 patients with advanced renal cell carcinoma treated with first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the CheckMate 214 trial were analyzed. TFS was defined as the area between two Kaplan-Meier curves for time from randomization to protocol therapy discontinuation and time from randomization to subsequent systemic therapy initiation or death, estimated as the difference in 60-month restricted mean times with confidence intervals (CIs) obtained using bootstrap sampling. Time on protocol therapy and TFS were further characterized as time with and without grade 2+ and 3+TRAEs. Survival functions were estimated in subgroups including International Metastatic Renal Cell Carcinoma Database Consortium risk groups using the Kaplan-Meier method. RESULTS: At 5 years from randomization, 48% of patients treated with NIVO+IPI and 37% of patients treated with SUN were alive. In the intent-to-treat population, 18% of the NIVO+IPI-treated and 5% of SUN-treated patients are surviving treatment-free. For favorable-risk patients, the 60-month mean TFS was 14.4 months for NIVO+IPI versus 5.5 months for SUN (difference 8.9 months (95% CI 4.9 to 12.8)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 5.0 and 2.1 months, respectively, and with grade 3+TRAEs was 1.2 and 0.3 months, respectively. For intermediate/poor-risk patients, the 60-month mean TFS was 10.1 months for NIVO+IPI versus 4.1 months for SUN (difference 6.1 months (95% CI 4.2 to 7.9)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 4.0 versus 2.0 months, respectively, and 0.6 versus 0.3 months with grade 3+TRAEs. CONCLUSIONS: Although overall survival was similar, favorable-risk patients treated with NIVO+IPI spent more time surviving treatment-free with and without toxicity versus SUN after 60 months of follow-up. Intermediate/poor-risk patients treated with NIVO+IPI had longer survival and longer TFS without toxicity versus SUN. TRIAL REGISTRATION NUMBER: NCT02231749.

Urine Biopsy as Dynamic Biomarker to Enhance Clinical Staging of Bladder Cancer in Radical Cystectomy Candidates.

PURPOSE: There is significant interest in identifying complete responders to neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) to potentially avoid removal of a pathologically benign bladder. However, clinical restaging after NAC is highly inaccurate. The objective of this study was to develop a next-generation sequencing-based molecular assay using urine to enhance clinical staging of patients with bladder cancer. METHODS: Urine samples from 20 and 44 patients with bladder cancer undergoing RC were prospectively collected for retrospective analysis for molecular correlate analysis from two clinical trials, respectively. The first cohort was used to benchmark the assay, and the second was used to determine the performance characteristics of the test as it correlates to responder status as measured by pathologic examination. RESULTS: First, to benchmark the assay, known mutations identified in the tissue (MT) of patients from the Accelerated Methotrexate, Vinblastine, Doxorubicin, Cisplatin trial (ClinicalTrials.gov identifier: NCT01611662, n = 16) and a cohort from University of California-San Francisco (n = 4) were cross referenced against mutation profiles from urine (MU). We then determined the correlation between MU persistence and residual disease in pre-RC urine samples from a second prospective clinical trial (The pT0 trial; ClinicalTrials.gov identifier: NCT02968732). Residual MU status correlated strongly with residual disease status (pT0 trial; n = 44; P = .0092) when MU from urine supernatant and urine pellet were assessed separately and analyzed in tandem. The sensitivity, specificity, PPV, and NPV were 91%, 50%, 86%, and 63% respectively, with an overall accuracy of 82% for this second cohort. CONCLUSION: MU are representative of MT and thus can be used to enhance clinical staging of urothelial carcinoma. Urine biopsy may be used as a reliable tool that can be further developed to identify complete response to NAC in anticipation of safe RC avoidance.

NCCN Guidelines® Insights: Bladder Cancer, Version 3.2024.

Bladder cancer, the sixth most common cancer in the United States, is most commonly of the urothelial carcinoma histologic subtype. The clinical spectrum of bladder cancer is divided into 3 categories that differ in prognosis, management, and therapeutic aims: (1) non-muscle-invasive bladder cancer (NMIBC); (2) muscle invasive, nonmetastatic disease; and (3) metastatic bladder cancer. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Bladder Cancer, including changes in the fifth edition of the WHO Classification of Tumours: Urinary and Male Genital Tumours and how the NCCN Guidelines aligned with these updates; new and emerging treatment options for bacillus Calmette-Guérin (BCG)-unresponsive NMIBC; and updates to systemic therapy recommendations for advanced or metastatic disease.

Role of Gut Microbiome in Neoadjuvant Chemotherapy Response in Urothelial Carcinoma: A Multi-institutional Prospective Cohort Evaluation.

Neoadjuvant chemotherapy (NAC) is linked with clinical advantages in urothelial carcinoma for patients with muscle-invasive bladder cancer (MIBC). Despite comprehensive research into the influence of tumor mutation expression profiles and clinicopathologic factors on chemotherapy response, the role of the gut microbiome (GM) in bladder cancer chemotherapy response remains poorly understood. This study examines the variance in the GM of patients with bladder cancer compared with healthy adults, and investigates GM compositional differences between patients who respond to chemotherapy versus those who exhibit residual disease.Our study reveals distinct clustering, effectively separating the bladder cancer and healthy cohorts. However, no significant differences were observed between chemotherapy responders and nonresponders within community subgroups. Machine learning models based on responder status outperformed clinical variables in predicting complete response (AUC 0.88 vs. AUC 0.50), although no single microbial species emerged as a fully reliable biomarker.The evaluation of short chain fatty acid (SCFA) concentration in blood and stool revealed no correlation with responder status. Still, SCFA analysis showed a higher abundance of Akkermansia (rs = 0.51, P = 0.017) and Clostridia (rs = 0.52, P = 0.018), which correlated with increased levels of detectable fecal isobutyric acid. Higher levels of fecal Lactobacillus (rs = 0.49, P = 0.02) and Enterobacteriaceae (rs = 0.52, P < 0.03) correlated with increased fecal propionic acid.In conclusion, our study constitutes the first large-scale, multicenter assessment of GM composition, suggesting the potential for a complex microbial signature to predict patients more likely to respond to NAC based on multiple taxa. SIGNIFICANCE: Our study highlights results that link the composition of the GM to the efficacy of NAC in MIBC. We discovered that patients with higher levels of Bacteroides experienced a worse response to NAC. This microbial signature shows promise as a superior predictor of treatment response over traditional clinical variables. Although preliminary, our findings advocate for larger, more detailed studies to validate these associations.

Validation of the Lung Immune Prognostic Index (LIPI) as a prognostic biomarker in metastatic renal cell carcinoma.

BACKGROUND: The Lung Immune Prognostic Index (LIPI) is associated with immune checkpoint inhibitors (ICI) outcomes across different solid tumors, particularly in non-small cell lung cancer. Data regarding the prognostic and/or predictive role of LIPI in metastatic renal cell carcinoma (mRCC) are still scarce. The aim of this study was to evaluate whether LIPI could be predictive of survival in mRCC patients. METHODS: We used patient level data from three different prospective studies (NIVOREN trial: nivolumab; TORAVA trial: VEGF/VEGFR-targeted therapy (TT); CheckMate 214: nivolumab-ipilimumab vs sunitinib). LIPI was calculated based on a derived neutrophils/(leukocyte-neutrophil) ratio > 3 and lactate-dehydrogenase >upper limit of normal, classifying patients into three groups (LIPI good, 0 factors;LIPI intermediate (int), 1 factor;LIPI poor, 2 factors) and/or into two groups (LIPI good, 0 factors;LIPI int/poor, 1-2 factors) according to trial sample size. Primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: In the Nivolumab dataset (n = 619), LIPI was significantly associated with OS (LIPI-good 30.1 vs 13.8 months in the LIPI int/poor; HR= 0.47) and PFS (HR=0.74). In the VEGF/VEGFR-TT dataset (n = 159), only a correlation with PFS was observed. In the CheckMate214 dataset (n = 1084), LIPI was significantly associated with OS (nivolumab-ipilimumab OS LIPI good vs int/poor: HR=0.55, p < 0.0001; sunitinib: OS LIPI good vs int/poor: 0.38, p < 0.0001) in both treatment groups in univariate and multivariate analysis. CONCLUSIONS: Pretreatment-LIPI correlated with worse survival outcomes in mRCC treated with either ICI or antiangiogenic therapy, confirming LIPI's prognostic role in mRCC irrespective of systemic treatment used.

Treatment-free survival outcomes from the phase II study of nivolumab and salvage nivolumab/ipilimumab in advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A).

BACKGROUND: As part of a partitioned survival analysis, treatment-free survival (TFS) can characterize the overall survival time patients spend between the cessation of immunotherapy and the start of subsequent therapy; both with and without toxicity. Significant TFS was reported for the nivolumab/ipilimumab arms of the CheckMate 067 and 214 trials for patients with advanced melanoma or renal cell carcinoma (aRCC), respectively, where immunotherapy was often halted for toxicity rather than a predefined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16-260 trial, which was designed to reduce toxicity and cap immunotherapy duration. METHODS: Data were analyzed from 128 patients with clear-cell aRCC treated with first-line nivolumab monotherapy for up to 2 years. Salvage nivolumab/ipilimumab for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (29% of patients). TFS was defined as the area between Kaplan-Meier curves for a time from registration to protocol therapy cessation and for a time from registration to subsequent systemic therapy initiation or death, estimated from 36-month mean times. The time on or off protocol treatment with grade 3+treatment-related adverse events (TRAEs) was also captured. RESULTS: At 36 months from enrollment, 68.3% of patients were alive: 96.8% of International Metastatic RCC Database Consortium (IMDC) favorable-risk patients and 56.6% of those with intermediate/poor-risk, respectively. The 36-month mean time on protocol therapy was 11.5 months including 0.6 months with grade 3+TRAEs (16.0 months for favorable-risk patients and 9.6 months for intermediated/poor-risk patients). The 36-month mean TFS for the whole population was 9.4 months (12.9 months including 1.5 months with grade 3+TRAEs for favorable-risk and 8.0 months including 1.0 months with grade 3+TRAEs for intermediate/poor-risk). At 36 months, 65.6% of favorable-risk patients and 27.1% of intermediate/poor-risk patients were alive and subsequent systemic treatment-free. CONCLUSIONS: Nivolumab monotherapy with salvage nivolumab/ipilimumab in non-responders is an active treatment approach in treatment-naïve patients with aRCC and, similar to nivolumab/ipilimumab in CheckMate 214, results in substantial TFS and toxicity-free TFS. TFS was greatest in patients with favorable-risk disease, supporting the use of an immunotherapy-only regimen in this population.

Phase I LITESPARK-001 study of belzutifan for advanced solid tumors: Extended 41-month follow-up in the clear cell renal cell carcinoma cohort.

BACKGROUND: Accumulation of the HIF-2α transcription factor is an oncogenic event implicated in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). In the phase I LITESPARK-001 study, the first-in-class HIF-2α inhibitor belzutifan demonstrated antitumor activity and an acceptable safety profile for pretreated patients with advanced ccRCC. Updated data with additional follow-up of > 40 months are presented. METHODS: LITESPARK-001 is an ongoing open-label study with a 3 + 3 dose-escalation design followed by an expansion phase. Patients with ccRCC enrolled at 7 sites received belzutifan 120 mg orally once daily until disease progression, unacceptable toxicity, or patient withdrawal. The data cutoff date was July 15, 2021. The primary end point was identifying the maximum tolerated dose and/or the recommended phase II dose. Secondary end points included objective response rate (ORR) and duration of response (DOR) per RECIST v1.1 by investigator assessment and safety. RESULTS: Median follow-up was 41.2 months (range, 38.2-47.7). Patients received a median of 3 (range, 1-9) prior systemic therapies. Of 55 patients, 14 (25 %) achieved an objective response. Median DOR was not reached (range, 3.1 + to 38.0 + months). Adverse events (AEs) attributed to study treatment by investigator assessment were reported in 53 patients (96 %). 22 patients (40 %) had grade 3 treatment-related AEs; the most common were anemia (n = 13; 24 %) and hypoxia (n = 7; 13 %). No grade 4 or 5 treatment-related AEs occurred. CONCLUSION: After a median follow-up of 41.2 months, belzutifan monotherapy demonstrated durable antitumor activity in patients with advanced ccRCC and acceptable safety. CLINICALTRIALS: gov. NCT02974738.

LITESPARK-012: pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab for advanced renal cell carcinoma.

Combination treatment with immunotherapy agents and/or vascular endothelial growth factor tyrosine kinase inhibitors are a standard of care for patients with advanced clear cell renal cell carcinoma (ccRCC). Novel therapeutic combinations that include the hypoxia-inducible factor 2α inhibitor belzutifan and the cytotoxic T-lymphocyte-associated protein 4 inhibitor quavonlimab are being investigated for their potential to further improve patient outcomes. This protocol describes the rationale and design of the randomized, phase III LITESPARK-012 study, which will evaluate the efficacy and safety of pembrolizumab plus lenvatinib with or without belzutifan or quavonlimab as first-line treatment for advanced ccRCC. Results from this study may support triplet combination therapies as a potential new standard of care for advanced ccRCC. Clinical trial registry: NCT04736706 (ClinicalTrials.gov).

Pembrolizumab Plus Axitinib Versus Sunitinib as First-line Treatment of Advanced Renal Cell Carcinoma: 43-month Follow-up of the Phase 3 KEYNOTE-426 Study.

Previous analyses of KEYNOTE-426, an open-label, phase 3 randomized study, showed superior efficacy of first-line pembrolizumab plus axitinib to sunitinib in advanced clear cell renal cell carcinoma (ccRCC). We report results of the final protocol-prespecified analysis of KEYNOTE-426. Patients received pembrolizumab 200 mg intravenously every 3 wk plus axitinib 5 mg orally twice daily or sunitinib 50 mg orally once daily (4 wk per 6-wk cycle). The dual primary endpoints were overall survival (OS) and progression-free survival (PFS) as per RECIST v1.1 by a blinded independent central review. The secondary endpoints included objective response rate (ORR) and duration of response (DOR). The median study follow-up was 43 (range, 36-51) mo. Benefit with pembrolizumab plus axitinib versus sunitinib was maintained for OS (hazard ratio [HR], 0.73 [95% confidence interval {CI}, 0.60-0.88]), PFS (HR, 0.68 [95% CI, 0.58-0.80]), and ORR (60% vs 40%). The median DOR was 24 (range, 1.4+ to 43+) versus 15 (range, 2.3-43+) mo in the pembrolizumab plus axitinib versus the sunitinib arm. No new safety signals emerged. These results support pembrolizumab plus axitinib as a standard of care for patients with previously untreated advanced ccRCC. PATIENT SUMMARY: Extended results of KEYNOTE-426 support pembrolizumab plus axitinib as the standard of care for advanced clear cell renal cell carcinoma.

Results From a Randomized Phase II Trial of Sunitinib and Gemcitabine or Sunitinib in Advanced Renal Cell Carcinoma with Sarcomatoid Features: ECOG-ACRIN E1808.

INTRODUCTION: Sarcomatoid renal cancer (sRCC) patients have poor outcomes. EA1808 evaluated sunitinib and gemcitabine (SG) and sunitinib alone (S) in sRCC in a randomized cooperative group phase II trial (NCT01164228). PATIENTS AND METHODS: Pts were aggregated 1:1 to SG (45 pts) or S (40 pts) using a 2-stage design. sRCC pts with ≤ 1 prior nonvascular endothelial growth factor tyrosine kinase inhibitor were stratified into prognostic groups: good (clear cell, < 20% sarcomatoid, PS 0), intermediate (20%-50% sarcomatoid, PS 0), and poor (nonclear cell or > 50% sarcomatoid or PS 1). The primary endpoint was response rate (RR). For SG, the null RR was 15% and a 30% RR was of interest. For S, a 20% RR was of interest vs. a 5% null rate. Secondary endpoints were progression-free survival, overall survival, and safety. RESULTS: Both arms met protocol criteria for stage 2 of accrual. A total of 47 pts were randomized to SG and 40 to S. The SG arm had 9 of 45 evaluable patient responses (RR of 20%; CI = [13%-31%]) not meeting the predetermined threshold for success. The sunitinib arm met its endpoint with 6/37 (RR of 16%; CI = [9%-27%]) evaluable responses. Grade ≥ 3 events were experienced by 36 in the SG arm and 17 in the sunitinib arm CONCLUSIONS: EA1808 was the largest and first randomized cytotoxic trial for sarcomatoid RCC. Sunitinib alone but not the SG met the preset threshold of success. Cytotoxic chemotherapy is only useful in limited clinical scenarios for sRCC.

A phase 1 study of nivolumab in combination with interferon-gamma for patients with advanced solid tumors.

This phase I, dose-escalation trial evaluates the safety of combining interferon-gamma (IFN-γ) and nivolumab in patients with metastatic solid tumors. Twenty-six patients are treated in four cohorts assessing increasing doses of IFN-γ with nivolumab to evaluate the primary endpoint of safety and determine the recommended phase two dose (RP2D). Most common adverse events are low grade and associated with IFN-γ. Three dose limiting toxicities are reported at the highest dose cohorts. We report only one patient with any immune related adverse event (irAE). No irAEs ≥ grade 3 are observed and no patients require corticosteroids. The maximum tolerated dose of IFN-γ is 75 mcg/m2, however based on a composite of safety, clinical, and correlative factors the RP2D is 50 mcg/m2. Exploratory analyses of efficacy in the phase I cohorts demonstrate one patient with a complete response, and five have achieved stable disease. Pre-planned correlative assessments of circulating immune cells demonstrate intermediate monocytes with increased PD-L1 expression correlating with IFN-γ dose and treatment duration. Interestingly, post-hoc analysis shows that IFN-γ induction increases circulating chemokines and is associated with an observed paucity of irAEs, warranting further evaluation. ClinicalTrials.gov Trial Registration: NCT02614456.

Flutamide With or Without PROSTVAC in Non-metastatic Castration Resistant (M0) Prostate Cancer.

BACKGROUND: Before 2018, there was no standard of care for non-metastatic (M0) castration resistant prostate cancer nmCRPC. Androgen receptor antagonists (ARAs) were commonly used sequentially nmCRPC. METHODS: This was a multicenter, randomized clinical trial comparing the ARA flutamide+/-PROSTVAC, a pox viral vaccine targeting PSA that includes T-cell co-stimulatory molecules. Eligible men had negative CT and Tc99 bone scans, and rising PSA on ADT. Previous treatment with ARA was a stratification factor. Patients were also evaluated for antigen-specific immune responses using intracellular cytokine staining. RESULTS: Thirty-three patients randomized to flutamide and 31 to flutamide+vaccine. The median age was 71.8 and 69.8 years, respectively. The median time to treatment failure after a median potential follow-up of 46.7 months was, 4.5 months (range 2-70) for flutamide alone vs. 6.9 months (2.5-40; P = .38) with flutamide+vaccine. Seven patients in each arm had a >50% PSA response. Antigen-specific responses were similar in both arms (58% of patients in flutamide alone and 56% in flutamide+vaccine). The treatments were well tolerated. The most common side effect > grade 2 was injection site reaction seen in 29/31 vaccine patients which were self-limiting. CONCLUSION: The combination of flutamide+PROSTVAC did not improve outcomes in men with nmCRPC compared with flutamide alone. (ClinicalTrials.gov Identifier: NCT00450463).

Phase II study of nivolumab and salvage nivolumab/ipilimumab in treatment-naïve patients with advanced non-clear cell renal cell carcinoma (HCRN GU16-260-Cohort B).

BACKGROUND: To determine the efficacy and toxicity of nivolumab monotherapy in treatment-naïve patients with non-clear cell renal cell carcinoma (nccRCC) and the efficacy of nivolumab/ipilimumab salvage therapy in patients with tumors unresponsive to initial nivolumab monotherapy. METHODS: Eligible patients with treatment-naïve nccRCC received nivolumab until progressive disease (PD), toxicity, or completion of 96 weeks of treatment (Part A). Patients with PD prior to, or stable disease (SD) at 48 weeks (prolonged SD) were potentially eligible to receive salvage nivolumab/ipilimumab (Part B). Patients were required to submit tissue from a metastatic lesion obtained within 12 months prior to study entry and prior to Part B for correlative studies. RESULTS: 35 patients with nccRCC were enrolled: 19 (54%) had papillary, 6 (17%) had chromophobe and 10 (29%) had unclassified histology. At median follow-up of 22.9 months, RECIST-defined objective response rate (ORR) was 5 of 35 (14.3% 95% CI 4.8% to 30.3%) (complete response (CR) 2 (5.7%) and partial response (PR) 3 (8.6%)). ORR by histology was: papillary-1/19 (5%); chromophobe-1/6 (17%); and unclassified-3/10 (30%). Nine patients (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified and 1 papillary) responding. ORR was 0/18, 3/11 (27%) and 2/6 (33%) for patients with tumor progammed death ligand 1 (PD-L1) expression of <5%, ≥5% or not measured, respectively. Median progression-free survival was 4.0 (2.7-4.3) months. Two of five responders have progressed. Thirty-two patients had PD or prolonged SD and therefore, were potentially eligible for salvage nivolumab/ipilimumab (Part B), but 15 patients did not enroll due to grade 2-3 toxicity (6) on nivolumab, symptomatic disease progression (5), or other reasons including no biopsy tissue (4). In the 17 Part B patients, there was one PR (6%) (unclassified/non-sarcomatoid). Grade >3 treatment-related adverse events were seen in 7/35 (20%) on nivolumab and 7/17 (41%) on salvage nivolumab/ipilimumab with one patient experiencing sudden death. CONCLUSIONS: Nivolumab monotherapy has limited activity in treatment-naïve nccRCC with most responses (4 of 5) seen in patients with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivolumab studies. Salvage treatment with nivolumab/ipilimumab was provided in half of these patients with minimal activity. TRIAL REGISTRATION NUMBER: NCT03117309.