Challenges and Considerations in Modern Adjuvant Therapy Trials in Renal Cell Carcinoma: A Call to Power.

Identification of effective adjuvant therapies for renal cell carcinoma remains challenging despite the development of immune checkpoint inhibitors. Enhancement of the design of trials of adjuvant therapy by focusing on populations with the highest risk and increasing the sample size is essential for reliable assessments of therapeutic efficacy.

Off-Protocol Radiation Therapy in Phase 3 Metastatic Solid Tumor Trials.

PURPOSE: Increasing data suggest that radiation therapy, particularly ablative radiation therapy, alters the natural history of metastatic disease. For patients with metastatic disease enrolled in prospective trials testing systemic therapy, the use of off-protocol radiation therapy to improve clinical symptoms or extend the duration of study systemic therapy may influence study endpoints. We sought to evaluate how often off-protocol radiation therapy was permitted among systemic therapy phase 3 trials, how often off-protocol radiation therapy is used, and whether off-protocol radiation therapy correlated with study outcomes. METHODS AND MATERIALS: Two-arm, superiority-design, phase 3 randomized trials testing systemic therapy were screened from ClinicalTrials.gov. Protocol availability was required to assess the trial approach to off-protocol radiation therapy if not described in the manuscript. Adjusted odds ratios with 95% CI were calculated by logistic regression. RESULTS: A total of 112 trials enrolling 80,134 patients were included, with publication dates between 2010 and 2019. Of these, off-protocol radiation therapy was allowed, not discussed, or prohibited during study systemic therapy in 52% (N =58), 25% (N = 28), and 23% (N = 26) of trials, respectively. However, only 2% (2 of 112) of trials reported off-protocol radiation therapy utilization rates, although no data were reported on the use of ablative off-protocol radiation therapy. No trials evaluated or adjusted for the potential influence of off-protocol radiation therapy on study endpoints. Among the subset of open-label studies, trials permissive toward off-protocol radiation therapy were more likely to meet their primary endpoint (adjusted odds ratio, 4.50; 95% CI, 1.23-20.23; P = .04). CONCLUSIONS: Although most trials allowed off-protocol radiation therapy during the receipt of the study systemic therapy, the influence of off-protocol radiation therapy, especially ablative radiation therapy, on study outcomes is underevaluated among phase 3 systemic therapy trials.

A meta-epidemiological analysis of post-hoc comparisons and primary endpoint interpretability among randomized noncomparative trials in clinical medicine.

OBJECTIVES: Randomized noncomparative trials (RNCTs) promise reduced accrual requirements vs randomized controlled comparative trials because RNCTs do not enroll a control group and instead compare outcomes to historical controls or prespecified estimates. We hypothesized that RNCTs often suffer from two methodological concerns: (1) lack of interpretability due to group-specific inferences in nonrandomly selected samples and (2) misinterpretation due to unlicensed between-group comparisons lacking prespecification. The purpose of this study was to characterize RNCTs and the incidence of these two methodological concerns. STUDY DESIGN AND SETTING: We queried PubMed and Web of Science on September 14, 2023, to conduct a meta-epidemiological analysis of published RNCTs in any field of medicine. Trial characteristics and the incidence of methodological concerns were manually recorded. RESULTS: We identified 70 RNCTs published from 2002 to 2023. RNCTs have been increasingly published over time (slope = 0.28, 95% CI 0.17-0.39, P < .001). Sixty trials (60/70, 86%) had a lack of interpretability for the primary endpoint due to group-specific inferences. Unlicensed between-group comparisons were present in 36 trials (36/70, 51%), including in the primary conclusion of 31 trials (31/70, 44%), and were accompanied by significance testing in 20 trials (20/70, 29%). Only five (5/70, 7%) trials were found to have neither of these flaws. CONCLUSION: Although RNCTs are increasingly published over time, the primary analysis of nearly all published RNCTs in the medical literature was unsupported by their fundamental underlying methodological assumptions. RNCTs promise group-specific inference, which they are unable to deliver, and undermine the primary advantage of randomization, which is comparative inference. The ongoing use of the RNCT design in lieu of a traditional randomized controlled comparative trial should therefore be reconsidered. PLAIN LANGUAGE SUMMARY: The typical way that doctors can learn whether new drugs are helpful is through a clinical trial. Often, doctors compare these new treatments to the control treatment being used in standard clinical practice. When researchers want to compare different treatments, they may decide to randomly assign one treatment or the other to trial participants. Like flipping a coin, randomly deciding which treatment to use can help researchers make the best comparisons between the new and control treatment by limiting certain biases. These trials are called "randomized comparative trials" and are the most common way researchers can improve medicine. A newer type of trial, called a "randomized noncomparative trial," has become increasingly popular in medicine. Like randomized comparative trials, this type of trial randomly decides which treatment participants receive. However, the "randomized noncomparative trial" is not designed to evaluate whether the new treatment results in better outcomes compared with the control treatment. Instead, the results of each randomized arm in the trial are compared to other patients, who are not a part of the trial, or to another measure set ahead of time by the researchers. This is justified by some researchers, who say that fewer participants are needed for such trials, which helps to finish the trial faster. However, directly comparing the results of patients after receiving a treatment on a clinical trial is one of the most important parts of the trial and the main reason why researchers would want to randomly assign treatments in the first place. To better understand how RNCTs are used in practice, we reviewed all such trials that have been completed in medicine to date. We found that more than half of RNCTs actually ended up comparing their patients anyway, despite saying they would not. This is a problem because these comparisons are not prespecified and may therefore be only reported when the result is what the researchers wanted. Furthermore, the main outcome of each trial was difficult to interpret in most trials because there was no effort to show that the enrolled patients were representative of any prespecified population that would facilitate comparisons with historical information. Overall, only five trials, or just 7% of the "randomized noncomparative trials" published in the medical literature, did not have either of these issues. As a result, this type of clinical trial does not seem to be a good way to improve medical care. If researchers want to learn which treatments are better, they should stick to the standard way to learn this-randomized comparative trials.

Evidenced-Based Prior for Estimating the Treatment Effect of Phase III Randomized Trials in Oncology.

PURPOSE: The primary results of phase III oncology trials may be challenging to interpret, given that results are generally based on P value thresholds. The probability of whether a treatment is beneficial, although more intuitive, is not usually provided. Here, we developed and released a user-friendly tool that calculates the probability of treatment benefit using trial summary statistics. METHODS: We curated 415 phase III randomized trials enrolling 338,600 patients published between 2004 and 2020. A phase III prior probability distribution for the treatment effect was developed on the basis of a three-component zero-mean mixture distribution of the observed z-scores. Using this prior, we computed the probability of clinically meaningful benefit (hazard ratio [HR] <0.8). The distribution of signal-to-noise ratios and power of phase III oncology trials were compared with that of 23,551 randomized trials from the Cochrane Database. RESULTS: The signal-to-noise ratios of phase III oncology trials tended to be much larger than randomized trials from the Cochrane Database. Still, the median power of phase III oncology trials was only 49% (IQR, 14%-95%), and the power was <80% in 65% of trials. Using the phase III oncology-specific prior, only 53% of trials claiming superiority (114 of 216) had a ≥90% probability of clinically meaningful benefits. Conversely, the probability that the experimental arm was superior to the control arm (HR <1) exceeded 90% in 17% of trials interpreted as having no benefit (34 of 199). CONCLUSION: By enabling computation of contextual probabilities for the treatment effect from summary statistics, our robust, highly practical tool, now posted on a user-friendly webpage, can aid the wider oncology community in the interpretation of phase III trials.

Upfront Versus Deferred Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma: A Systematic Review and Individual Patient Data Meta-analysis.

BACKGROUND AND OBJECTIVE: Despite its well-established role in metastatic renal cell carcinoma (mRCC), the optimal timing of cytoreductive nephrectomy (CN) is unclear. The aim of this systematic review is to compare the overall survival (OS) between upfront (uCN) and deferred (dCN) CN. METHODS: The MEDLINE, EMBASE, and Web of Science databases were queried (end of search date: August 26, 2023) for studies comparing OS between uCN and dCN in mRCC patients. We reconstructed individual patient data from published Kaplan-Meier survival curves and performed one- and two-stage meta-analyses, using 6- and 12-mo landmarks to mitigate immortal time bias. We also performed subgroup analyses according to systemic therapy (ST) type and Memorial Sloan Kettering Cancer Center (MSKCC)/International Metastatic RCC Database Consortium (IMDC) risk scores. We assessed the risk of bias using the Risk of Bias in Non-randomized Studies of Interventions and Risk of Bias 2.0 tools. KEY FINDINGS AND LIMITATIONS: We identified 12 (two randomized trials and ten retrospective cohorts) eligible studies with a total of 3323 (2610 uCN and 713 dCN) patients. There were no statistically significant differences in the baseline characteristics of the two groups, other than the number of metastases and ST type. The overall risk of bias was high in nine out of 12 studies. Deferred CN was associated with superior OS in the primary analysis (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.65-0.84; 5-yr life expectancy difference 5.15 mo, 95% CI 3.23-7.08), all secondary analyses, as well as the tyrosine kinase inhibitor-treated (HR 0.61, 95% CI 0.51-0.74), immune checkpoint inhibitor-treated (HR 0.67, 95% CI 0.46-0.97), and intermediate IMDC/MSKCC risk (HR 0.73, 95% CI 0.55-0.97) subgroups. CONCLUSIONS AND CLINICAL IMPLICATIONS: Deferred CN is associated with superior OS compared with uCN in mRCC patients treated with contemporary STs. Randomized studies are warranted to confirm these findings. Predictive models are needed to optimize the selection of patients most likely to benefit from dCN. PATIENT SUMMARY: In this report, we compared the outcomes of nephrectomy performed before (upfront) or after (deferred) starting systemic therapy for patients with metastatic kidney cancer. We found that deferred nephrectomy is associated with superior survival compared with upfront nephrectomy, irrespective of the systemic therapy regimens used.

Belzutifan Efficacy and Tolerability in Patients with Sporadic Metastatic Clear Cell Renal Cell Carcinoma.

BACKGROUND AND OBJECTIVE: Belzutifan, a hypoxia-inducible factor 2 alpha inhibitor, was approved initially for patients with von Hippel-Lindau disease and more recently for sporadic, metastatic clear cell renal cell carcinoma (ccRCC) based on the results of LITESPARK-005. There is a paucity of data regarding real-world experience with belzutifan in patients with sporadic, metastatic ccRCC. This study aims to describe clinical outcomes with belzutifan in patients with sporadic, metastatic ccRCC. METHODS: A retrospective study of 22 patients who received belzutifan at MD Anderson Cancer Center prior to the Food and Drug Administration approval was conducted. Progression-free survival (PFS) and objective response rate (ORR) were assessed by a blinded radiologist using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. PFS and overall survival (OS) were measured from belzutifan initiation. KEY FINDINGS AND LIMITATIONS: The median follow-up time was 14.9 mo. Most patients had International Metastatic RCC Database Consortium intermediate-risk disease, more than three metastatic sites, and a median of five prior lines of treatment at initiation of belzutifan; all patients received prior immune checkpoint therapy (ICT) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). The median PFS was 8.51 mo (95% confidence interval [CI] 0-18.4) and ORR was 36.4%. The median OS was 14.72 mo (95% CI 7.34-22.10). Of 22 patients, four (18.2%) patients required dose reductions and three (13.6%) patients discontinued belzutifan because of adverse drug events (ADEs). The most common ADEs were anemia (77.3%; 17/22) and hypoxia (36.4%; 8/22). There were no treatment-related deaths. CONCLUSIONS AND CLINICAL IMPLICATIONS: In a heavily pretreated cohort of patients with sporadic, metastatic ccRCC, belzutifan had meaningful clinical activity and was well tolerated. These real-world results add to the results of LITESPARK-005 and support the use of belzutifan after progression on ICT and VEGFR-TKIs. PATIENT SUMMARY: Belzutifan is a new medicine used to treat a type of clear cell kidney cancer that has spread to other parts of the body (metastasized). A study at MD Anderson Cancer Center followed 22 patients who were treated with belzutifan, and found that it worked to control the cancer for almost 9 mo and caused the cancer to shrink in 36% of patients. This study confirms that belzutifan can be effective and safe, even after other treatments have not worked.

Secondary Endpoint Utilization and Publication Rate among Phase III Oncology Trials.

Secondary endpoints (SEP) provide crucial information in the interpretation of clinical trials, but their features are not yet well understood. Thus, we sought to empirically characterize the scope and publication rate of SEPs among late-phase oncology trials. We assessed SEPs for each randomized, published phase III oncology trial across all publications and ClinicalTrials.gov, performing logistic regressions to evaluate associations between trial characteristics and SEP publication rates. After screening, a total of 280 trials enrolling 244,576 patients and containing 2,562 SEPs met the inclusion criteria. Only 22% of trials (62/280) listed all SEPs consistently between ClinicalTrials.gov and the trial protocol. The absolute number of SEPs per trial increased over time, and trials sponsored by industry had a greater number of SEPs (median 9 vs. 5 SEPs per trial; P < 0.0001). In total, 69% of SEPs (1,770/2,562) were published. The publication rate significantly varied by SEP category [X2 (5, N = 2,562) = 245.86; P < 0.001]. SEPs that place the most burden on patients, such as patient-reported outcomes and translational correlatives, were published at 63% (246/393) and 44% (39/88), respectively. Trials with more SEPs were associated with lower overall SEP publication rates. Overall, our findings are that SEP publication rates in late-phase oncology trials are highly variable based on the type of SEP. To avoid undue burden on patients and promote transparency of findings, trialists should weigh the biological and clinical relevance of each SEP together with its feasibility at the time of trial design. SIGNIFICANCE: In this investigation, we characterized the utilization and publication rates of SEPs among late-phase oncology trials. Our results draw attention to the proliferation of SEPs in recent years. Although overall publication rates were high, underpublication was detected among endpoints that may increase patient burden (such as translational correlatives and patient-reported outcomes).

Towards Treatment Effect Interpretability: A Bayesian Re-analysis of 194,129 Patient Outcomes Across 230 Oncology Trials.

Most oncology trials define superiority of an experimental therapy compared to a control therapy according to frequentist significance thresholds, which are widely misinterpreted. Posterior probability distributions computed by Bayesian inference may be more intuitive measures of uncertainty, particularly for measures of clinical benefit such as the minimum clinically important difference (MCID). Here, we manually reconstructed 194,129 individual patient-level outcomes across 230 phase III, superiority-design, oncology trials. Posteriors were calculated by Markov Chain Monte Carlo sampling using standard priors. All trials interpreted as positive had probabilities > 90% for marginal benefits (HR < 1). However, 38% of positive trials had ≤ 90% probabilities of achieving the MCID (HR < 0.8), even under an enthusiastic prior. A subgroup analysis of 82 trials that led to regulatory approval showed 30% had ≤ 90% probability for meeting the MCID under an enthusiastic prior. Conversely, 24% of negative trials had > 90% probability of achieving marginal benefits, even under a skeptical prior, including 12 trials with a primary endpoint of overall survival. Lastly, a phase III oncology-specific prior from a previous work, which uses published summary statistics rather than reconstructed data to compute posteriors, validated the individual patient-level data findings. Taken together, these results suggest that Bayesian models add considerable unique interpretative value to phase III oncology trials and provide a robust solution for overcoming the discrepancies between refuting the null hypothesis and obtaining a MCID.

Improving the clinical meaning of surrogate endpoints: An empirical assessment of clinical progression in phase III oncology trials.

Disease progression in clinical trials is commonly defined by radiologic measures. However, clinical progression may be more meaningful to patients, may occur even when radiologic criteria for progression are not met, and often requires a change in therapy in clinical practice. The objective of this study was to determine the utilization of clinical progression criteria within progression-based trial endpoints among phase III trials testing systemic therapies for metastatic solid tumors. The primary manuscripts and protocols of phase III trials were reviewed for whether clinical events, such as refractory pain, tumor bleeding, or neurologic compromise, could constitute a progression event. Univariable logistic regression computed odds ratios (OR) and 95% CI for associations between trial-level covariates and clinical progression. A total of 216 trials enrolling 148,190 patients were included, with publication dates from 2006 through 2020. A major change in clinical status was included in the progression criteria of 13% of trials (n = 27), most commonly as a secondary endpoint (n = 22). Only 59% of trials (n = 16) reported distinct clinical progression outcomes that constituted the composite surrogate endpoint. Compared with other disease sites, genitourinary trials were more likely to include clinical progression definitions (16/33 [48%] vs. 11/183 [6%]; OR, 14.72; 95% CI, 5.99 to 37.84; p < .0001). While major tumor-related clinical events were seldom considered as disease progression events, increased attention to clinical progression may improve the meaningfulness and clinical applicability of surrogate endpoints for patients with metastatic solid tumors.

A Pilot Study of the CD38 Antagonist Daratumumab in Patients with Metastatic Renal Cell Carcinoma or Muscle-Invasive Bladder Cancer.

PURPOSE: We performed a pilot study of daratumumab (an mAb directed against CD38) in muscle-invasive bladder cancer (MIBC) and treatment-refractory metastatic renal cell carcinoma (mRCC). EXPERIMENTAL DESIGN: Patients with MIBC underwent baseline transurethral resection of the bladder tumor followed by four weekly doses of daratumumab prior to cystectomy. Patients with mRCC underwent baseline and sequential biopsies after eight weekly doses. The primary endpoint was safety. The secondary endpoints were pathologic complete response rate for the MIBC cohort and objective response rate and progression-free survival for the mRCC cohort. Exploratory analyses included immune monitoring and overall survival. A Bayesian sequential monitoring design for toxicity was used for excessive toxicity. RESULTS: In both the MIBC (n = 8) and mRCC (n = 8) cohorts, no toxicity events were encountered. In the MIBC cohort, one patient experienced pathologic complete response rate. In the mRCC cohort, no objective responses were reported, and the median progression-free survival was 1.5 months (95% confidence interval, 1.1-1.8 months). Immune monitoring found significant reductions in NK cells in circulation in both cohorts after treatment. In the tissue analysis, IHC found evidence of diminished CD38 presence in mRCC with treatment, whereas the baseline levels in MIBC were low. CONCLUSION: Treatment with daratumumab was safe. No signal of efficacy was detected in mRCC, and conclusions on the activity in MIBC were limited. Evidence of daratumumab targeting CD38 was detected in circulating immune cells and within the tumor microenvironment of mRCC and MIBC. SIGNIFICANCE: In this prospective clinical trial of daratumumab, treatment in patients with MIBC and mRCC was safe. Limited efficacy was observed. Treatment with daratumumab resulted in CD38-expressing immune cell subsets to be targeted both in circulation and within the tumor microenvironment.

Increasing Power in Phase III Oncology Trials With Multivariable Regression: An Empirical Assessment of 535 Primary End Point Analyses.

PURPOSE: A previous study demonstrated that power against the (unobserved) true effect for the primary end point (PEP) of most phase III oncology trials is low, suggesting an increased risk of false-negative findings in the field of late-phase oncology. Fitting models with prognostic covariates is a potential solution to improve power; however, the extent to which trials leverage this approach, and its impact on trial interpretation at scale, is unknown. To that end, we hypothesized that phase III trials using multivariable PEP analyses are more likely to demonstrate superiority versus trials with univariable analyses. METHODS: PEP analyses were reviewed from trials registered on ClinicalTrials.gov. Adjusted odds ratios (aORs) were calculated by logistic regressions. RESULTS: Of the 535 trials enrolling 454,824 patients, 69% (n = 368) used a multivariable PEP analysis. Trials with multivariable PEP analyses were more likely to demonstrate PEP superiority (57% [209 of 368] v 42% [70 of 167]; aOR, 1.78 [95% CI, 1.18 to 2.72]; P = .007). Among trials with a multivariable PEP model, 16 conditioned on covariates and 352 stratified by covariates. However, 108 (35%) of 312 trials with stratified analyses lost power by categorizing a continuous variable, which was especially common among immunotherapy trials (aOR, 2.45 [95% CI, 1.23 to 4.92]; P = .01). CONCLUSION: Trials increasing power by fitting multivariable models were more likely to demonstrate PEP superiority than trials with unadjusted analysis. Underutilization of conditioning models and empirical power loss associated with covariate categorization required by stratification were identified as barriers to power gains. These findings underscore the opportunity to increase power in phase III trials with conventional methodology and improve patient access to effective novel therapies.

Successful management of pre-existing psoriatic arthritis through targeting the IL-23/IL-17 axis in cancer patients receiving immune checkpoint inhibitor therapy: a case series.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with cancer. However, these therapies are associated with adverse events including de novo immune-related adverse events or flare of pre-exiting autoimmune disorders. Up to 80% of patients with cancer and pre-existing psoriasis (PsO) or psoriatic arthritis (PsA) experience PsO/PsA flare after initiating ICIs. Targeting the interleukin (IL)-17/IL-23 axis is a mainstream of the PsO/PsA treatment. However, whether this treatment can effectively control PsO/PsA with ICI exposure while preserving anti-tumour efficacy remains unknown. CASE REPORTS: We report three patients with PsA and cancer, who received ICIs for their cancer treatment. All patients were male. Two patients had clear cell renal cell carcinoma, and one had melanoma. Two patients received anti-PD-1 antibody monotherapy, while one patient received combined anti-CTLA-4 and PD-1 antibody therapy. One patient had been receiving anti-IL-17A antibody (secukinumab), while the other two patients started anti-IL-17A antibody (ixekizumab) and anti-IL-23 antibody (guselkumab) after their PsA flared up during ICI treatment. Of note, with the anti-IL-17A or anti-IL-23 antibody treatment, their PsA remained in remission, and they well tolerated the ICI therapy. Importantly, all three patients showed persistent tumour responses to ICI therapy, including two complete remissions and one stable disease, respectively. CONCLUSIONS: These three cases suggest that targeting the IL-17/23 axis may be an effective and safe approach for patients with cancer and pre-existing PsA being considered for ICI therapy.

Body composition as a determinant of the therapeutic index with androgen signaling inhibition.

BACKGROUND: Androgen signaling is central to prostate cancer and men's health. Prior data indicates that increasing body fat is unfavorable in the localized setting yet associated with favorable outcomes in men with metastatic disease. Understanding the biological links between adiposity and prostate cancer may optimize the therapeutic index with ASI. We hypothesized that host adiposity and androgen synthesis are linked to the efficacy and toxicity of ASI for men with metastatic castration-resistant prostate cancer (mCRPC). METHODS: A post-hoc analysis was done of NCT02703623 where men with mCRPC (n = 186) were treated for 8 weeks with abiraterone acetate, prednisone, and apalutamide (AAPA), and a satisfactory response was defined as a PSA decline >50%. Body composition was measured on baseline CT scans. Germline DNA WES was performed with a focus on variants in steroidogenic genes. Adipokine levels were measured in pre-treatment plasma. RESULTS: Germline polymorphisms in 3 genes involved in androgen synthesis (AKR1C3 rs12529, CYP17A1 rs6162, SRD5A2 rs523349) were associated with differences in body composition at baseline on ADT alone (prior to receipt of AAPA). Elevated subcutaneous adipose tissue index (SATi, p = 0.02), visceral adipose tissue index (VATi, p = 0.03), and BMI (p = 0.04) were associated with satisfactory response to AAPA. Leptin had positive correlation with VATi (r = 0.47) and SATi (r = 0.48). CONCLUSION: Inherited polymorphisms in androgen synthesis correlated with differences in body composition after exposure to ADT and warrant further investigation as candidate markers for body composition toxicity. Elevated subcutaneous and visceral adiposity were associated with improved response to ASI.

Clinical Characteristics, Management, and Outcomes of Patients with Renal Medullary Carcinoma: A Single-center Retrospective Analysis of 135 Patients.

BACKGROUND AND OBJECTIVE: SMARCB1-deficient renal medullary carcinoma (RMC) is a rare kidney cancer associated with sickle cell hemoglobinopathies with poor outcomes described only in case reports and small series. We report disease and management characteristics as well as contemporary survival outcomes in a large cohort of patients with RMC. METHODS: Data were extracted retrospectively from all patients with RMC treated at MD Anderson Cancer Center between January 2003 and December 2023. Multivariable Cox regression was used to estimate overall survival (OS) by diagnosis period. KEY FINDINGS AND LIMITATIONS: Among 135 patients (median follow-up of 54.9 mo), only nine did not harbor a sickle hemoglobinopathy and were categorized as having renal cell carcinoma, unclassified with medullary phenotype (RCCU-MP). Most patients (78%) presented with metastatic disease, predominantly to the retroperitoneal lymph nodes (81.7%), and hematuria was the most frequent presenting symptom (60%) in RMC associated with sickle hemoglobinopathy. Survival outcomes improved by diagnosis year (adjusted hazard ratio 0.70, 95% confidence interval 0.53-0.92, p = 0.01). RCCU-MP occurred in slightly older patients with median OS of 19.5 mo from diagnosis, did not show a predilection to the right kidney or male predominance, and afflicted mainly Caucasians (89%). The study is limited by its retrospective nature conducted at one center. CONCLUSIONS AND CLINICAL IMPLICATIONS: RMC frequently presents with hematuria and is highly likely to spread to the retroperitoneal lymph nodes. Survival outcomes are improving with contemporary management. RCCU-MP is very rare and may be slightly less aggressive. PATIENT SUMMARY: Renal medullary carcinoma (RMC) is a rare and aggressive subtype of kidney cancer afflicting primarily young men and women of African descent. There exist limited data regarding patient demographics and disease characteristics. We reported our institution's experience in treating patients with RMC. The first symptom most patients with RMC reported was blood in the urine, and the most common places where the cancer spread were the lymph nodes around the kidney. Patients with RMC are living longer with contemporary treatments.

Pan-cancer subclonal mutation analysis of 7,827 tumors predicts clinical outcome.

Intra-tumor heterogeneity is an important driver of tumor evolution and therapy response. Advances in precision cancer treatment will require understanding of mutation clonality and subclonal architecture. Currently the slow computational speed of subclonal reconstruction hinders large cohort studies. To overcome this bottleneck, we developed Clonal structure identification through Pairwise Penalization, or CliPP, which clusters subclonal mutations using a regularized likelihood model. CliPP reliably processed whole-genome and whole-exome sequencing data from over 12,000 tumor samples within 24 hours, thus enabling large-scale downstream association analyses between subclonal structures and clinical outcomes. Through a pan-cancer investigation of 7,827 tumors from 32 cancer types, we found that high subclonal mutational load (sML), a measure of latency time in tumor evolution, was significantly associated with better patient outcomes in 16 cancer types with low to moderate tumor mutation burden (TMB). In a cohort of prostate cancer patients participating in an immunotherapy clinical trial, high sML was indicative of favorable response to immune checkpoint blockade. This comprehensive study using CliPP underscores sML as a key feature of cancer. sML may be essential for linking mutation dynamics with immunotherapy response in the large population of non-high TMB cancers.

Bayesian Interim Analysis and Efficiency of Phase III Randomized Trials.

IMPORTANCE: Improving the efficiency of interim assessments in phase III trials should reduce trial costs, hasten the approval of efficacious therapies, and mitigate patient exposure to disadvantageous randomizations. OBJECTIVE: We hypothesized that in silico Bayesian early stopping rules improve the efficiency of phase III trials compared with the original frequentist analysis without compromising overall interpretation. DESIGN: Cross-sectional analysis. SETTING: 230 randomized phase III oncology trials enrolling 184,752 participants. PARTICIPANTS: Individual patient-level data were manually reconstructed from primary endpoint Kaplan-Meier curves. INTERVENTIONS: Trial accruals were simulated 100 times per trial and leveraged published patient outcomes such that only the accrual dynamics, and not the patient outcomes, were randomly varied. MAIN OUTCOMES AND MEASURES: Early stopping was triggered per simulation if interim analysis demonstrated ≥ 85% probability of minimum clinically important difference/3 for efficacy or futility. Trial-level early closure was defined by stopping frequencies ≥ 0.75. RESULTS: A total of 12,451 simulations (54%) met early stopping criteria. Trial-level early stopping frequency was highly predictive of the published outcome (OR, 7.24; posterior probability of association, >99.99%; AUC, 0.91; P < 0.0001). Trial-level early closure was recommended for 82 trials (36%), including 62 trials (76%) which had performed frequentist interim analysis. Bayesian early stopping rules were 96% sensitive (95% CI, 91% to 98%) for detecting trials with a primary endpoint difference, and there was a high level of agreement in overall trial interpretation (Bayesian Cohen's κ, 0.95; 95% CrI, 0.92 to 0.99). However, Bayesian interim analysis was associated with >99.99% posterior probability of reducing patient enrollment requirements ( P < 0.0001), with an estimated cumulative enrollment reduction of 20,543 patients (11%; 89 patients averaged equally over all studied trials) and an estimated cumulative cost savings of 851 million USD (3.7 million USD averaged equally over all studied trials). CONCLUSIONS AND RELEVANCE: Bayesian interim analyses may improve randomized trial efficiency by reducing enrollment requirements without compromising trial interpretation. Increased utilization of Bayesian interim analysis has the potential to reduce costs of late-phase trials, reduce patient exposures to ineffective therapies, and accelerate approvals of effective therapies. KEY POINTS: Question: What are the effects of Bayesian early stopping rules on the efficiency of phase III randomized oncology trials?Findings: Individual-patient level outcomes were reconstructed for 184,752 patients from 230 trials. Compared with the original interim analysis strategy, in silico Bayesian interim analysis reduced patient enrollment requirements and preserved the original trial interpretation. Meaning: Bayesian interim analysis may improve the efficiency of conducting randomized trials, leading to reduced costs, reduced exposure of patients to disadvantageous treatments, and accelerated approval of efficacious therapies.

Molecular Characterization of Metastatic Oncocytoma With Exceptional Response to Treatment: A Case Report.

Comprehensive molecular characterization and effective therapy in a rare case of metastatic renal oncocytoma.

Lost in the plot: missing visual elements in Kaplan-Meier plots of phase III oncology trials.

Missing visual elements (MVE) in Kaplan-Meier (KM) curves can misrepresent data, preclude curve reconstruction, and hamper transparency. This study evaluated KM plots of phase III oncology trials. MVE were defined as an incomplete y-axis range or missing number at risk table in a KM curve. Surrogate endpoint KM curves were additionally evaluated for complete interpretability, defined by (1) reporting the number of censored patients and (2) correspondence of the disease assessment interval with the number at risk interval. Among 641 trials enrolling 518 235 patients, 116 trials (18%) had MVE in KM curves. Industry sponsorship, larger trials, and more recently published trials were correlated with lower odds of MVE. Only 3% of trials (15 of 574) published surrogate endpoint KM plots with complete interpretability. Improvements in the quality of KM curves of phase III oncology trials, particularly for surrogate endpoints, are needed for greater interpretability, reproducibility, and transparency in oncology research.