Sequential parallel comparison design with binary and time-to-event outcomes.

Sequential parallel comparison design (SPCD) has been proposed to increase the likelihood of success of clinical trials especially trials with possibly high placebo effect. Sequential parallel comparison design is conducted with 2 stages. Participants are randomized between active therapy and placebo in stage 1. Then, stage 1 placebo nonresponders are rerandomized between active therapy and placebo. Data from the 2 stages are pooled to yield a single P value. We consider SPCD with binary and with time-to-event outcomes. For time-to-event outcomes, response is defined as a favorable event prior to the end of follow-up for a given stage of SPCD. We show that for these cases, the usual test statistics from stages 1 and 2 are asymptotically normal and uncorrelated under the null hypothesis, leading to a straightforward combined testing procedure. In addition, we show that the estimators of the treatment effects from the 2 stages are asymptotically normal and uncorrelated under the null and alternative hypothesis, yielding confidence interval procedures with correct coverage. Simulations and real data analysis demonstrate the utility of the binary and time-to-event SPCD.

Can Radiologic Staging With Multiparametric MRI Enhance the Accuracy of the Partin Tables in Predicting Organ-Confined Prostate Cancer?

OBJECTIVE: The purpose of this study is to investigate the accuracy of multiparametric MRI with endorectal coil and Partin tables in predicting organ-confined (OC) prostate cancer in a contemporary cohort undergoing radical prostatectomy (RP) and to assess the possible added value of radiologic staging based on multiparametric MRI to the predictive accuracy of Partin tables. MATERIALS AND METHODS: One hundred fifty-eight consecutive subjects underwent 3-T multiparametric MRI with endorectal coil before RP between November 2010 and November 2013. Data were randomly split 60% and 40% into derivation (n = 95) and validation (n = 62) datasets. Multiparametric MRI was used to assess the radiologic stage, and logistic regression models were created using the derivation dataset and were fit on the independent validation dataset using multiparametric MRI staging alone and with prostate-specific antigen (PSA) level as the covariate. The probability of each patient to harbor OC disease was calculated using an updated version of Partin tables, using either clinical staging from digital rectal examination (DRE) or radiologic staging (multiparametric MRI). The AUC was calculated to evaluate accuracy of these predictive methods. RESULTS: The accuracy of multiparametric MRI to predict OC disease on pathologic analysis was greater (AUC, 0.88) than that of Partin tables (AUC, 0.70) and improved when multiparametric MRI was combined with PSA level (AUC, 0.91). The accuracy of Partin nomograms to predict OC disease decreased (AUC, 0.63) when staging was based on multiparametric MRI versus DRE. CONCLUSION: The superior predictive accuracy of multiparametric MRI compared with Partin tables to predict OC disease validates the results of smaller previously published studies. Although there is no added benefit of substituting multiparametric MRI stage for clinical stage when using Partin tables, multiparametric MRI staging information is valuable as a stand-alone test.

Open-Label, Single-Arm Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Clear Cell Renal Cell Carcinoma.

PURPOSE: Pembrolizumab, a programmed death 1 inhibitor, demonstrated promising single-agent activity in untreated patients with various cancer types. The phase II KEYNOTE-427 study evaluated efficacy and safety of single-agent pembrolizumab in treatment-naive patients with advanced clear cell renal cell carcinoma (ccRCC; cohort A) and advanced non-ccRCC (cohort B). Results of cohort A are reported. METHODS: In this open-label, single-arm phase II study, patients with advanced ccRCC received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. The primary end point was objective response rate by RECIST, version 1.1. RESULTS: In the total population (N = 110), median time from enrollment to data cutoff was 35.9 (range, 29.5-40.3) months. Objective response rate was 36.4% with four (3.6%) complete responses and 36 (32.7%) partial responses; disease control rate was 58.2% (95% CI, 48.4 to 67.5). Most patients (68.2%) had a decrease in target lesions, including 30.9% with a reduction ≥ 60%. Median duration of response was 18.9 (range, 2.3-37.6+) months; 64.1% of responders had a response ≥ 12 months (Kaplan-Meier). Median progression-free survival was 7.1 months (95% CI, 5.6 to 11.0). Median overall survival was not reached; 12-month and 24-month overall survival rates were 88.2% and 70.8%, respectively. Durable responses were observed across all International Metastatic RCC Database Consortium categories. Grade 3-5 treatment-related adverse events were reported in 30.0% of patients, of which colitis and diarrhea were most frequent. CONCLUSION: Single-agent pembrolizumab showed promising antitumor activity as a first-line treatment in patients with advanced ccRCC, with durable responses across International Metastatic RCC Database Consortium categories. Safety and tolerability profile of pembrolizumab monotherapy was comparable to what has been previously described in other tumor types.

Open-Label, Single-Arm, Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma.

PURPOSE: Programmed death 1 (PD-1) pathway inhibitors have not been prospectively evaluated in patients with non-clear cell renal cell carcinoma (nccRCC). The phase II KEYNOTE-427 study (cohort B) was conducted to assess the efficacy and safety of single-agent pembrolizumab, a PD-1 inhibitor, in advanced nccRCC. METHODS: Patients with histologically confirmed, measurable (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) nccRCC and no prior systemic therapy received pembrolizumab 200 mg intravenously once every 3 weeks for ≤ 24 months. The primary end point was objective response rate (ORR) per RECIST v1.1. RESULTS: Among enrolled patients (N = 165), 71.5% had confirmed papillary, 12.7% had chromophobe, and 15.8% had unclassified RCC histology. Most patients (67.9%) had intermediate or poor International Metastatic RCC Database Consortium risk status and tumors with programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 (61.8%). The median time from enrollment to database cutoff was 31.5 months (range, 22.7-38.8). In all patients, the ORR was 26.7%. The median duration of response was 29.0 months; 59.7% of responses lasted ≥ 12 months. The ORR by CPS ≥ 1 and CPS < 1 status was 35.3% and 12.1%, respectively. The ORR by histology was 28.8% for papillary, 9.5% for chromophobe, and 30.8% for unclassified. Overall, the median progression-free survival was 4.2 months (95% CI, 2.9 to 5.6); the 24-month rate was 18.6%. The median overall survival was 28.9 months (95% CI, 24.3 months to not reached); the 24-month rate was 58.4%. Overall, 69.7% of patients reported treatment-related adverse events, most commonly pruritus (20.0%) and hypothyroidism (14.5%). Two deaths were treatment related (pneumonitis and cardiac arrest). CONCLUSION: First-line pembrolizumab monotherapy showed promising antitumor activity in nccRCC. The safety profile was similar to that observed in other tumor types.

New prostate cancer prognostic grade group (PGG): Can multiparametric MRI (mpMRI) accurately separate patients with low-, intermediate-, and high-grade cancer?

PURPOSE: Our objective is to determine the accuracy of multiparametric MRI (mpMRI) in predicting pathologic grade of prostate cancer (PCa) after radical prostatectomy (RP) using simple apparent diffusion coefficient metrics and, specifically, whether mpMRI can accurately separate disease into one of two risk categories (low vs. higher grade) or one of three risk categories (low, intermediate, or high grade) corresponding to the new prognostic grade group (PGG) criteria. METHODS: This retrospective, HIPAA-compliant, IRB-approved study included 140 patients with PCa who underwent 3 T mpMRI with endorectal coil and transrectal ultrasound-guided (TRUS-G) biopsy before RP. MpMRI was used to classify lesions using a two-tier (low-grade/PGG 1 vs. high-grade/PGG 2-5) or a three-tier system (low-grade/PGG 1 vs. intermediate-grade/PGG 2 vs. high-grade/PGG 3-5). Accuracy of mpMRI was compared against RP for each system. RESULTS: The predictive accuracy of mpMRI using the two-tier system is higher than when using three-tier system (0.77 and 0.45, respectively). There were similar rates of undergrading between mpMRI and TRUS-G biopsy compared to RP (16% & 21%; respectively); rate of overgrading was higher for mpMRI vs. TRUS-G biopsy compared to RP (42% & 17%, respectively). When mpMRI and TRUS-G biopsy are combined, rate of undergrading is 1.4% and overgrading is 11%. CONCLUSIONS: MpMRI predictive accuracy is higher when using a two-tier vs. a three-tier system, suggesting that advanced metrics may be necessary to delineate intermediate- from high-grade disease. Rates of under- and overgrading decreased when mpMRI and TRUS-G biopsy are combined, suggesting that these techniques may be complementary in predicting tumor grade.