Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma.

BACKGROUND: Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously. Overall survival was the key secondary end point. Safety was a secondary end point. RESULTS: A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo. As of September 15, 2023, the median follow-up was 57.2 months. The disease-free survival benefit was consistent with that in previous analyses (hazard ratio for recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87). A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = 0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups. Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy. CONCLUSIONS: Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo, among participants with clear-cell renal-cell carcinoma at increased risk for recurrence after surgery. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).

Blood Pressure Visit Intensification in Treatment (BP-Visit) Findings: a Pragmatic Stepped Wedge Cluster Randomized Trial.

BACKGROUND: Shortening time between office visits for patients with uncontrolled hypertension represents a potential strategy for improving blood pressure (BP). OBJECTIVE: We evaluated the impact of multimodal strategies on time between visits and on improvement in systolic BP (SBP) among patients with uncontrolled hypertension. DESIGN: We used a stepped-wedge cluster randomized controlled trial with three wedges involving 12 federally qualified health centers with three study periods: pre-intervention, intervention, and post-intervention. PARTICIPANTS: Adult patients with diagnosed hypertension and two BPs ≥ 140/90 pre-randomization and at least one visit during post-randomization control period (N = 4277). INTERVENTION: The core intervention included three, clinician hypertension group-based trainings, monthly clinician feedback reports, and monthly meetings with practice champions to facilitate implementation. MAIN MEASURES: The main measures were change in time between visits when BP was not controlled and change in SBP. A secondary planned outcome was changed in BP control among all hypertension patients in the practices. KEY RESULTS: Median follow-up times were 34, 32, and 32 days and the mean SBPs were 142.0, 139.5, and 139.8 mmHg, respectively. In adjusted analyses, the intervention did not improve time to the next visit compared with control periods, HR = 1.01 (95% CI: 0.98, 1.04). SBP was reduced by 1.13 mmHg (95% CI: -2.10, -0.16), but was not maintained during follow-up. Hypertension control (< 140/90) in the practices improved by 5% during intervention (95% CI: 2.6%, 7.3%) and was sustained post-intervention 5.4% (95% CI: 2.6%, 8.2%). CONCLUSIONS: The intervention failed to shorten follow-up time for patients with uncontrolled BP and showed very small, statistically significant improvements in SBP that were not sustained. However, the intervention showed statistically and clinically relevant improvement in hypertension control suggesting that the intervention affected clinician decision-making regarding BP control apart from visit frequency. Future practice initiatives should consider hypertension control as a primary outcome. CLINICAL TRIAL: www.ClinicalTrials.gov Identifier: NCT02164331.

A new statistical test for latent class in censored data due to detection limit.

Biomarkers of interest in urine, serum, or other biological matrices often have an assay limit of detection. When concentration levels of the biomarkers for some subjects fall below the limit, the measures for those subjects are censored. Censored data due to detection limits are very common in public health and medical research. If censored data from a single exposure group follow a normal distribution or follow a normal distribution after some transformations, Tobit regression models can be applied. Given a Tobit regression model and a detection limit, the proportion of censored data can be determined. However, in practice, it is common that the data can exhibit excessive censored observations beyond what would be expected under a Tobit regression model. One common cause is heterogeneity of the study population, that is, there exists a subpopulation who lack such biomarkers and their values are always under the detection limit, and hence are censored. In this article, we develop a new test for testing such latent class under a Tobit regression model by directly comparing the amount of observed censored data with what would be expected under the Tobit regression model. A closed form of the test statistic as well as its asymptotic properties are derived based on estimating equations. Simulation studies are conducted to investigate the performance of the new test and compare the new one with the existing ones including the Wald test, likelihood ratio test, and score test. Two real data examples are also included for illustrative purpose.