Indirect comparison of capmatinib treatment from GEOMETRY mono-1 trial to SOC in German patients with locally advanced or metastatic NSCLC harboring METex14 skipping mutations.

BACKGROUND: This study provides comparative evidence of the selective MET inhibitor capmatinib versus standard of care (SOC) in first-line (1 L) and second-line (2 L) non-small cell lung cancer (NSCLC) patients with METex14 mutations in German routine care. METHODS: SOC data were collected from German routine care via retrospective chart review. Analyses were conducted as naive and propensity score adjusted (PSA) comparisons to capmatinib-treated patients within the GEOMETRY mono-1 trial. Effectiveness endpoints included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), time to CNS progression (CNSprog), and exploratory safety endpoints. RESULTS: The SOC arm included 119 patients in 1 L and 46 in 2 L versus 60 patients in 1 L and 81 in 2 L treated with capmatinib, with balanced baseline characteristics after PSA. In 1 L, the naive comparison showed a significant benefit of capmatinib versus SOC for OS (median: 25.49 vs 14.59 months; HR 0.58; 95 % CI 0.39-0.87; P = 0.011), PFS (median: 12.45 vs 5.03 months; HR: 0.44; 95 % CI: 0.31-0.63; P < 0.001), and ORR (event rate: 68.3 vs 26.9 %; RR 2.54; 95 % CI 1.80-3.58; P < 0.001). In 2 L, OS, PFS, and ORR showed positive trends favoring capmatinib over SOC. Capmatinib treatment in the 1 L and 2 L led to significant benefit in CNSprog. PSA analyses showed consistent results to naive analysis. Exploratory safety endpoints indicated a manageable safety profile for capmatinib. CONCLUSIONS: The present study demonstrates the important role of capmatinib in providing robust clinically meaningful benefit to patients with NSCLC harboring METex14 mutations and its significant role in preventing the development of brain metastases.

Tisagenlecleucel vs. historical standard of care in children and young adult patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia.

In the absence of randomized controlled trials comparing tisagenlecleucel vs. standard of care (SOC) in pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (r/r ALL), the objective was to compare the efficacy of tisagenlecleucel with historical controls from multiple disease registries using patient-level adjustment of the historical controls. The analysis is based on patient-level data of three tisagenlecleucel studies (ELIANA, ENSIGN and CCTL019B2001X) vs. three registries in Germany/Austria. Statistical analyses were fully pre-specified and propensity score weighting of the historical controls by fine stratification weights was used to adjust for relevant confounders identified by systematic literature review. Results showed high comparability of cohorts after adjustment with absolute SMD ≤ 0.1 for all pre-specified confounders and favorable outcomes for tisagenlecleucel compared to SOC for all examined endpoints. Hazard ratios for OS(Intention to treat)ITT,adjusted, EFS(Full analysis set)FAS,naïve and RFSFAS,naïve were 0.54 (95% CI: 0.41-0.71, p < 0.001), 0.67 (0.52-0.86, p = 0.001) and 0.77 (0.51-1.18, p = 0.233). The OSITT, adjusted, EFSFAS,naïve and RFSFAS,naive survival probability at 2 years was 59.49% for tisagenlecleucel vs. 36.16% for SOC population, 42.31% vs. 30.23% and 59.60% vs. 54.57%, respectively. Odds ratio for ORRITT,adjusted was 1.99 (1.33-2.97, p < 0.001). Results for OS and ORR were statistically significant after adjustment for confounders and provide evidence supporting a superiority of tisagenlecleucel in r/r ALL given the good comparability of cohorts after adjustment for confounders.

Surrogate threshold effect based on a meta-analysis for the predictive value of progression-free survival for overall survival in hormone receptor-positive, HER2-negative metastatic breast cancer.

PURPOSE: Clinical trials investigating therapies for metastatic breast cancer (mBC) generally use progression-free survival (PFS) as primary endpoint, which is not accepted as patient-relevant outcome within the German benefit assessment. Hence a validation of PFS as surrogate endpoint for overall survival (OS) is needed, e.g., in the indication of HR+, HER2-negative mBC. METHODS: A systematic search was conducted. RCT were included if at least one study arm investigated fulvestrant, letrozole, tamoxifen, exemestane, or anastrozole. Additionally, hazard ratios reported for OS/PFS including confidence interval or standard error were mandatory. Pearson correlation coefficient was calculated to estimate the relation of surrogate endpoint PFS and patient-relevant outcome OS as well as the surrogate threshold effect (STE) which is used to determine thresholds for the estimate of the surrogate endpoint. RESULTS: 16 studies with 5324 patients in total were included in the analyses. The correlation between hazard ratios of PFS and OS was statistically significant (r = 0.72, 95% CI 0.35-0.90) representing a positive linear relationship. STE analysis was applied. The meta-regression model revealed a STE for HRPFS of 0.60 and sensitivity analyses underlined robustness of the results. CONCLUSIONS: Based on the derived STE, it is possible to draw conclusions on a significant effect in OS for a hypothetical trial demonstrating an upper confidence limit of HRPFS < 0.60 in PFS. However, only final OS results are able to confirm if a clinical relevant difference in survival time can be achieved.

Metabolite profiling reveals new insights into the regulation of serum urate in humans.

Serum urate, the final breakdown product of purine metabolism, is causally involved in the pathogenesis of gout, and implicated in cardiovascular disease and type 2 diabetes. Serum urate levels highly differ between men and women; however the underlying biological processes in its regulation are still not completely understood and are assumed to result from a complex interplay between genetic, environmental and lifestyle factors. In order to describe the metabolic vicinity of serum urate, we analyzed 355 metabolites in 1,764 individuals of the population-based KORA F4 study and constructed a metabolite network around serum urate using Gaussian Graphical Modeling in a hypothesis-free approach. We subsequently investigated the effect of sex and urate lowering medication on all 38 metabolites assigned to the network. Within the resulting network three main clusters could be detected around urate, including the well-known pathway of purine metabolism, as well as several dipeptides, a group of essential amino acids, and a group of steroids. Of the 38 assigned metabolites, 25 showed strong differences between sexes. Association with uricostatic medication intake was not only confined to purine metabolism but seen for seven metabolites within the network. Our findings highlight pathways that are important in the regulation of serum urate and suggest that dipeptides, amino acids, and steroid hormones are playing a role in its regulation. The findings might have an impact on the development of specific targets in the treatment and prevention of hyperuricemia.