Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.     

Associations of common SNPs in the SORT1, GCKR,LPL, APOA1, CETP,LDLR, APOE genes with lipid trait levels in an Algerian population sample

Genome-wide association studies have identified many lipid-associated loci primarily in European and Asian populations. In view of the differences between ethnic groups in terms of the frequency and impact of these variants, our objective was to evaluate the relationships between eight lipid-associated variants (considered individually and in combination) and fasting serum triglyceride, total cholesterol, HDL- and LDL-cholesterol levels in an Algerian population sample (ISOR study, n = 751). Three SNPs (in SORT1, CETP and GCKR) were individually associated with lipid level variations. Moreover, the risk allele scores for total cholesterol, triglyceride and LDL-C levels (encompassing between three and six SNPs) were associated with their corresponding lipid traits. Our study is the first to show that some of the lipid-associated loci in European populations are associated with lipid traits in Algerians. Although our results will have to be confirmed in other North African populations, this study contributes to a better understanding of genetic susceptibility to lipid traits in Algeria.     

Using Weighted Hospital Service Area Networks to Explore Variation in Preventable Hospitalization

Objective

To demonstrate the use of multiple‐membership multilevel models, which analytically structure patients in a weighted network of hospitals, for exploring between‐hospital variation in preventable hospitalizations.

Data Sources

Cohort of 267,014 people aged over 45 in NSW, Australia.

Study Design

Patterns of patient flow were used to create weighted hospital service area networks (weighted‐HSANs) to 79 large public hospitals of admission. Multiple‐membership multilevel models on rates of preventable hospitalization, modeling participants structured within weighted‐HSANs, were contrasted with models clustering on 72 hospital service areas (HSAs) that assigned participants to a discrete geographic region.

Data Collection/Extraction Methods

Linked survey and hospital admission data.

Principal Findings

Between‐hospital variation in rates of preventable hospitalization was more than two times greater when modeled using weighted‐HSANs rather than HSAs. Use of weighted‐HSANs permitted identification of small hospitals with particularly high rates of admission and influenced performance ranking of hospitals, particularly those with a broadly distributed patient base. There was no significant association with hospital bed occupancy.

Conclusion

Multiple‐membership multilevel models can analytically capture information lost on patient attribution when creating discrete health care catchments. Weighted‐HSANs have broad potential application in health services research and can be used across methods for creating patient catchments.