Tumor Mutational Burden as a Predictive Biomarker for Response to Immune Checkpoint Inhibitors: A Review of Current Evidence.

Treatment with immune checkpoint inhibitors (ICPIs) extends survival in a proportion of patients across multiple cancers. Tumor mutational burden (TMB)-the number of somatic mutations per DNA megabase (Mb)-has emerged as a proxy for neoantigen burden that is an independent biomarker associated with ICPI outcomes. Based on findings from recent studies, TMB can be reliably estimated using validated algorithms from next-generation sequencing assays that interrogate a sufficiently large subset of the exome as an alternative to whole-exome sequencing. Biological processes contributing to elevated TMB can result from exposure to cigarette smoke and ultraviolet radiation, from deleterious mutations in mismatch repair leading to microsatellite instability, or from mutations in the DNA repair machinery. A variety of clinical studies have shown that patients with higher TMB experience longer survival and greater response rates following treatment with ICPIs compared with those who have lower TMB levels; this includes a prospective randomized clinical trial that found a TMB threshold of ≥10 mutations per Mb to be predictive of longer progression-free survival in patients with non-small cell lung cancer. Multiple trials are underway to validate the predictive values of TMB across cancer types and in patients treated with other immunotherapies. Here we review the rationale, algorithm development methodology, and existing clinical data supporting the use of TMB as a predictive biomarker for treatment with ICPIs. We discuss emerging roles for TMB and its potential future value for stratifying patients according to their likelihood of ICPI treatment response. IMPLICATIONS FOR PRACTICE: Tumor mutational burden (TMB) is a newly established independent predictor of immune checkpoint inhibitor (ICPI) treatment outcome across multiple tumor types. Certain next-generation sequencing-based techniques allow TMB to be reliably estimated from a subset of the exome without the use of whole-exome sequencing, thus facilitating the adoption of TMB assessment in community oncology settings. Analyses of multiple clinical trials across several cancer types have demonstrated that TMB stratifies patients who are receiving ICPIs by response rate and survival. TMB, alongside other genomic biomarkers, may provide complementary information in selecting patients for ICPI-based therapies.

Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes.

BACKGROUND: Recently developed technologies for the treatment of type 1 diabetes mellitus include a variety of pumps and pumps with glucose sensors. METHODS: In this 1-year, multicenter, randomized, controlled trial, we compared the efficacy of sensor-augmented pump therapy (pump therapy) with that of a regimen of multiple daily insulin injections (injection therapy) in 485 patients (329 adults and 156 children) with inadequately controlled type 1 diabetes. Patients received recombinant insulin analogues and were supervised by expert clinical teams. The primary end point was the change from the baseline glycated hemoglobin level. RESULTS: At 1 year, the baseline mean glycated hemoglobin level (8.3% in the two study groups) had decreased to 7.5% in the pump-therapy group, as compared with 8.1% in the injection-therapy group (P<0.001). The proportion of patients who reached the glycated hemoglobin target (<7%) was greater in the pump-therapy group than in the injection-therapy group. The rate of severe hypoglycemia in the pump-therapy group (13.31 cases per 100 person-years) did not differ significantly from that in the injection-therapy group (13.48 per 100 person-years, P=0.58). There was no significant weight gain in either group. CONCLUSIONS: In both adults and children with inadequately controlled type 1 diabetes, sensor-augmented pump therapy resulted in significant improvement in glycated hemoglobin levels, as compared with injection therapy. A significantly greater proportion of both adults and children in the pump-therapy group than in the injection-therapy group reached the target glycated hemoglobin level. (Funded by Medtronic and others; ClinicalTrials.gov number, NCT00417989.)

Accuracy performance of the Medtronic NexSensor™ for 6 days in an inpatient setting using abdomen and buttocks insertion sites.

BACKGROUND: Users of continuous glucose monitoring are concerned with product accuracy and choice of insertion site. The Medtronic NexSensor™ was evaluated for accuracy during 6 days of wear when inserted in the abdomen and buttocks areas. METHODS: Adults (ages 18-75) with type 1 diabetes wore two sensors simultaneously for 6 days, one each inserted in the abdomen and buttocks. Subjects underwent a frequent blood sampling study for 12 hours, during which time reference blood glucose values were obtained every 15 minutes and compared to sensor values. RESULTS: Sixty-three subjects were enrolled, and 61 subjects completed the study. The mean agreement rate between sensor and blood glucose values was 75.5% [95% confidence interval (CI), 69.5, 81.4] at the abdomen site, 73.8% (95% CI, 68.8, 78.8) at the buttocks site, and 75.6% (95% CI, 70.8, 80.4) when sensor and reference data were combined between sites. Over 90% of paired sensor-reference values on Clarke error grids were within the A and B ranges. The mean absolute relative differences were 17.1% at the abdomen site, 16.5% at the buttocks site, and 16.8% when sites were combined. CONCLUSION: The NexSensor was accurate for inpatient, frequent-sample testing for 6 days when inserted into the abdomen and buttocks. The results of this study also provide evidence that both the abdomen and buttocks are suitable as sensor insertion sites.

Baseline predictors of A1C reduction in adults using sensor-augmented pump therapy or multiple daily injection therapy: the STAR 3 experience.

BACKGROUND: Baseline characteristics from the adult cohort of a randomized controlled trial comparing sensor-augmented pump (SAP) and multiple daily injection (MDI) therapy were analyzed for significant relationships with -0.5% A1C change at 1 year of therapy without incidence of severe hypoglycemia (defined as A1C benefit). METHODS: Baseline characteristics were compared with A1C benefit. Statistically significant predictors were analyzed further to determine appropriate cutpoints of relative A1C benefit. RESULTS: Baseline A1C ≥9.1%, age at randomization ≥36 years, and age at diabetes diagnosis of ≥17 years were associated with a greater SAP benefit relative to MDI than other cutpoints. CONCLUSIONS: People with type 1 diabetes who had a high A1C and who were older at diagnosis and older at randomization experienced the most benefit from SAP therapy.

Improved A1C by switching to continuous subcutaneous insulin infusion from injection insulin therapy in type 2 diabetes: A retrospective claims analysis.

AIMS: This study was a real-world, retrospective evaluation of the clinical effectiveness of switching to continuous subcutaneous insulin infusion (CSII) among managed care enrollees with type 2 diabetes for whom multiple daily injections (MDI) had presumably failed. METHODS: Administrative claims with integrated A1C values from a large and geographically diverse health plan were analyzed. RESULTS: Statistically significant A1C reductions (from the baseline period to follow-up period, mean follow-up 17 months) were achieved with CSII. Among subjects using a long-acting and rapid-acting insulin regimen at baseline, A1C decreased to mean follow-up A1C by 0.8% and to minimum follow-up A1C by 1.2% (p<0.001). The proportion of subjects at target (A1C<7%) increased significantly from baseline to follow-up (8.4-22.9% [using mean A1C] and 32.8% [using minimum A1C]; both p<0.001). The rate of severe hypoglycemic events was similar from baseline to follow-up. CONCLUSIONS: CSII was associated with significant reductions in A1C without an increase in hypoglycemic events in insulin-taking people with type 2 diabetes, including subjects previously using a long-acting and rapid-acting insulin regimen.

Resource utilization with insulin pump therapy for type 2 diabetes mellitus.

OBJECTIVES: To evaluate the effects of switching from multiple daily injection (MDI) therapy to insulin pump therapy, also called continuous subcutaneous insulin infusion (CSII), on antidiabetic drug and healthcare resource utilization. STUDY DESIGN: This study was a retrospective analysis of administrative claims data from a large geographically diverse health plan in the United States from January 1, 2005, through April 30, 2008. METHODS: Changes in antidiabetic drug use, antidiabetic drug switching and augmentation, and healthcare utilization during the baseline period and after CSII initiation were assessed using paired t test. RESULTS: There were 3649 possible subjects, of whom 943 met the criteria for analysis. The mean number of antidiabetic drugs used decreased by 46% after CSII initiation, and the mean reduction in antidiabetic drug utilization was 0.67; both were statistically significant. More than one-third of subjects who were taking antidiabetic drugs before CSII initiation discontinued oral therapy after CSII initiation. The number of subjects using multiple antidiabetic drugs significantly decreased after CSII initiation by 58%, and rates of switching or augmenting significantly decreased from 42% at baseline to 25% after CSII initiation.The rates of emergency department visits and inpatient admissions significantly decreased, and the rate of ambulatory visits significantly increased. CONCLUSIONS: CSII was associated with significant decreases in antidiabetic drug and healthcare resource utilization, contributing to stability of care. The evidence from this study indicates that CSII should be considered as an option for patients with type 2 diabetes mellitus who are using MDI and are experiencing a high degree of antidiabetic drug and healthcare resource utilization.