Association of Extended Dosing Intervals or Delays in Pembrolizumab-based Regimens With Survival Outcomes in Advanced Non-small-cell Lung Cancer.

BACKGROUND: Besides modeling/simulation-based analysis, no post-approval studies have evaluated the optimal administration frequency of pembrolizumab in non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We performed a multicenter retrospective cohort study to evaluate the association between survival outcomes and treatment extensions/delays of pembrolizumab-based regimens in patients with advanced NSCLC. Those who had received at least 4 cycles in routine practice were divided into 2 groups: nonstandard (Non-Std, ≥ 2 cycles at intervals > 3 weeks + 3 days) and standard (Std, all cycles every 3 weeks or 1 cycle > 3 weeks + 3 days). RESULTS: Among 150 patients, 92 (61%) were eligible for the study (Non-Std, 27; Std, 65). The reasons for patients with extensions/delays in the Non-Std group included: immune-related adverse events (irAEs) (33%), non-irAE-related medical issues (26%), and patient-physician preference (41%). The Non-Std group was more likely to have a higher programmed death-ligand 1 tumor proportion score, a higher number of treatment cycles, and pembrolizumab monotherapy. Univariate and 6-month landmark analyses showed longer median overall survival and progression-free survival in the Non-Std group compared with the Std group. After multivariable adjustment for confounding factors, there was no significant difference in overall survival (hazard ratio, 1.2; 95% confidence interval, 0.3-4.8; P = .824) or progression-free survival (hazard ratio, 2.6; 95% confidence interval, 0.7-9.6; P = .157) between the 2 groups. CONCLUSION: Our study shows that a significant proportion of patients with advanced NSCLC receive pembrolizumab-based regimens with extended intervals or delays in routine clinical practice and with similar outcomes to those receiving treatment at label-specified 3-week intervals. Given the durability of benefit seen and the potential for cost reduction and decreased infusion frequency in these patients, this requires validation in prospective trials.

A Tlx2-Cre mouse line uncovers essential roles for hand1 in extraembryonic and lateral mesoderm.

Hand1 regulates development of numerous tissues within the embryo, extraembryonic mesoderm, and trophectoderm. Systemic loss of Hand1 results in early embryonic lethality but the cause has remained unknown. To determine if Hand1 expression in extraembryonic mesoderm is essential for embryonic survival, Hand1 was conditionally deleted using the HoxB6-Cre mouse line that expresses Cre in extraembryonic and lateral mesoderm. Deletion of Hand1 using HoxB6-Cre resulted in embryonic lethality identical to systemic knockout. To determine if lethality is due to Hand1 function in extraembryonic mesoderm or lateral mesoderm, we generated a Tlx2-Cre mouse line expressing Cre in lateral mesoderm but not extraembryonic tissues. Deletion of Hand1 using the Tlx2-Cre line results in embryonic survival with embryos exhibiting herniated gut and thin enteric smooth muscle. Our results show that Hand1 regulates development of lateral mesoderm derivatives and its loss in extraembryonic mesoderm is the primary cause of lethality in Hand1-null embryos.

Sonic hedgehog signaling is required for sympathetic nervous system development.

Sonic hedgehog (Shh) plays critical roles during nervous system development, yet little is known about its function in the sympathetic nervous system. Using a mouse Shh null line, we examined the roles of Shh during SNS development. Loss of Shh did not prevent formation of the sympathetic trunk, but the ganglia are hypoplastic and misspatterned. Neuronal differentiation was delayed in Shh mutant embryos showing that Shh is required for correct developmental timing in addition to its role in sympathetic nervous system patterning. Immunohistochemical analyses of the ganglia for expression of the pan-neuronal marker beta3-tubulin, the noradrenergic biosynthetic enzyme tyrosine hydroxylase and the glial marker B-FABP showed that Shh is not required for differentiation of sympathetic neurons or glia.