Purpose: neoMONARCH assessed the biological effects of abemaciclib in combination with anastrozole in the neoadjuvant setting. Patients and Methods: Postmenopausal women with stage I-IIIB HR þ /HER2 À breast cancer were randomized to a 2-week lead-in of abemaciclib, anastrozole, or abemaciclib plus anastrozole followed by 14 weeks of the combination. The primary objective evaluated change in Ki67 from baseline to 2 weeks of treatment. Additional objectives included clinical, radiologic, and pathologic responses, safety, as well as gene expression changes related to cell proliferation and immune response. Results: Abemaciclib, alone or in combination with anastrozole, achieved a significant decrease in Ki67 expression and led to potent cell-cycle arrest after 2 weeks of treatment compared with anastrozole alone. More patients in the abemaciclib-containing arms versus anastrozole alone achieved complete cell-cycle arrest (58%/68% vs. 14%, P < 0.001). At the end of treatment, following 2 weeks lead-in and 14 weeks of combination therapy, 46% of intent-to-treat patients achieved a radiologic response, with pathologic complete response observed in 4%. The most common all-grade adverse events were diarrhea (62%), constipation (44%), and nausea (42%). Abemaciclib, anastrozole, and the combination inhibited cell-cycle processes and estrogen signaling; however, combination therapy resulted in increased cytokine signaling and adaptive immune response indicative of enhanced antigen presentation and activated T-cell phenotypes. Conclusions: Abemaciclib plus anastrozole demonstrated biological and clinical activity with generally manageable toxicities in patients with HR þ /HER2 À early breast cancer. Abemaciclib led to potent cell-cycle arrest, and in combination with anastrozole, enhanced immune activation.

Patients with extensive-stage small-cell lung cancer (ED-SCLC) need improved outcomes in the relapsed/refractory setting. This phase II study evaluated the safety and efficacy of prexasertib, a checkpoint kinase 1 inhibitor, in platinum-sensitive and platinum-refractory ED-SCLC. Prexasertib demonstrated response rates of 5.2% in platinum-sensitive and 0% in platinum-refractory ED-SCLC. Prexasertib did not show prespecified efficacy as monotherapy in ED-SCLC. Background: This study assessed the checkpoint kinase 1 inhibitor prexasertib in patients with extensive-stage smallcell lung cancer (ED-SCLC). Patients and Methods: This was a parallel-cohort phase II study of 105 mg/m 2 prexasertib once every 14 days for patients who progressed after no more than two prior therapies and had platinum-sensitive (Cohort 1) or platinum-resistant/platinum-refractory (Cohort 2) disease. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Exploratory endpoints included biomarker identification and assessment of an alternative regimen (Cohort 3: 40 mg/m 2 days 1-3, 14-day cycle). Results:

Trauma with hemorrhagic shock (T/HS), has been shown to result in liver injury marked by hepatocyte apoptosis and heart failure marked by cardiomyocyte apoptosis, both of which we have shown to be prevented by IL-6 administration at resuscitation, and Stat3 largely mediated this. As specific mediators have not been delineated, we investigated the unfolded protein response (UPR), which, with marked activation, can lead to apoptosis. Prior studies of hepatic and cardiac injury examined limited repertoires of UPR elements, making it difficult to assess the role of the UPR in T/HS. This study describes the first global examination of the UPR transcriptome in the liver and heart following T/HS, demonstrating organ-specific UPR transcriptome changes. The non-canonical UPR chaperone, Hsp70, was most dysregulated following T/HS and may contribute to hepatocyte protection via an IL-6-mediated pathway, identifying a potential new therapeutic strategy to prevent hepatocyte death and organ dysfunction in T/HS.

BackgroundIn the phase 2 study JAHH (NCT02708095), treatment with baricitinib, an oral selective Janus kinase 1/2 inhibitor approved for the treatment of rheumatoid arthritis, resulted in significant improvements in patients with active SLE receiving standard background therapy compared with placebo.1 Expression of type I-associated interferon (IFN) responsive genes (IRGs) is elevated in patients with SLE.2 We developed a robust quantitative assay to measure changes in the IFN signature, and examined the relationship between the IFN signature and measures of clinical outcome.Methods314 patients were randomized 1:1:1 to receive placebo, baricitinib 2- or 4 mg once daily for 24 weeks in study JAHH. Total RNA isolated from whole blood was analyzed using a multiplex assay panel of 6 IRGs at baseline, and Weeks 2, 12, and 24. The assay was developed and optimized using RNA samples from 1760 patients with SLE enrolled in phase 3 trials of tabalumab (an anti-B cell activating factor monoclonal antibody),(2) along with healthy controls. The IFN signature assay produced a bimodal distribution.Results70% of patients had an elevated IFN signature at baseline. Baricitinib significantly reduced the IFN signature by Week 24 compared with placebo (2 mg:−20%, 4 mg:−24%, p0.05), with decreases observed as early as Week 2. In patients who had a high IFN signature at baseline, baricitinib 4 mg significantly reduced the IFN signature at Weeks 12 (-24%) and 24 (-23%) compared with placebo (p0.01); decreases were also observed at Weeks 12 and 24 with baricitinib 2 mg, but the difference from placebo was not statistically significant. Baricitinib 4 mg treatment resulted in significant clinical improvement in the resolution of arthritis or rash determined by the SLEDAI-2K.1 However, the effect of baricitinib on IFN signature reduction (change from baseline and absolute baseline value) did not correlate with SLEDAI-2K-defined clinical improvement at Week 12 or 24.ConclusionsA dose-dependent decrease in the IFN signature was observed in baricitinib-treated patients with SLE. Baricitinib treatment resulted in clinical improvement across various measures of SLE disease activity.1 Response was observed with baricitinib regardless of the change in the IFN gene signature. These data suggest that the clinical improvement observed in baricitinib-treated patients with SLE may be the result of baricitinib-mediated effects on multiple cytokine pathways that may include, but are not limited to, IFN signaling. Ongoing studies using gene arrays are now surveying global immune pathways to better characterize the mechanism of action of baricitinib in SLE.Funding Source(s):Eli Lilly and CompanyReferencesWallace, D. et al. DOI:10.1136/annrheumdis-2018-eular.1918Hoffman,W. et al. Arthritis Rheumatol 2017;69:643–654.