Background: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. Patients and methods: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for !5 years AE abemaciclib for 2 years. Cohort 1 enrolled patients with !4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor !5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (!20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. Results: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib þ ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) ¼ 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P ¼ 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR ¼ 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR ¼ 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. Conclusion: Abemaciclib þ ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.

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Purpose The antisense oligonucleotide, LY2275796, blocks expression of eIF-4E, an mRNA translation regulator upregulated in tumors. This Phase I study sought an appropriate LY2275796 dose in patients with advanced tumors. Experimental Design A 3-day loading dose, then weekly maintenance doses, were given to 1–3 patient cohorts, beginning with 100 mg and escalating. Plasma samples were collected to determine LY2275796 concentrations; tumor biopsies, to quantify eIF-4E mRNA/protein. Results Thirty patients with Stage 4 disease received ≥1 LY2275796 dose. A dose-limiting toxicity was observed at 1200 mg, with 1000 mg the maximum-tolerated dose. Across all dose levels, most patients (87%) had only grade 1–2 toxicities. LY2275796 pharmacokinetics supported the dosing regimen. Comparison of pre- and post-dose biopsies showed eIF-4E decreased in most patients. Fifteen patients had progressive disease, and seven patients achieved stable disease (minimum of 6 weeks) as best response, with two patients on therapy >3 months (one with melanoma, one with cystadenocarcinoma of the head/neck). Conclusions LY2275796 was well tolerated up to 1000 mg. Since tumor eIF-4E expression was decreased, but no tumor response observed, LY2275796 should be studied combined with other treatment modalities.