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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Two years of adjuvant abemaciclib combined with endocrine therapy (ET) resulted in a significant improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) that persisted beyond the 2-year treatment period in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer (EBC). Here, we report 5-year efficacy results from a prespecified overall survival (OS) interim analysis. In the intent-to-treat population, with a median follow-up of 54 months, the benefit of abemaciclib was sustained with hazard ratios of 0.680 (95% CI, 0.599 to 0.772) for IDFS and 0.675 (95% CI, 0.588 to 0.774) for DRFS. This persistence of abemaciclib benefit translated to continuous separation of the curves with a deepening in 5-year absolute improvement in IDFS and DRFS rates of 7.6% and 6.7%, respectively, compared with rates of 6% and 5.3% at 4 years and 4.8% and 4.1% at 3 years. With fewer deaths in the abemaciclib plus ET arm compared with the ET-alone arm (208 v 234), statistical significance was not reached for OS. No new safety signals were observed. In conclusion, abemaciclib plus ET continued to reduce the risk of developing invasive and distant disease recurrence beyond the completion of treatment. The increasing absolute improvement at 5 years is consistent with a carryover effect and further supports the use of abemaciclib in patients with high-risk EBC.

Purpose: Many patients with HR+, HER2- early breast cancer (EBC) will not experience recurrence or have distant recurrence with currently available standard therapies. However, up to 30% of patients with high-risk clinical and/or pathologic features may experience distant recurrence, many in the first few years. Superior treatment options are needed to prevent early recurrence and development of metastases for this group of patients. Abemaciclib is an oral, continuously dosed, CDK4/6 inhibitor approved for HR+, HER2- advanced breast cancer (ABC). Efficacy and safety of abemaciclib in ABC supported evaluation in the adjuvant setting., Methods: This open-label, phase III study included patients with HR+, HER2-, high-risk EBC, who had surgery and, as indicated, radiotherapy and/or adjuvant/neoadjuvant chemotherapy. Patients with four or more positive nodes, or one to three nodes and either tumor size ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%, were eligible and randomly assigned (1:1) to standard-of-care adjuvant endocrine therapy (ET) with or without abemaciclib (150 mg twice daily for 2 years). The primary end point was invasive disease-free survival (IDFS), and secondary end points included distant relapse-free survival, overall survival, and safety., Results: At a preplanned efficacy interim analysis, among 5,637 randomly assigned patients, 323 IDFS events were observed in the intent-to-treat population. Abemaciclib plus ET demonstrated superior IDFS versus ET alone ( P = .01; hazard ratio, 0.75; 95% CI, 0.60 to 0.93), with 2-year IDFS rates of 92.2% versus 88.7%, respectively. Safety data were consistent with the known safety profile of abemaciclib., Conclusion: Abemaciclib when combined with ET is the first CDK4/6 inhibitor to demonstrate a significant improvement in IDFS in patients with HR+, HER2- node-positive EBC at high risk of early recurrence.

Purpose Cognitive impairment is reported frequently by cancer survivors. There are no proven treatments. We evaluated a cognitive rehabilitation program (Insight) and compared it with standard care in cancer survivors self-reporting cognitive symptoms. Patients and Methods We recruited adult cancer survivors with a primary malignancy (excluding central nervous system malignancies) who had completed three or more cycles of adjuvant chemotherapy in the previous 6 to 60 months and reported persistent cognitive symptoms. All participants received a 30-minute telephone consultation and were then randomly assigned to the 15-week, home-based intervention or to standard care. Primary outcome was self-reported cognitive function (Functional Assessment of Cancer Therapy Cognitive Function [FACT-COG] perceived cognitive impairment [PCI] subscale): difference between groups after intervention (T2) and 6 months later (T3). Results A total of 242 participants were randomly assigned: median age, 53 years; 95% female. The primary outcome of difference in FACT-COG PCI was significant, with less PCI in the intervention group at T2 ( P < .001). This difference was sustained at T3 ( P < .001). At T2, there was a significant difference in all FACT-COG subscales, favoring the intervention. Neuropsychological results were not significantly different between the groups at T2 or T3. There were significantly lower levels of anxiety/depression and fatigue in the intervention group at T2. There were significant improvements in stress in the intervention group at both time points. There was no significant difference in quality of life between the groups at T2, but the intervention group had better quality of life at T3. Conclusion The intervention, Insight, led to improvements in cognitive symptoms compared with standard care. To our knowledge, this is the first large randomized controlled trial showing an improvement in self-reported cognitive function in cancer survivors, indicating that this intervention is a feasible treatment.

Background: Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2-positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain., Methods: In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2-positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T., Results: Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms., Conclusion: Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care., (© 2015 by American Society of Clinical Oncology.)

Purpose: Prolonged and disabling fatigue is prevalent after cancer treatment, but the early natural history of cancer-related fatigue (CRF) has not been systematically examined to document consistent presence of symptoms. Hence, relationships to cancer, surgery, and adjuvant therapy are unclear., Patients and Methods: A prospective cohort study of women receiving adjuvant treatment for early-stage breast cancer was conducted. Women (n = 218) were enrolled after surgery and observed at end treatment and at 1, 3, 6, 9, and 12 months as well as 5 years. Structured interviews and self-report questionnaires were used to record physical and psychologic health as well as disability and health care utilization. Patients with CRF persisting for 6 months were assessed to exclude alternative medical and psychiatric causes of fatigue. Predictors of persistent fatigue, mood disturbance, and health care utilization were sought by logistic regression., Results: The case rate for CRF was 24% (n = 51) postsurgery and 31% (n = 69) at end of treatment; it became persistent in 11% (n = 24) at 6 months and 6% (n = 12) at 12 months. At each time point, approximately one third of the patients had comorbid mood disturbance. Persistent CRF was predicted by tumor size but not demographic, psychologic, surgical, or hematologic parameters. CRF was associated with significant disability and health care utilization., Conclusion: CRF is common but generally runs a self-limiting course. Much of the previously reported high rates of persistent CRF may be attributable to factors unrelated to the cancer or its treatment.