#13 Background: BIG 1-98 compares letrozole (Let), tamoxifen (Tam) and sequences of Let and Tam as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. Initial results (published in 2005) demonstrated the superiority of Let over Tam in significantly prolonging disease-free survival (DFS) and reducing the risk of relapse in distant sites. Following these results, investigators were informed of the treatment allocation for patients randomized to Tam alone, and about one third of these patients opted to receive Let. The three Let-containing treatments remained blinded. We now evaluate Let and Tam given in sequence compared with Let alone and update the comparison of Let alone and Tam alone.
 Methods: 6182 patients were randomized to the 4-arm option (entry Sep99-May03) [Tam x 5 years (Tam), Let x 5 (Let), Tam x 2→Let x 3 (Tam→Let), or Let x 2→Tam x 3 (Let→Tam)]. Another 1828 patients were randomized to the 2-arm option (Tam vs. Let; entry Mar98-Mar00). The primary endpoint was DFS (time from randomization to first occurrence of invasive breast cancer recurrence, invasive contralateral breast cancer, second non-breast malignancy, or death from any cause). The presentation will focus on the clinically-relevant comparisons evaluating Tam→Let vs. Let and Let→Tam vs. Let, assessed from the time of randomization. Acknowledging multiple comparisons, the hazard ratios are presented with 99% confidence intervals (CIs).
 Results: The median follow-up time is 71 months. Hazard ratios comparing treatments from time of initial randomization in terms of DFS, overall survival, and time to distant recurrence are displayed below.
 
 With this long term follow-up, adverse events for Let and Tam are consistent with the known safety profile of both agents.
 A protocol-specified update of the previously-reported comparison of Let x 5 vs. Tam x 5 (i.e., the monotherapy arms, including patients in both the 2-arm and 4-arm options; N=4922) suggests improved survival for patients treated with Let (HR=0.87, 95% CI=0.75-1.02, p=0.08, 76 months median follow-up). In this comparison, about a quarter of the patients in the Tam arm crossed over to Let after 3-5 years of Tam.
 Conclusion: The sequential treatments did not improve DFS compared with Let alone. Trends support initial use of Let in patients at higher risk of relapse. Patients commenced on Let can be switched to Tam if required. Updated results of the monotherapy comparison suggest superior overall survival with Let compared with Tam. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 13.
Background: Abemaciclib is an orally administered, selective inhibitor of cyclin-dependent kinases 4 & 6 that is dosed on a twice daily continuous schedule. Abemaciclib has demonstrated clinical efficacy with a generally tolerable safety profile in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer in combination with fulvestrant in MONARCH 2 (NCT02107703) and in combination with non-steroidal aromatase inhibitors (NSAI) in MONARCH 3 (NCT02246621). These analyses were conducted to evaluate if patient and disease characteristics may better inform in whom and when abemaciclib should be initiated to define optimal treatment strategies. Methods: MONARCH 2 and 3 enrolled patients with HR+, HER2- advanced breast cancer. In MONARCH 2, patients whose disease had progressed while receiving endocrine therapy were treated with abemaciclib/placebo plus fulvestrant. In MONARCH 3, patients were treated with abemaciclib/placebo plus NSAI as initial therapy for advanced disease. An exploratory pooled analysis of the two studies was performed to determine significant prognostic factors. Efficacy results (progression-free survival [PFS] and objective response rate [ORR] in patients with measurable disease) were examined for patient subgroups corresponding to each of the identified significant prognostic factors. Subpopulation treatment effect pattern plot (STEPP) methodology was performed to examine the association between treatment-free interval (TFI) following adjuvant endocrine therapy and outcomes of endocrine therapy alone or in combination with abemaciclib in MONARCH 3. Results: Analyses of clinical factors in over 1000 patients confirmed the following to have prognostic value: bone-only disease, liver metastases, tumor grade, progesterone receptor (PgR) status, and ECOG performance status. Prognosis was poor in patients with liver metastases, PgR-negative tumors, and high-grade tumors. While all subpopulations benefited from the addition of abemaciclib to endocrine therapy regardless of prognosis, substantial benefit of abemaciclib was observed in poor prognosis subgroups, characterized by large increases in PFS (hazard ratios = 0.4 to 0.5) and ORR (over 30%). In addition, STEPP analysis of TFI on a subset of the MONARCH 3 population showed that patients with the shortest TFI appeared to have a poorer prognosis and received more benefit from the addition of abemaciclib compared to patients with longer TFI. Conclusions: This exploratory analysis has provided data that could help optimize treatment strategies by identifying that patients with poor prognostic factors may receive greater benefit from the addition of abemaciclib to endocrine therapy. Citation Format: Goetz MP, O'Shaughnessy J, Sledge Jr. GW, Martin M, Lin Y, Forrester T, Mockbee C, Smith IC, Di Leo A, Johnston S. The benefit of abemaciclib in prognostic subgroups: An exploratory analysis of combined data from the MONARCH 2 and 3 studies [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS6-02.
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