Hobday, TJ

Abstract Cyclin dependent kinase 4 and 6 inhibitors (CDK4/6i) are standard first line (1L) and second line (2L) treatments of ER+ MBC. However, the optimal treatment strategy after progression on a CDK 4/6i is unknown. Given concern for rapid disease progression after discontinuation of CDK4/6is (Bashour, J Cancer 2017), further data on responses to subsequent lines of therapy post CDK4/6i are needed. We performed a single institution retrospective review of patients (pts) with ER+ MBC who received 1L or 2L CDK4/6i to examine the prescribing patterns and clinical responses to post-CDK4/6i treatment. Methods: We identified 136 ER+ MBC pts prescribed a CDK4/6i at Mayo Clinic Rochester (from 12/2014 to 2/2018) on 1L or 2L who received at least 30 days of therapy and ≥ two clinic visits during treatment. For the 1L and 2L cohorts we assessed the time to treatment failure during (TTF-1) and after CDK4/6i therapy (TTF-2). TTF was defined as time from start of therapy to discontinuation for any cause. Additionally, we assessed overall survival (OS) post CDK4/6i discontinuation (defined as the date of TTF-1 to death or last follow up). Results: The study cohort included 81 and 55 pts treated with 1L and 2L CDK4/6is, respectively. In the 1L cohort, palbociclib/letrozole (82.3%) and palbociclib/fulvestrant (13.6%) were most commonly prescribed. Treatment was discontinued in 39/81 pts due to: progression (84.6%), intolerability (7.7%), and other (7.7%). The median TTF-1 was 19.7 mo (95% CI 11.2 – 25.4 mo). Subsequent treatment and response data were available in 37/39 pts that progressed on 1L CDK4/6i. The most commonly prescribed regimens included single-agent hormonal therapy (29.7%), everolimus/exemestane (27.0%), and single agent chemotherapy (21.7%). The overall median TTF-2 were as follows: everolimus/exemestane 13.2 mo [95%CI 0.33 mo – not reached (NR)]; single agent hormonal therapy 3.1 mo (95%CI 1.4 – 5.4 mo); and single agent chemotherapy 4.1 mo (95%CI 1.4 - 5.4 mo). With a median post-CDK4/6i follow up of 11.2 mo, we observed 8 deaths and the median OS-post CDK4/6i was NR. In the 2L cohort, common regimens were palbociclib/letrozole (63.6%) and palbociclib/fulvestrant (27.3%). Treatment was discontinued in 30/55 pts due to: progression (73.3%), intolerability (13.3%), and other (13.3%). The median TTF-1 in the 2L cohort was 8.3 mo (95%CI 4.6 – 12.7 mo). Subsequent treatment data were available in 24/30 pts and included single-agent hormonal therapy [n=7 (29.2%); median TTF-2 4.7 mo; 95%CI 1.9 – 14.0 mo], everolimus/exemestane [n=6 (25.0%); median TTF-2 3.2 mo, 95% CI 0.8-10.1 mo)] and single agent chemotherapy [n=6 (25.0%); median TTF-2 2.6 mo; 95%CI 1.7 mo – NR)]. With a median post-CDK4/6i follow up 18.7 mo in the 2L cohort, we observed 11 deaths, and the median OS-post CDK4/6i was 11.8 mo (95%CI 11.8 mo – NR). Conclusions: Single and combination-based endocrine strategies are commonly administered post-CDK4/6i without clinical evidence for rapid deterioration. The observation of a median treatment duration lasting >12 months in patients receiving everolimus/exemestane post-CDK4/6i supports ongoing studies evaluating drugs that target PI3K/mTOR pathway in combination and following progression on a CDK4/6i. Citation Format: Giridhar KV, Choong GM, Leon-Ferre RA, O'Sullivan CC, Ruddy KJ, Haddad TC, Hobday TJ, Peethambaram PP, Moynihan TJ, Loprinzi CL, Liu MC, Suman VJ, Goetz MP. Clinical management of metastatic breast cancer (MBC) after CDK 4/6 inhibitors: A retrospective single-institution study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-09.

Abstract Background We evaluated the safety and efficacy of L+T in pts with 0–2 prior lines of chemotherapy (CT) for HER2+ MBC. In the context of this phase II trial, we evaluated metabolic response by FDG-PET and explored the relationship between metabolic response and clinical outcomes. Methods: Pts with measurable, HER2+ MBC were eligible. Cohort 1: No prior T, L, or CT +T for MBC, and >1 yr from adjuvant T, if received. Cohort 2: 1–2 prior lines of CT for MBC, including T, or relapse within 1 yr of adjuvant T. Pts received L 1,000 mg QD + T (2 mg/kg weekly or 6 mg/kg Q3W). Staging studies were done with CT or MRI at baseline (BL) and every 2 cycles (1 cycle=4 weeks [wks]). Objective response was assessed by local investigator according to RECIST 1.0. FDG-PET/CT was performed at BL, Wk 1, and Wk 8 per NCI guidelines. Central quality assurance, review, and analysis were performed on FDG-PET studies. Up to 5 target lesions were identified on BL FDG-PET images based on hypermetabolic uptake. Percent change in the summed maximum standardized uptake value (SUVmax) of target lesions was calculated at Wk 1 or Wk 8, compared to BL. Metabolic response was assessed according to EORTC criteria for % change in SUVmax (progressive disease [PD]: ≥25% increase; partial response [PR]: ≥25% decrease; stable disease [SD]: <25% change). Metabolic response at Wk 1 was compared to Wk 8 as well as to clinical outcome, including objective response, clinical benefit, and progression-free survival (PFS). Results: 87 pts were registered to the study. Of these, one pt did not begin protocol therapy and one pt did not have MBC on further testing, and are not included. 81/85 pts had FDG-PET data at Wk 1; 75/85 had data at Wk 8. Metabolic PR at Wk 1 was observed in 28/39 (72%) pts in Cohort 1 and 20/42 (48%) pts in Cohort 2. Metabolic PR at Wk 8 was observed in 27/34 (79%) pts in Cohort 1 and 18/41 (44%) pts in Cohort 2. Wk 1 and Wk 8 metabolic responses were similar. In cohort 1, 18/28 (64%) pts who achieved Wk 1 metabolic PR had clinical benefit by RECIST. Of pts with Wk 1 metabolic SD, 2/9 (22%) had clinical benefit. In cohort 2, 9/20 (45%) pts who achieved Wk 1 metabolic PR had clinical benefit; 5/22 (23%) who achieved Week 1 metabolic SD had clinical benefit. Exploratory analysis of progression-free survival (PFS) showed that pts in Cohort 1 who achieved Wk 1 metabolic PR experienced a median PFS of 9.3 months ([mos]; 95% CI 5.6−22.3); for pts with metabolic SD, median PFS was 1.9 mos (95% CI 0.8−5.5). For pts in Cohort 2, Wk 1 metabolic PR was associated with median PFS of 5.6 mos (95% CI 3.7−7.8), whereas for pts with metabolic SD, median PFS was 3.7 mos (95% CI 1.8−5.5). Conclusions: L+T is associated with a high rate of early and sustained metabolic response by FDG-PET. Exploratory analyses suggest that metabolic PR may be associated with clinical benefit and longer PFS. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-07.