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.
Background: HF occur in about 75% of midlife women and are associated with quality of life disruption and premature endocrine therapy discontinuation among breast cancer survivors. Estrogen therapy, effective for HF, is contraindicated in hormone receptor-positive breast cancer (BC). Previous studies have suggested that Oxy could be effective in managing HF. Methods: This randomized, placebo (P)-controlled trial enrolled women who had experienced HF ≥28 times per week over >30 days and of sufficient severity to seek treatment. Patients (pts) were randomized to receive oral Oxy at two doses: 2.5mg BID for 6 weeks (Oxy2.5), 2.5mg BID for a week with subsequent increase to 5mg BID (Oxy5), or matching P, in equal ratios. Baseline and monthly questionnaires were administered including a HF diary, the HF related daily interference scale (HFRDIS) and a symptom experience questionnaire. The primary endpoint was intra-patient change in weekly HF score and frequency from baseline to end of study compared using Kruskal-Wallis tests. Results: 150 pts were accrued between 2/23/2017-3/5/2018. 4 pts cancelled before starting treatment and were excluded from analyses. This interim report includes the first 104 pts for which at least one post-baseline evaluation was available. Baseline characteristics were well-balanced between the arms. Sixty-two percent were on tamoxifen or an aromatase inhibitor for the duration of the study. Pts on both Oxy doses had a significantly greater reduction in HF score and frequency compared to P. Pts on Oxy2.5 had a mean change in HF score of -10 (SD 7.4) vs -5.1 (SD 9.7) with P, p=0.003; and a mean change in average weekly number of HF of -4.6 (SD 3.1) vs -2.3 (SD 3.9), p=0.002. Pts on Oxy5 had a mean change in HF score of -16.2 (SD 5.1) vs -5.1 (SD 9.7) with P, p<0.001; and a mean change in average weekly number of HF of -7.0 (SD 4.0) vs -2.3 (SD 3.9), p<0.001. Repeated measures mixed models confirmed that, after adjusting for baseline values, both Oxy arms had significantly lower HF scores and frequency compared to P (p<0.001). HFRDIS revealed that pts in both Oxy arms experienced improvement in the following HF interference measures: work, social activities, leisure activities, sleep, relations, life enjoyment, and overall quality of life. Pts on Oxy5 also had improvement in HF interference with mood. Pts on Oxy2.5 experienced more stomach pain (p=0.031), diarrhea (p=0.007), nausea (p=0.04), headaches (0.032), episodes of confusion (0.012), dry mouth (p=0.003) and dry eyes (0.027) compared to P. Pts on Oxy5 experienced more constipation (0.004), dry mouth (0.001) and difficulty urinating (0.004) compared to P. There were no differences in study discontinuation due to adverse effects between either Oxy arm and P (Oxy2.5 vs P, p=0.653; Oxy5 vs P, p=0.483). Conclusions: Oxy is superior to P for management of HF. Oxy2.5 and 5 were both associated with significant improvements in HF scores and frequency as well as improvement in HF interference with several quality of life measures. While pts on Oxy experienced more side effects than pts on P, rates of discontinuation due to adverse events were low. This study was supported by the Breast Cancer Research Foundation. Citation Format: Leon-Ferre RA, Novotny PJ, Faubion SS, Ruddy KJ, Flora D, Dakhil C, Rowland KM, Graham ML, Le-Lindqwister N, Loprinzi CL. A randomized, double-blind, placebo-controlled trial of oxybutynin (Oxy) for hot flashes (HF): ACCRU study SC-1603 [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 GS6-02.
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