Background: Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are widely used as first-line therapy for hormone receptor–positive metastatic breast cancer (HR+ MBC). Although abemaciclib monotherapy is also FDA-approved for treatment of disease progression on endocrine therapy, there is limited insight into the clinical activity of abemaciclib after progression on prior CDK4/6i. Patients and Methods: We identified patients with HR+ MBC from 6 cancer centers in the United States who received abemaciclib after disease progression on prior CDK4/6i, and abstracted clinical features, outcomes, toxicity, and predictive biomarkers. Results: In the multicenter cohort, abemaciclib was well tolerated after a prior course of CDK4/6i (palbociclib)-based therapy; a minority of patients discontinued abemaciclib because of toxicity without progression (9.2%). After progression on palbociclib, most patients (71.3%) received nonsequential therapy with abemaciclib (with ≥1 intervening non-CDK4/6i regimens), with most receiving abemaciclib with an antiestrogen agent (fulvestrant, 47.1%; aromatase inhibitor, 27.6%), and the remainder receiving abemaciclib monotherapy (19.5%). Median progression-free survival for abemaciclib in this population was 5.3 months and median overall survival was 17.2 months, notably similar to results obtained in the MONARCH-1 study of abemaciclib monotherapy in heavily pretreated HR+/HER2-negative CDK4/6i-naïve patients. A total of 36.8% of patients received abemaciclib for ≥6 months. There was no relationship between the duration of clinical benefit while on palbociclib and the subsequent duration of treatment with abemaciclib. RB1, ERBB2, and CCNE1 alterations were noted among patients with rapid progression on abemaciclib. Conclusions: A subset of patients with HR+ MBC continue to derive clinical benefit from abemaciclib after progression on prior palbociclib. These results highlight the need for future studies to confirm molecular predictors of cross-resistance to CDK4/6i therapy and to better characterize the utility of abemaciclib after disease progression on prior CDK4/6i.

Purpose: While FGFR1 amplification has been described in breast cancer, the optimal treatment approach for FGFR1amplified (FGFR1 þ ) metastatic breast cancer (MBC) remains undefined.Experimental Design: We evaluated clinical response to endocrine and targeted therapies in a cohort of patients with hormone receptor-positive (HR þ )/HER2 À MBC and validated the functional role of FGFR1-amplification in mediating response/resistance to hormone therapy in vitro.Results: In the clinical cohort (N ¼ 110), we identified that patients with FGFR1 þ tumors were more likely to have progesterone receptor (PR)-negative disease (47% vs. 20%; P ¼ 0.005), coexisting TP53 mutations (41% vs. 21%; P ¼ 0.05), and exhibited shorter time to progression with endocrine therapy alone and in combination with CDK4/6 inhibitor, but not with a mTOR inhibitor (everolimus), adjusting for key prognostic variables in multivariate analysis. Furthermore, mTOR-based therapy resulted in a sustained radiological and molecular response in an index case of FGFR1 þ HR þ /HER2 À MBC. In preclinical models, estrogen receptor-positive (ER þ )/FGFR1-amplified CAMA1 human breast cancer cells were only partially sensitive to fulvestrant, palbociclib, and alpelisib, but highly sensitive to everolimus. In addition, transduction of an FGFR1 expression vector into ER þ T47D cells induced resistance to fulvestrant that could be overcome by added TORC1 inhibition, but not PI3K or CDK4/6 inhibition.Conclusions: Collectively, these findings suggest that while FGFR1 amplification confers broad resistance to ER, PI3K, and CDK4/6 inhibitors, mTOR inhibitors might have a unique therapeutic role in the treatment of patients with ER þ /FGFR1 þ MBC.

This study compared the efficacy of two protocols for oral care using either chlorhexidine or benzydamine as oral rinses to alleviate mucositis in children undergoing chemotherapy. Eligible participants were randomised to receive either protocol for 3 weeks in a two-period crossover design. The occurrence of ulcerative lesions and severity of mucositis were measured at baseline and twice weekly, using the modified Oral Assessment Guide (OAG). Data were continuously analysed by plotting them directly on predefined sequential charts. According to this sequential analysis, the study could be terminated at the 34th within subject comparison, with a statistically significant reduction in ulcerative lesions (P<0.05) and severity of mucositis (P<0.05) in children on the chlorhexidine protocol. These findings suggest that chlorhexidine together with oral care might be helpful in alleviating mucositis when given prophylactically to children on chemotherapy, but the therapeutic benefit needs to be confirmed in a larger trial.

1057 Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are widely used for pts with HR+/HER2- MBC. The MONARCH-1 trial of abemaciclib monotherapy in pre-treated pts demonstrated a median progression free survival (PFS) of 6.0 months, leading to approval as monotherapy in a CDK4/6i-naïve population. There are no data on abemaciclib in HR+/HER2- MBC after progressive disease (PD) with CDK4/6i. Methods: We evaluated clinical outcomes in pts with HR+/HER2- MBC who received abemaciclib following PD on prior palbociclib or ribociclib at 4 US academic centers. We conducted genomic analysis utilizing next-generation sequencing of tissue samples and blood (cell-free/cfDNA) when available. Results: From 2/2015 through 1/2019, 58 pts with HR+/HER2- MBC received abemaciclib following PD on prior palbociclib. 20 pts (34%) received sequential courses of therapy, while 38 pts (66%) had at least one intervening non-CDK4/6i regimen. 14 pts (24%) received abemaciclib monotherapy and 44 pts (76%) received it in combination with an antiestrogen, including fulvestrant (52%), an aromatase inhibitor (22%), and tamoxifen (2%). 22 pts (38%) required dose reduction, while 7 (12%) discontinued due to toxicity. At data cutoff (1/23/2019), 20 pts (34%) had early PD (duration < 90 days), while 21 pts (36%) had treatment duration exceeding 6 months, including 10 who remain on treatment at interim analysis (range 181-413 days). The median PFS was 5.8 months (95%CI 3.4 – 8.0). Preliminary analysis of cfDNA revealed RB1 and FGFR1 alterations in pts with PD on abemaciclib. Additional analyses with mature clinical data and genomic sequencing will be provided at the meeting. Conclusions: This is the first multi-center experience to demonstrate that a substantial proportion of pts continue to derive clinical benefit with abemaciclib after prior CDK4/6i, highlighting the potential for its use following CDK4/6 blockade. A second subset had early progression, suggesting cross-resistance to CDK4/6i via common pathways. Future effort should be directed towards validating potential biomarkers to guide optimal utilization of continued CDK4/6 blockade in HR+/HER2- MBC.