bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of abemaciclib in patients (pts) with brain metastases (BM) secondary to HR+, HER2- metastatic breast cancer (MBC).
Authors: Anders Carey K. , Le Rhun Emilie , Bachelot Thomas Denis , Yardley Denise A. , Awada Ahmad , Conte Pier Franco , Kabos Peter , Bear Melissa , Yang Zhengyu , Chen Yanyun , Tolaney Sara M. 
Published: May 2019

1017 Background: Abemaciclib is a selective CDK4 & 6 inhibitor approved to treat HR+, HER2- MBC pts on a continuous dosing schedule as monotherapy or in combination with endocrine therapy (ET). Clinical data demonstrate abemaciclib penetrates the blood brain barrier resulting in comparable concentrations in tissues and plasma. Methods: JPBO is a Simon 2-stage trial evaluating abemaciclib in 6 pt cohorts with BM secondary to HR+ MBC, non-small cell lung cancer, or melanoma. Here, we report on HR+, HER2- MBC pts. Eligible pts had ≥1 new or not previously irradiated measurable BM ≥10mm or a progressive previously irradiated BM. Pts receiving ET at the time of enrollment were permitted to continue the same ET provided that extracranial (EC) disease was stable ≥3 months and the CNS progression occurred on the ET. Abemaciclib was orally administered 200mg BID. Primary endpoint was objective intracranial response rate (OIRR; [CR+PR]) based on Neuro-Oncology BM response assessment criteria (RANO-BM). Secondary endpoints included intracranial clinical benefit rate, PFS, and safety. Results: 58 HR+, HER2- MBC pts were enrolled and 52 pts were evaluable. Pts had a median of 4 prior systemic therapies, 75% of pts had prior chemotherapies (0-6, median of 2), and 71% of pts had prior ET (0-4, median of 1), in the metastatic setting. 50% of pts had prior whole brain radiotherapy, 39% stereotactic radiosurgery, and 8% surgical resection of BM. Median time from radiation to study enrollment was 9.4 months. Out of the 52 evaluable patients, 3 pts had a confirmed intracranial response (6% OIRR), and 38% of pts showed a decrease in the sum of their intracranial target lesions. Intracranial clinical benefit rate (CR+PR+SD persisting for ≥ 6 months) was 25%. Median PFS was 4.4 months (95% CI, 2.6-5.5). Safety and tolerability were similar to previous reports for abemaciclib. Conclusions: Abemaciclib demonstrated intracranial clinical benefit in heavily pretreated HR+, HER2- MBC pts with BM in this study. Further evaluations are ongoing to identify ABC patients with BM who might benefit most from abemaciclib. Clinical trial information: NCT02308020.
In-depth gene expression analysis of premenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with ribociclib-containing therapy in the Phase III MONALEESA-7 trial.
Authors: Lu Yen-Shen , Hurvitz Sara A. , Su Fei , He Wei , Tripathy Debu , Campos Gomez Saul , Jung Kyung Hae , Colleoni Marco , Wheatley-Price Paul , Kuemmel Sherko , Harbeck Nadia , Franke Fabio Andre , Im Seock-Ah , Chow Louis , Taran Tetiana , Rodriguez-Lorenc Karen , Babbar Naveen , Bardia Aditya 
Published: May 2019

1018 Background: The Phase III MONALEESA-7 study (NCT02278120) is the first dedicated trial of endocrine therapy (ET) ± a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in premenopausal patients (pts) with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) ABC. The study demonstrated that the addition of ribociclib (RIB) to a nonsteroidal aromatase inhibitor (NSAI) or tamoxifen (TAM) + goserelin (GOS) significantly extended progression-free survival (PFS; hazard ratio [HR] 0.55; Tripathy D, et al. Lancet Oncol. 2018). Here we present a gene expression analysis of baseline tumor mRNA from MONALEESA-7. Methods: Premenopausal pts with HR+/HER2− ABC were treated with RIB or placebo (PBO) + GOS with either an NSAI (letrozole or anastrozole) or TAM. Baseline archival tumor samples from 360 of 672 intent-to-treat (ITT) pts were evaluated for gene expression (RIB n = 185; PBO n = 175) using a customized NanoString nCounter® GX 800-gene panel containing relevant breast cancer, CDK, and proliferation pathway–related genes. Pt subgroups were classified as having low or high mRNA expression using median expression as the cutoff. Results: PFS benefit in the biomarker-assessed group was similar to that in the ITT population. A trend toward a more pronounced PFS benefit with RIB was observed in pts with high vs low expression of CCND1 (HR 0.38 vs 0.67, respectively), IGF1R (HR 0.33 vs 0.77), and ERBB3 (HR 0.33 vs 0.76). The PFS benefit seen with RIB also trended to be greater in pts with low vs high expression of CCNE1 (HR 0.38 vs 0.65, respectively) and MYC (HR 0.37 vs 0.69). The PFS benefit with RIB was similar in pts with high vs low expression of FGFR1 (HR 0.45 vs 0.61, respectively), ESR1 (HR 0.57 vs 0.57), and tumor proliferation genes, such as MKI67 (HR 0.50 vs 0.51). Conclusions: This is the first gene expression analysis of a large set of premenopausal pts with ABC. The benefit with RIB was generally consistent across gene expression subgroups, although the magnitude varied in certain subsets. This analysis suggests that there may be unique resistance mechanisms to ET ± CDK4/6 inhibitors in premenopausal pts with ABC. Clinical trial information: NCT02278120.
Genomic landscape of de novo stage IV breast cancer.
Authors: Garrido-Castro Ana Christina , Spurr Liam , Hughes Melissa E , Li Yvonne Y. , Cherniack Andrew D. , Bychkovsky Brittany L. , Barroso-Sousa Romualdo , Di Lascio Simona , Files Janet , Kumari Priti , Cerami Ethan , Krop Ian E. , MacConaill Laura E , Lindeman Neal Ian , Rollins Barrett J , Johnson Bruce E. , Wagle Nikhil , Winer Eric P. , Dillon Deborah , Lin Nancy U. 
Published: May 2019

1022 Background: Genomic profiling of primary and recurrent metastatic breast cancer (rMBC) has revealed potential resistance mechanisms to therapy. In contrast, de novo stage IV breast cancer (DNIV) represents an opportunity to elucidate metastatic drivers in the absence of treatment selection. Methods: Targeted NGS (Oncopanel, OP) using multiplexed copy number variation (CNV) and mutation (mut) detection across the full coding regions of 300 genes and selected intronic regions of 35 genes was performed on either primary or metastatic samples collected in patients (pts) with DNIV or rMBC. Mut/CNV in primary and metastatic tumors were compared per subtype between DNIV and rMBC using Fisher´s exact test (significant p<0.05). FDR were computed ( q<0.25). Results: Between 8/2013-9/2016, of 929 pts who underwent OP testing 212 presented with DNIV; 136 HR+/HER2- (64%); 35 HR+/HER2+ (17%); 25 TNBC (12%); 16 HR-/HER2+ (8%). In 168 (79%) pts, the primary was tested; 44 had a metastatic site tested. Comparison of primary HR+/HER2- tumors showed that DNIV pts were more likely to harbor mut in CDKN1B, SETD2 and PMS2 and less likely to have TP53 mut than rMBC (Table). Metastases in HR+/HER2- DNIV (n=29) had higher mut in CDH1, PTCH1 and CTNNB1 and fewer CCND1 amplification (amp) than rMBC (n=121), albeit these findings lost significance after FDR correction. DNIV primary TNBC (n=19) was significantly enriched for CIITA mut (26% vs. 0%; q=0.046) and MYB amp (21% vs. 0%, q=0.098) compared to rMBC (n=101). TP53 mut, amp in RAD21, MYC, MYB, PTK2 and EGFR, and deletions in CDKN2A/2B and MAP2K4 significantly predicted poorer overall survival in DNIV. Conclusions: DNIV primary and metastatic tumors have distinct genomic profiles compared to rMBC. Alterations in genes involved in epigenetic modulation ( KMT2D, SETD2) and epithelial-mesenchymal transition ( CDH1, PTCH1, CTNNB1) are more prevalent in HR+/HER2- DNIV. DNIV TNBC is enriched for CIITA mut, described to promote immune escape via reduced MHC class II expression. If validated, these findings may provide insight into mechanisms underlying metastatic potential. [Table: see text]
Immunotherapy predictive biomarkers in metastatic breast cancer (MBC).
Authors: Ross Jeffrey S. , Sokol Ethan , Albacker Lee A. , Frampton Garrett M. , Pavlick Dean , Elvin Julia Andrea , Vergilio Jo-Anne , Killian Jonathan Keith , Ngo Nhu , Lin Douglas I. , Ramkissoon Shakti , Severson Eric Allan , Ali Siraj Mahamed , Schrock Alexa Betzig , Chung Jon , Reddy Prasanth , McGregor Kimberly , Alexander Brian , Sivapiragasam Abirami , Miller Vincent A. 
Published: May 2019

1023 Background: We queried whether comprehensive genomic profiling (CGP) of mBC subtypes could identify biomarkers that have been linked to responsiveness to immunotherapy (IO) treatments. Methods: DNA was extracted from 3,871mBC: 1,388 ER+/HER2-, 1,969 HER2 amplified (amp) and 643 TNBC. CGP was performed using a hybrid-capture assay. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci in 564 cases. PD-L1 was determined by IHC (Dako 22C3). Results: Patient ages were similar. Genomic alterations (GA)/tumor were similar ranging from 5.9 to 7.3. MTOR pathway targets were common; lowest in TNBC. CDH1 and ESR1 GA most frequent in ER+/HER2- cases. ERBB2 short variant (SV) mut were most frequent in ER+/HER2- and HER2 amp and not seen in TNBC. Other kinase targets were uncommon except for FGFR1 GA in ER+/HER2-. BRCA1/ 2 GA least frequent in HER2 amp. AR was amplified in 1% of all mBC. Markers of potential IO benefit: CD274 ( PD-L1) amp (1-3%), BRAF GA (1-4%), TMB of ≥10 mut/Mb (8-12%), TMB of ≥20 mut/Mb (2-3%), MSI-High (0.1-0.4%), PBRM1 GA (1%) and low (1-10%) or high (0-3%) PD-L1 staining. Potential markers of resistance: inactivating GA in STK11 (1-2%) and MDM2 amplification (3-6%). Examples of mBC patients responding to IO therapies will be presented. Conclusions: In addition to guiding targeted therapy selection, CGP shows potential to identify GA linked to response and resistance to IO in mBC. The demonstrations of clinical benefit of immunotherapy in mBC supports the need for the development of biomarkers used to guide the use of ICPI drugs for these patients. [Table: see text]
Trastuzumab emtansine (T-DM1) and ribociclib, an oral inhibitor of cyclin dependent kinase 4 and 6 (CDK 4/6), for patients with metastatic HER2-positive breast cancer.
Authors: Spring Laura , Goel Shom , Sutherland Sara , Supko Jeffrey G. , Juric Dejan , Isakoff Steven J. , Mayer Erica L. , Moy Beverly , Tolaney Sara M. , Bardia Aditya 
Published: May 2019

1028 Background: Current therapeutic efforts in the management of HER2+ MBC focus on targeting the HER receptor family, however co-inhibition of targets downstream of the HER2 pathway, such as cyclin D-CDK 4/6, could enhance therapeutic efficacy. We conducted a phase 1b study of the CDK4/6 inhibitor ribociclib and T-DM1 in patients (pts) with HER2+ MBC. The primary objective was to determine the recommended phase 2 dose (RP2D) of ribociclib plus T-DM1. Secondary objectives included safety, PK assessments, and efficacy. Methods: Pts with HER2+ MBC who previously received at least 1 taxane and trastuzumab-containing regimen in any setting were eligible. Pts with previous CDK4/6 inhibitor exposure, QTcF > 450msec, or unstable brain metastases were excluded. Ribociclib was given orally for 2 weeks of a 21-day cycle (days 8-21), with T-DM1 given at 3.6 mg/kg every 3 weeks on day 1. A standard 3+3 dose escalation design was used to evaluate various doses of ribociclib in combination with T-DM1 to determine the RP2D. Results: From 5/2016 – 10/2018, 10 pts (8/10 ER+) were enrolled with a median age of 53 (38-72) and median of 1 (0-2) prior therapies for MBC. During dose-escalation, pts received doses of 300 mg (n = 3), 400 mg (n = 3), 500 mg (n = 3), and 600 mg (n = 1). No DLTs were observed. The most common treatment related grade 3 or higher AEs were neutropenia (50%), infection (20%), anemia (10%), and thrombocytopenia (10%). 4/10 pts had dose reductions due to toxicity. The average concentration of ribociclib at steady state was similar at each dose level, ranging from 273 to 413 ng/mL. Among 9 evaluable pts, the ORR was 33% (3/9) and the other 6 pts had stable disease. After a median follow-up time of 10.9 months, the median PFS was 12.5 months (95% CI [10.5. 20.9]). Biomarker results will be presented at the meeting. Conclusions: Co-targeting HER2 and CDK4/6 with the combination of ribociclib with T-DM1 was well tolerated with evidence of clinical activity. Based on PK analysis and dose reductions, 400 mg is the RP2D. Further evaluation is warranted for patients with HER2+ MBC. Clinical trial information: NCT02657343.
Alpelisib (ALP) with fulvestrant (FUL) in patients (pts) with PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC): Primary or secondary resistance to prior endocrine therapy (ET) in the SOLAR-1 trial.
Authors: Juric Dejan , Loibl Sibylle , Andre Fabrice , Mingorance J. Ignacio Delgado , Forget Frederic , Levy Christelle , Masuda Norikazu , Campone Mario , Conte Pier Franco , Iwata Hiroji , Mayer Ingrid A. , Rugo Hope S. , Wilke Celine , Ridolfi Antonia , Lteif Agnes , Ciruelos Eva 
Published: May 2019

1038 Background: A contributor to ETR, phosphatidylinositol 3-kinase (PI3K) pathway hyperactivation can result from mutations to PIK3CA; ~40% of pts with HR+, HER2– ABC exhibit tumors with this mutation. Use of the oral α-specific PI3K inhibitor ALP + FUL significantly improved progression-free survival (PFS) in pts with a PIK3CA mutation (HR 0.65; 95% CI, 0.50-0.85; P<0.001) in SOLAR-1, which included both ET sensitive (ETS) and ETR pts (Table). ETS pts were later excluded by a protocol amendment. ETR was further defined as primary (1R) or secondary (2R) per ESMO criteria in both 1L and 2L pts. This subgroup analysis evaluated pts with a PIK3CA mutation based on tx line and endocrine status. Methods: SOLAR-1 was a phase 3, randomized, double-blind study of ALP 300 mg QD or PBO Q28d + FUL 500 mg Q28d + C1d15 in men and postmenopausal women with HR+, HER2– ABC whose disease progressed on/after an aromatase inhibitor. PFS was estimated by Kaplan-Meier method and median PFS (mPFS) presented by tx arm. A stratified Cox proportional hazards model estimated HR and 2-sided 95% CI. Results: Of 341 pts in the PIK3CA mutant cohort, 39 (11%) were ETS; 302 (89%) were ETR. mPFS in the ALP vs PBO arms was 22.1 vs 19.1 mo (HR 0.87; 95% CI, 0.35-2.17) for ETS pts and 9.4 vs 4.2 mo (HR 0.64; 95% CI, 0.48-0.84) for ETR pts. For ETR pts, mPFS for 1L (n=138) was 9.0 vs 4.7 mo (HR 0.69; 95% CI, 0.46-1.05) and for 2L (n=161) was 10.9 vs 3.7 mo (HR 0.61; 95% CI, 0.42-0.89). Conclusions: In SOLAR-1, mPFS was improved with ALP + FUL vs PBO + FUL across ETR pts in 1L and 2L. Representation of ETS pts was low in SOLAR-1, which included more ETR pts. Analysis of the PI3K pathway in ETS pts is warranted in future studies. Clinical trial information: NCT02437318. [Table: see text]
Alpelisib (ALP) + endocrine therapy (ET) in patients (pts) with PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor-2-negative (HER2-) advanced breast cancer (ABC): First interim BYLieve study results.
Authors: Rugo Hope S. , Ruiz Borrego Manuel , Chia Stephen K. L. , Juric Dejan , Turner Nicholas C. , Drullinsky Pamela , Lerebours Florence , Bianchi Giulia Valeria , Nienstedt Carolyn C. , Ridolfi Antonia , Thuerigen Astrid , Ciruelos Eva 
Published: May 2019

1040 Background: In the phase 3 SOLAR-1 study, ALP + fulvestrant (FUL) improved PFS in pts with HR+, HER2– ABC with a PIK3CA mutation overall and in the small group of pts with prior cyclin-dependent kinase 4/6 inhibitor (CDKi) use. We report interim data from the BYLieve study in pts with PIK3CA-mutated ABC and prior CDKi exposure. Methods: BYLieve is an ongoing, phase 2, open-label, non-comparative study of ALP 300 mg QD + ET in men and women with PIK3CA-mutated HR+, HER2– ABC whose disease progressed on/after CDKi + ET. Pts are permitted ≤2 prior anticancer therapies and ≤1 prior chemotherapy regimen for ABC. Pts with prior CDKi and AI ( FUL cohort) receive ALP and FUL 500 mg Q28d + C1d15 IM. Pts with prior CDKi and FUL ( LET cohort) receive ALP and letrozole (LET) 2.5 mg PO QD. In this preplanned interim analysis, conducted after ≥20 pts in FUL had ≥6 mo of follow-up, descriptive data are reported for preliminary safety and efficacy in the FUL and LET cohorts. Results: At data cutoff, 64 and 36 pts were enrolled in the FUL and LET cohorts, respectively; 39 pts ( FUL, n = 21; LET, n = 18) have safety and efficacy data with ≥6 mo follow-up and are reported here. Data on 100 pts enrolled at the time of data cutoff will be presented. In the 39 pts with ≥6 mo follow-up, median ALP duration was 5.3 and 5.5 mo in FUL and LET, respectively; median duration of FUL and LET was 5.6 mo. Median relative ALP dose intensity was 93% ( FUL) and 87% ( LET). Most common grade ≥3 adverse events were hyperglycemia (38.1% ( FUL) and 27.8% ( LET)) and rash (4.8% ( FUL) and 27.8% ( LET)). Only 2 pts (5%; 1 pt per cohort) discontinued due to an AE. In pts with centrally confirmed PIK3CA mutation (n = 20 ( FUL); n = 17 ( LET)), ORR was 20% ( FUL) and 18% ( LET), CBR was 40% ( FUL) and 35% ( LET). Efficacy and safety data for the 100 enrolled pts will be presented at the meeting. Conclusions: Pending further readout of the ongoing BYLieve trial, safety and tolerability of ALP and hormonal therapy in pts with prior CDKi are consistent with those of SOLAR-1; discontinuation due to toxicity was rare. NCT03056755. Clinical trial information: NCT02437318.
Efficacy and safety of talazoparib (TALA) or physician's choice of therapy (PCT) in United States patients (pts) with HER2- germline BRCA1/2-mutated (gBRCAm) locally advanced/metastatic breast cancer (LA/MBC) in the EMBRACA study.
Authors: Diab Sami , Rugo Hope S. , Mina Lida A. , Puhalla Shannon , Mahtani Reshma L. , Henry Norah Lynn , Denduluri Neelima , Yardley Denise A. , Wang Yao , Arruda Lillian Shahied , Tudor Iulia Cristina , Gauthier Eric Roland , Czibere Akos Gabor , Litton Jennifer Keating , Hurvitz Sara A. 
Published: May 2019

1044 Background: TALA is a poly(ADP-ribose) polymerase (PARP) inhibitor approved in the US for HER2- g BRCAm LA/MBC. Approval was based on results from the Phase 3 EMBRACA trial comparing efficacy/safety of TALA (1 mg/d) to PCT (capecitabine, eribulin, gemcitabine, vinorelbine) in HER2- g BRCAm LA/MBC pts. This analysis describes outcomes in US pts included in the pivotal study. Methods: Clinical findings from US pts enrolled in EMBRACA were analyzed. Pt characteristics, progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), and safety/adverse events (AEs) were among the parameters assessed. Results: Of 431 randomized pts, 156 pts (36%) were from the US (TALA: 99; PCT: 57). Pt characteristics were balanced, although a higher percentage in the TALA arm had more poor prognostic features (eg, triple-negative breast cancer, disease-free interval < 12 mo, and more disease sites). TALA improved PFS, ORR, CBR, and duration of response (DOR) vs PCT (Table). 22% of pts in the TALA arm had a continued objective response at month 12 vs 0 pts in the PCT arm. The most common AEs in the TALA arm included anemia, neutropenia, thrombocytopenia, fatigue, nausea, alopecia, and headache; hematologic grade 3/4 AEs occurred more often than nonhematologic AEs. Conclusions: In US pts with HER2- g BRCAm LA/MBC, TALA demonstrated significant improvements in outcomes vs PCT with a manageable safety profile. Clinical trial information: NCT01945775. [Table: see text]
A phase II study of pembrolizumab in combination with palliative radiotherapy (RT) for hormone receptor-positive (HR+) metastatic breast cancer (MBC).
Authors: Barroso-Sousa Romualdo , Krop Ian E. , Trippa Lorenzo , Tan-Wasielewski Zhenying , Li Tianyu , Osmani Wafa , Andrews Chelsea , Dillon Deborah , Richardson Edward T. , Winer Eric P. , Mittendorf Elizabeth A. , Schoenfeld Jonathan Daniel , Tolaney Sara M. 
Published: May 2019

1047 Background: RT is frequently used for palliation in MBC. In animal models its use has been reported to induce distant (abscopal) tumor responses when combined with immune checkpoint inhibitors. Here, we report the safety and efficacy of palliative RT plus pembrolizumab in a phase II single-arm study in patients (pts) with HR+/HER2- MBC. Methods: Eligible pts had HR+/HER2- MBC, ECOG PS <2, indication for palliative RT, and ≥1 measurable lesion outside of the RT field; there was no limit on prior lines of therapy. A total RT dose of 20 Gray was delivered over 5 daily fractions. Pembrolizumab was given at 200 mg IV 2-7 days before day 1 of RT, then every 3 weeks until disease progression. The primary endpoint was objective response rate (ORR) outside the field of radiation by RECIST v1.1. Using the Simons “optimal” method, if ≥ 1/8 pts responded during the first stage, 19 more would be enrolled. If ≥ 3/27 responded, the null hypothesis (ORR=3%) would be rejected in favor of a 20% ORR. Predefined secondary endpoints included progression free survival (PFS) and toxicity. Analyses associating PD-L1 expression, tumor-infiltrating lymphocytes (TIL), and neutrophil/lymphocyte ratio (NLR) with outcomes were exploratory. Results: Eight women were enrolled into the first stage of the trial; no objective responses were seen, and the study was closed to further accrual. The median age was 59y (37-68y), 6 (75%) had ECOG PS 1, all had bone and 5 (63%) had liver metastases. The median number of prior cytotoxic therapies for MBC was 2 (range 0 to 8). While one patient had a PR by RECIST criteria, this patient experienced concurrent clinical progression. Two pts had SD < 16 weeks and 5 had PD as best response. The median PFS was 1.4 months (95% CI 0.4 – 2.1). All-cause adverse events occurred in 87.5% of pts (G3-4, 12.5%). TIL were available for 6 pts: 4 had ≤10%, and 2 > 10%. Among 5 pts with PD-L1 status available, 2 were positive. Six pts had NLR > 4. Conclusions: Pembrolizumab combined with RT was well-tolerated, and no unexpected adverse events were observed; however, clinical benefit of the combination was not demonstrated in this heavily pretreated HR+ population. Clinical trial information: NCT03051672.