Single-agent Endocrine Therapy Research Articles

Abstract PO4-05-08: Primary endocrine therapy resistance in patients with de novo HR+/HER2- metastatic breast Cancer: a National Cancer Information Database Analysis in China

Abstract Background: Endocrine therapy resistance was classifed as primary and secondary, guiding the first-line (1L) treatment choices for hormone receptor positive, HER2-negative (HR+/Her2-) metastatic breast cancer (mBC). However, it is unknown whether it is primary ET resistance or not to the stage IV de novo patients. Therefore, We performed a retrospective study to predict primary resistance in advance in de novo patients and have a more appropriate treatment strategy. Methods: We identified newly diagnosed with stage IV de novo HR+/HER2- mBC patients received single-agent endocrine therapy (ET) or ET plus CDK4/6 inhibitors (CDK4/6i) in 1L setting from January 1, 2020 to Jun 30, 2022, using the National Cancer Information Database (NCID) in China. Primary ET resistance (PER) was defined as switching to second-line treatment within 6 months after receiving the 1L ET±CDK4/6i, whereas secondary ET resistance (SER) patients were those who received 1L ET±CDK4/6i treatment more than six months. The Chi-Square test was used to compare the baseline characteristics of PER and SER patients. Result: A total of 217 patients who met the inclusion criteria were included in the analysis, among which 161 patients received single-agent ET and 56 patients received ET plus CDK4/6i. 18.4% of the patients were classified as PER patients, whereas 81.6% showed SER patients. PER patients were younger (median age of 52 years vs. 58 years in SER patients, p=0.01). In terms of clinicopathological characteristics, patients with PER have a higher percentage of liver metastases (14/40 (35%) vs. 20/177 (11.3%) in SER, p< 0.01), distant lymph node metastases (19/40 (34%) vs. 45/177 (25.4%) in SER, p = 0.01), and bone metastases (30/40(75%) vs. 97/177(54.8%) in SER, p = 0.02). Furthermore, the PER rate was 21.7% (35/161) in patients received single-agent ET, compare with 8.9% (5/56) in ET plus CDK4/6i patients, p=0.04. Regarding the following treatment pattern in the PER patients, a high percentage of patients received chemotherapy, accounting for 50%, 30% still received another endocrine therapy, and the remaining 20% patients received CDK4/6i combined with endocrine therapy. Conclusions: There is still a significant proportion of de novo HR+/HER2- mBC patients with primary endocrine resistance, a relatively low proportion of PER in patients receiving endocrine in combination with CDK4/6i. Table. The proportion of primary endocrine resistance across treatment regimens in de novo HR+/HER2- metastatic breast Cancer Citation Format: Zhanhong Chen, Xiying Shao, Yabing Zheng, Wenming Cao, Junqing Chen, Weizhu Wu, Ting Wang, Xiaojia Wang. Primary endocrine therapy resistance in patients with de novo HR+/HER2- metastatic breast Cancer: a National Cancer Information Database Analysis in China [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-05-08.

Abstract PO2-27-05: Composite biomarkers for the prediction of progression-free survival with CDK4/6 inhibitors in metastatic HR+/HER2- breast cancer

Abstract CDK4/6 inhibitors are widely used in combination with endocrine therapy in the treatment of HR+/HER2- metastatic breast cancer. Generally the CDK4/6 inhibitors lead to a doubling of progression-free survival (PFS) over single agent endocrine therapy. In spite of a known mechanism of action, biomarkers to define the duration of response to CDK4/6 inhibitors with either aromatase inhibitors (AI) or fulvestrant (FUL) remain lacking. A cohort of over 300 patients receiving standard of care CDK4/6 inhibitor combination therapy for metastatic disease were consented for participation (NCT04526587). The duration of PFS in both AI and FUL treated sub-groups were comparable to that observed in randomized clinical trials. In this cohort progesterone receptor-status (HR 0.70, p=0.0123), visceral disease (HR 1.55, p=0.0013), prior endocrine therapy (HR 2.34, p< 0.001), and type of endocrine therapy (HR 2.16, p< 0.001) were associated with duration of PFS. To develop biomarkers, gene expression analyses was performed on 313 tumor samples representing over 200 individual patients. Focusing on the pre-treatment metastatic biopsy, established signatures associated with prognosis in HR+/HER2- breast cancer were employed to determine association with response to combination therapy in the metastatic setting. Proliferation-associated signatures were associated with shorter PFS. For example, an established RB loss signature was associated with PFS in both AI (HR 1.9, p=0.009) and FUL (HR 2.8, p=0.007) treated patients. Clinically employed signatures (e.g. OncotypeDx and Mammaprint) harbored variable associations with outcomes. Random Survival Forest feature selection was applied to individual and combined prognostic signatures. This approach resulted in a potent classifier for progression-free survival (HR 10, p< 1E-20). To enable applicability to different manifestations of disease, significant clinical pathological variables were incorporated into the model so that there was equivalent performance in AI and FUL treated patients for prediction of PFS. This predictive algorithm was also strongly associated with overall survival (HR 4.6, p=2.7E-8). Ongoing studies are evaluating the algorithms prospectively in NCT04526587. Citation Format: Agnieszka Witkiewicz, Jianxin Wang, Erik Knudsen, Ellis Levine, Tracey O'Connor. Composite biomarkers for the prediction of progression-free survival with CDK4/6 inhibitors in metastatic HR+/HER2- breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-27-05.

Abstract PO2-16-10: Characterising HER2-low status in metastatic breast cancer: a real-world retrospective study of patients at a metropolitan cancer centre in Australia

Abstract Background: Traditionally, breast cancer subtyping has described patients as HER2-negative or HER2-positive, with the latter being those in whom HER2-directed therapies are utilised. A proportion of HER2-negative cancers can be classified as “HER2-low” as they express IHC 1+ or 2+ and are non-amplified on in-situ hybridisation (ISH). Until recently, our widely available HER2-targeted therapies have proven to be ineffective in this subtype. The DESTINY-BREAST04 trial (Modi et al, NEJM 2022) showed progression-free and overall survival efficacy of HER2-directed therapy using the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) in HER2-low disease, suggesting a need to identify this population for selected therapy. This study evaluated a real-world population of metastatic breast cancer (MBC) patients treated according to traditional breast cancer subtypes to determine the frequency of HER2-low histology, with a focus on selection of first-line therapy. Methods: This retrospective audit identified patients being treated for MBC at a single tertiary hospital (Austin Health in Melbourne, Australia) over a 3.5 year period. Patients were identified from an electronic database, with a date of last follow-up as August 2022. Medical records were interrogated for clinicopathological information including review of pathology reports for breast cancer subtypes. Traditional breast cancer subtypes were defined as (i) ER positive and HER2-negative (HER2 0 or 1+, or 2+ and non-amplified); (ii) HER2-positive (HER2 3+ and/or amplified) and (iii) TNBC (negative for ER and PgR, and HER2 0 or 1+, or 2+ and non-amplified). Selection and duration of first-line treatment for MBC was also recorded. Results: Between March 2018 and August 2022, 202 MBC patients were identified. Based on traditional subtypes, 126 (62%) were ER positive and HER2-negative, 46 (23%) were HER2-positive, 26 (13%) were TNBC and 4 (2%) were unknown. In the total population, 87 (43%) were classified as having HER2-low disease based on retrospective pathology reports. HER2-low represented 61% of ER positive, HER2-non amplified patients and 45% of TNBC patients. Metastatic specimen data was known for 172 cases and of these, 95 patients (55%) were re-biopsied on metastatic progression. This occurred more commonly with HER2-positive (81%) and ER positive HER2-negative (78%) primaries. The most common change in subtype was loss of ER, which occurred in 7 patients (3%). Changes in HER2 status occurred in 29 (14%) of patients, most commonly as either an increase from 1+ to 2+ or decrease from 1+ to 0. HER2-low status remained consistent for 67% of patients who underwent biopsy on recurrence. For patients with ER positive HER2-negative MBC, first-line combination therapy with a CDK4/6 inhibitor + AI was preferred (51%), followed by single agent endocrine therapy (30%) and chemotherapy (17%). The majority (84%) of HER2-positive patients received first-line dual HER2 therapy (trastuzumab and pertuzumab) with taxane chemotherapy. Half of TNBC patients received upfront chemotherapy, with physician preference being capecitabine (45%). There was no significant difference in PFS between the HER2-low vs. HER2-0 cohorts, for either ER positive or TNBC subtypes. No patients in this series were treated based on HER2-low definition due to no funded access to such therapies at the time. Conclusion: HER2-low has emerged as an identifier for patients who may respond to HER2-directed therapies using ADCs such as T-DXd. However, its clinical significance as a discrete clinical subtype remains uncertain. In this retrospective audit, HER2-low patients were identified in both ER positive and TNBC subtypes. Dynamic changes in HER2 staining occurred infrequently. Further evaluation is needed to address whether HER2-low expression provides any prognostic value and whether prospective reporting of HER2-low status may alter how these new HER2-directed therapies are used in future. Citation Format: Michelle Li, Belinda Yeo. Characterising HER2-low status in metastatic breast cancer: a real-world retrospective study of patients at a metropolitan cancer centre in Australia [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-16-10.

Practical Guidance on Abemaciclib in Combination with Adjuvant Endocrine Therapy for Treating Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative High-Risk Early Breast Cancer.

The most common subtype of breast cancer is hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, accounting for 65-70% of all breast cancer cases diagnosed in the United States. Until 2015, single-agent endocrine therapy (ET) was the recommended first-line treatment for metastatic HR-positive, HER2-negative breast cancer. However, the paradigm has since shifted, as targeted therapy is now recommended in combination with ET. The cyclin-dependent kinase (CDK) 4/6 inhibitors have revolutionized the treatment of this breast cancer subtype, and combining either palbociclib, ribociclib, or abemaciclib with ET is now the standard first-line treatment for metastatic disease. Results of clinical trials in the metastatic setting have demonstrated that treatment with the combination of a CDK4/6 inhibitor and ET rather than ET alone is associated with longer overall survival, longer progression-free survival, and better objective response rates. Each of the CDK4/6 inhibitors has been investigated in combination with ET in patients with early-stage HR-positive, HER2-negative breast cancer who are at high risk of relapse. In October 2021, abemaciclib was the first CDK4/6 inhibitor approved in combination with ET by the US Food and Drug Administration for adjuvant treatment of patients with HR-positive, HER2-negative, high-risk early breast cancer. Herein, we provide practical guidance on the use of abemaciclib in combination with ET for HR-positive, HER2-negative, high-risk early breast cancer to assist clinicians in their day-to-day practice, and we review clinically relevant topics of dosing, side effect management, sequencing and optimal timing for initiation, and patient selection.

Thymidine kinase activity levels in serum can identify HR+ metastatic breast cancer patients with a low risk of early progression (SWOG S0226)

Background Some patients with metastatic breast cancer (MBC) stay on endocrine therapy (ET) for years and others progress quickly. Serum thymidine kinase activity (TKa), an indicator of cell-proliferation, is a potential biomarker for monitoring ET and predicting MBC outcome. We have previously reported TKa as being prognostic in MBC in SWOG S0226. Here, new data on progression within 30/60 days post sampling, with a new, FDA approved version of DiviTum®TKa highlighting differences vs. a Research Use Only version is reported. Methods 1,546 serum samples from 454 patients were assessed, collected at baseline and at 4 subsequent timepoints during treatment. A new predefined cut-off tested the ability to predict disease progression. A new measuring unit, DuA (DiviTum® unit of Activity) is adopted. Results A DiviTum®TKa score <250 DuA provides a much lower risk of progression within 30/60 days after blood draw, the negative predictive value (NPV) was 96.7% and 93.5%, respectively. Patients <250 DuA experienced significantly longer progression-free survival and overall survival, demonstrated at baseline and for all time intervals. Conclusions DiviTum®TKa provides clinically meaningful information for patients with HR+ MBC. Low TKa levels provide such a high NPV for rapid progression that such patients might forego additional therapy added to single agent ET. Trial registration: NCT00075764

Clinical management of metastatic hormone receptor-positive, HER2-negative breast cancer (MBC) after CDK 4/6 inhibitors: a retrospective single-institution study.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), in combination with endocrine therapy (ET), are standard either in the first (1L) or second-line (2L) setting for the treatment of hormone receptor (HR) positive, HER2-negative metastatic breast cancer (MBC). However, the optimal sequencing of treatments after progression on CDK4/6i remains unknown. We performed a single-institution analysis to identify treatments and outcomes after progression on a CDK4/6i. We identified patients with HR-positive, HER2-negative MBC prescribed a CDK4/6i in the 1L or 2L settings from December 2014 to February 2018 at Mayo Clinic in Rochester, Minnesota. Outcomes were collected through September 30, 2020. Palbociclib, in combination with letrozole or fulvestrant, was the most prescribed CDK4/6i. The 1L and 2L CDK4/6i cohorts exhibited comparable overall survival (OS), but progression-free survival (PFS) was longer in the 1L than the 2L cohort [28.2months (95% CI 19.6-34.9) vs 19.8months (95% CI 15.7-29.6)]. The most common post-CDK4/6i treatments were PI3K/mTOR inhibitors (PI3K/mTORi), single-agent ET, or chemotherapy. PFS in the 1L CDK4/6i cohort following PI3K/mTORi was 8.5months (95% CI 5.5months-NE), single-agent ET was 6.0months (95% CI 3.3-14.0months), and chemotherapy PFS was 5.4months (95% CI 3.3months-NE). Following progression on a CDK 4/6i, mPFS was short, with similar PFS times comparing chemotherapy and ET, with slightly longer PFS for targeted strategies (PI3K/mTOR). These results highlight a major need to better understand the mechanisms of CDK4/6i resistance and identify new therapeutic strategies for these patients.

Abstract PD1-06: Apobec mutagenesis is a pervasive feature of poor prognosis breast cancer associating with ESR1 wild type, endocrine resistant disease

Abstract Background: Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) enzymes drive genomic instability in breast cancer (BC) characterized by specific single base substitution mutation signatures (COSMIC S2 and S13). Computational algorithms have the potential to derive signatures from targeted sequencing assays with relatively small genomic footprints. We sought to develop a computational approach to identify APOBEC mutagenesis in samples subjected to targeted sequencing and to characterize the genomic and clinical features of APOBEC-positive BC. Methods: We retrieved clinical and genomic data from 4,595 consecutive BCs that had been subjected to targeted sequencing using the FDA-approved MSK-IMPACT assay. Additional whole exome sequencing (WES) data were retrieved from publicly available datasets, including TCGA (primary BC, n=1019) and Bertucci et al. cohorts (metastatic BC, n=617). APOBEC-related mutational signatures were computed by using the SigMA algorithm (Gulhan, Nat Genet 2019) for MSK-IMPACT samples with at least 5 single nucleotide variants (SNV) (n=2,983). Survival analyses were performed by using Kaplan Meier method with log-rank test and Cox proportional-hazards models. Results: A significant positive correlation between APOBEC exposure calculated by SigMA vs other computational tools (e.g., DeconstructSig, SigProfiler, MutationalPatterns) was found (r=0.99). After down-sampling the WES data from the TCGA BC dataset to the genomic footprint of MSK-IMPACT, SigMA showed high concordance in determining APOBEC exposures (r=0.78). BCs with high APOBEC exposure were enriched for pathogenic somatic mutations affecting several genes, including PIK3CA, CDH1 and GATA3 (q&amp;lt;0.05), as compared to tumors with no/low APOBEC. In the MSK-IMPACT cohort, median APOBEC mutational exposure was significantly higher in metastatic than primary samples (0.27 vs 0.19, p&amp;lt;0.001) and was the dominant mutational signature in 26% of primary and 34% of metastatic BC. A significant enrichment for APOBEC exposure in the metastatic setting was observed in both hormone receptor-positive (HR+) (p&amp;lt;0.001) and triple-negative (TN) (p&amp;lt;0.001) subtypes. Invasive lobular BCs displayed a higher proportion of cases with high APOBEC mutagenesis when compared to invasive ductal BCs in both primary and metastatic setting (p&amp;lt;0.001). Enrichment of APOBEC in metastatic samples could be due to signature acquisition or enrichment in poor prognosis tumors, to address this, we assessed the presence of APOBEC mutational exposure in patients with paired samples, which included 352 primary/metastasis (P/M) cases and 514 metastasis/metastasis (M/M) cases. Strikingly, no statistically significant increment of APOBEC exposure was found in the P/M nor in the M/M cohort (Wilcoxon signed-rank test p&amp;gt;0.05), overall and in different BC subtypes. We also assessed the association between APOBEC and response to endocrine therapy (ET). Patients with metastatic HR+ BC and APOBEC as dominant signature had a statistically significant lower progression-free survival (PFS) on first-line single-agent ET (aromatase inhibitors or SERDs; median PFS of 9.7 versus 14.7 months, p&amp;lt;0.001). This difference was more pronounced in patients treated with SERD with a median PFS of 4.7 and 14.3 months for APOBEC-dominant and APOBEC non-dominant tumors (p&amp;lt;0.001), respectively. Conclusions: Evidence for APOBEC mutagenesis is present in &amp;gt;30% of metastatic breast cancers and associated with resistance to ET. Unlike ESR1 mutations, which are acquired as a late event in metastatic HR+ BCs, APOBEC mutagenesis is commonly present in paired primary and metastatic BCs, indicating its relatively early onset and potential role in driving the poor prognosis of these cancers. Citation Format: Antonio Marra, Andrea Gazzo, Pier Selenica, Xin Pei, Avantika Gupta, Fresia Pareja, Giuseppe Curigliano, Reuben Harris, Nadeem Riaz, Jorge S. Reis-Filho, Sarat Chandarlapaty. Apobec mutagenesis is a pervasive feature of poor prognosis breast cancer associating with ESR1 wild type, endocrine resistant disease [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD1-06.

Abstract OT1-12-02: Trial in progress: Phase 2, open-label study to evaluate the safety and efficacy of praluzatamab ravtansine in metastatic HER2 non-amplified breast cancer as monotherapy and combination with pacmilimab

Abstract Background: Probody® therapeutic candidates (Pb-Tx) are masked antibodies designed to be conditionally activated in the tumor microenvironment by tumor-associated proteases. This allows Pb-Tx to address previously undruggable targets that are highly expressed in both tumor and normal tissues. Praluzatamab ravtansine is a masked antibody-drug conjugate targeting CD166 with a DM4 payload. A phase 1 monotherapy study showed safety and durable clinical activity (clinical benefit rate at 24 weeks [CBR24] 28%) in patients (pts) with metastatic HR-positive/HER2 non–amplified breast cancer (mHR+/HER2− BC) or metastatic triple-negative breast cancer (mTNBC). Pacmilimab, a masked PD-L1 inhibitor, demonstrated monotherapy activity in pts with TNBC with an acceptable tolerability profile.Trial design: This phase 2, open-label study with 3 parallel arms (~40 evaluable/arm) will evaluate praluzatamab ravtansine monotherapy (7 mg/kg Q3W) in pts with mHR+/HER2− BC or mTNBC, and praluzatamab ravtansine (7 mg/kg Q3W) combined with pacmilimab (1200 mg Q3W) in pts with mTNBC. Adult pts with an ECOG PS 0–1, measurable disease, and willingness to receive ocular prophylaxis for DM4-related toxicities will be enrolled. Key eligibility criteria for the mHR+/HER2− BC cohort include 2–4 prior regimens in the metastatic setting (excluding single-agent endocrine therapy). No CD166 screening required for HR+/HER2− BC but mTNBC must be CD166+. Pts with mTNBC must have received 1–3 prior metastatic regimens. For mTNBC pts who receive the doublet, key exclusion criteria include known PDL1 negative tumor, history of autoimmune disease, and progression within 120 days of 1st dose of an immuno-oncology agent. Pts with corneal disorders will be excluded. Primary endpoint is overall response rate (ORR) assessed by an independent radiology committee per RECIST v1.1. Secondary endpoints include ORR by investigator, duration of response, CBR16 &amp; 24, progression-free survival, and overall survival. This study will also evaluate safety and tolerability, pharmacokinetics, and antidrug antibodies with praluzatamab ravtansine as monotherapy and in combination with pacmilimab. This trial is enrolling (NCT04596150). Citation Format: Kathy Miller, Leisha A. Emens, Sara M. Tolaney, Sara A. Hurvitz, Erika Hamilton, Virginia Paton, Alison Hannah, Valentina Boni. Trial in progress: Phase 2, open-label study to evaluate the safety and efficacy of praluzatamab ravtansine in metastatic HER2 non-amplified breast cancer as monotherapy and combination with pacmilimab [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-12-02.

A clinical calculator to predict disease outcomes in women with hormone receptor-positive advanced breast cancer treated with first-line endocrine therapy.

Endocrine therapy (ET) is an effective strategy to treat hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) but nearly all patients eventually progress. Our goal was to develop and validate a web-based clinical calculator for predicting disease outcomes in women with HR+ABC who are candidates for receiving first-line single-agent ET. The meta-database comprises 891 patient-level data from the control arms of five contemporary clinical trials where patients received first-line single-agent ET (either aromatase inhibitor or fulvestrant) for ABC. Risk models were constructed for predicting 24-months progression-free survival (PFS-24) and 24-months overall survival (OS-24). Final models were internally validated for calibration and discrimination using ten-fold cross-validation. Higher number of sites of metastases, measurable disease, younger age, lower body mass index, negative PR status, and prior endocrine therapy were associated with worse PFS. Final PFS and OS models were well-calibrated and associated with cross-validated time-dependent area under the curve (AUC) of 0.61 and 0.62, respectively. The proposed ABC calculator is internally valid and can accurately predict disease outcomes. It may be used to predict patient prognosis, aid planning of first-line treatment strategies, and facilitate risk stratification for future clinical trials in patients with HR+ABC. Future validation of the proposed models in independent patient cohorts is warranted.

Results from VERONICA: A randomized, phase II study of second-/third-line venetoclax (VEN) + fulvestrant (F) versus F alone in estrogen receptor (ER)-positive, HER2-negative, locally advanced, or metastatic breast cancer (LA/MBC).

1004 Background: For patients (pts) with ER-positive, HER2-negative MBC, CDK4/6 inhibitors + endocrine therapy (ET) is standard first-line treatment, with single-agent ET considered for second-line. Nevertheless, most pts progress. A novel therapeutic target is the antiapoptotic protein BCL2, which is overexpressed in ̃85% of primary ER-positive breast cancers. VEN is a potent, selective BCL2 inhibitor that has shown promising clinical activity in pts with ER-positive and BCL2-positive MBC who have received prior ET. We report the prespecified primary and updated (for overall survival [OS]) analysis of VERONICA (NCT03584009), a phase II study of VEN + F vs F in ER-positive, HER2-negative LA/MBC. Methods: Pts were ≥18-year-old women with ER-positive, HER2-negative LA/MBC, who received ≤2 prior lines of ET and no prior chemotherapy in the LA/MBC setting and experienced disease recurrence/progression during/after CDK4/6 inhibitor therapy (received ≥8 weeks prior). Pts were randomized 1:1 to VEN (oral; 800 mg daily) + F (intramuscular; 500 mg day 1 and 15 of cycle 1; day 1 of subsequent 28-day cycles) or F, and were treated until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end. Pts were stratified by prior lines of therapy in the LA/MBC setting (1 vs 2) and BCL2 status (high vs low). Primary endpoint was clinical benefit rate (CBR; complete response, partial response, and stable disease ≥24 weeks). Secondary endpoints included progression-free survival (PFS) and OS; safety and exploratory subgroup analyses were also conducted. Results: At primary analysis (cutoff: Aug 5, 2020), 103 pts had been randomized (intention-to-treat [ITT] population). Median age was 58.0 and 59.5 years in the VEN + F and F arms, respectively. CBR was similar between arms (VEN + F: 11.8% [n = 6/51; 95% confidence interval (CI) 4.44–23.87]; F: 13.7% [7/51; 5.70–26.26]; risk difference: -1.96% [95% CI -16.86–12.94]). Median PFS was 2.69 months (95% CI 1.94–3.71) in the VEN + F vs 1.94 months (1.84–3.55) in the F arm (stratified hazard ratio: 0.94 [95% CI 0.61–1.45]). Results for CBR and PFS were similar in the BCL2-high and -low subgroups vs the ITT population. More grade 3–4 adverse events (AEs) were observed in the VEN + F vs F arm (n = 13/50 [26%] vs 6/51 [11.8%]). AEs observed with VEN + F were consistent with their individual safety profiles. At updated analysis (cutoff: Oct 22, 2020), OS data were not mature (35.0% event/pt ratio); median OS was 16.99 months in the VEN + F vs not reached in the F arm (stratified hazard ratio: 2.06 [1.04–4.09]). Conclusions: From the primary analysis, VERONICA did not show an improved CBR or PFS with VEN + F, vs F alone, in pts with endocrine- and CDK4/6 inhibitor-refractory LA/MBC. Biomarker analysis is ongoing. Clinical trial information: NCT03584009 .

Combination cyclin-dependent kinase 4/6 inhibitors and endocrine therapy versus endocrine monotherapy for hormonal receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: A systematic review and meta-analysis.

PurposeThis meta-analysis aimed to assess the efficacy and safety of cyclin-dependent kinase (CDK) 4/6 inhibitors plus endocrine therapy (ET) in hormonal receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC).MethodsWe searched PubMed, Embase, Cochrane, ClinicalTrials.gov., ASCO, ESMO and AACR databases from inception to October 10, 2019 for randomized controlled trials (RCTs) that compared CDK 4/6 inhibitors plus ET to single-agent ET with no treatment-line restriction. The main outcomes analyzed were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), and adverse events (AEs).ResultsOf 938 identified studies, 9 RCTs with 5043 women were eligible and included. Compared with ET alone, CDK 4/6 inhibitors and ET combination improved in PFS (hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.50–0.59, p< 0.00001) and OS (HR 0.77, 95% CI 0.69–0.85, p< 0.00001), regardless of ET strategies (HR 0.54, 95% CI 0.50–0.59 in PFS; HR 0.77, 95% CI 0.69–0.85 in OS), treatment line of advanced disease (HR 0.52, 95% CI 0.46–0.59 in PFS; HR 0.75, 95% CI 0.66–0.85 in OS) and menopausal status (HR 0.54, 95% CI 0.50–0.58 in PFS; HR 0.76, 95% CI 0.68–0.84 in OS). Higher risk of grade 3/4 AEs (RR 2.66, 95% CI 2.44–2.90, p < 0.00001) were observed in the combination group than in the ET group.ConclusionsCombination therapy with CDK 4/6 inhibitors and ET prolongs survival in HR+/ HER2- ABC. This combination is a better therapeutic strategy than endocrine monotherapy in HR+/HER2- ABC, regardless of treatment line, menopausal status and other individual characteristics.

Abstract PD7-09: A phase 1/1b study of LSZ102, an oral selective estrogen receptor degrader (SERD), in combination with ribociclib in patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC) who had progressed after endocrine therapy (ET)

Abstract Background: The combination of ribociclib (an oral CDK4/6 inhibitor) and ET improved survival outcomes in patients (pts) with ER+ ABC in comparison to single-agent ET. In preclinical models, LSZ102 (an experimental oral SERD) demonstrated synergistic activity with ribociclib. This phase 1/1b, open-label study evaluates single-agent LSZ102 (Arm A) and LSZ102 in combination with ribociclib (Arm B) or alpelisib (Arm C) in pts with ER+ ABC who had progressed after ET. Here we present preliminary data from dose escalation of Arm B. Methods: Dose-escalation evaluated daily (QD) LSZ102 at different doses plus ribociclib starting at 300 mg QD either in a 3-week on/1-week (3w/1w) off or in continuous regimen. Pts (aged ≥18 years; ECOG PS 0-1) with histologically confirmed ER+ ABC and progression after ET were enrolled. Prior fulvestrant and/or CDK4/6 inhibitor therapy were permitted. The primary objective was to characterize the safety and tolerability of LSZ102 and ribociclib in combination and identify a recommended dose for expansion (RDE). Secondary objectives included preliminary antitumor activity and characterization of pharmacokinetics. Results: As of 30-Nov-2018, 76 pts were enrolled. The median age of pts was 59 years, 78% (n=59) were Caucasian, 75% (n=57) had an ECOG PS of 0, 63% (n=48) had received prior fulvestrant, and 43% (n=33) a prior CDK4/6 inhibitor; the median number of prior lines of therapy (metastatic setting) was 4 (range 0-10). Pts received LSZ102 QD in combination with ribociclib QD either in a 3w/1w (n=42) or continuous (n=24) regimen, fasted, fed or without regard to food. LSZ102 twice daily (BID) was also explored with a ribociclib BID continuous regimen (n=10). Doses of LSZ102 ranged from 200-600 mg QD and 200-300 mg BID. Doses of ribociclib ranged from 200-600 mg and 200-400 mg in the 3w/1w and continuous regimens, respectively. At data cut-off, 47 pts had discontinued treatment, 42 due to disease progression. Three dose-limiting toxicities were reported: decreased appetite (1 pt) and febrile neutropenia and sepsis (1 pt), all in the 3w/1w regimen. The most common treatment-related adverse events (AEs) were nausea (48.7%), diarrhea (31.6%), fatigue (26.3%), and neutropenia (25.0%). The most common treatment-related grade 3 or 4 AE was neutropenia (10.5%). Four pts (5.3%) required dose reduction due to an AE. Median PFS was 6.0 months. Of 71 evaluable pts, 11% (n=8) had a PR, 39% (n=28) had a best overall response of SD and 16% (n=11) had non-CR/non-PD. ORR, DCR and CBR ≥6 months (includes non-CR/non-PD) were 11% (n=8), 66% (n=47) and 21% (n=15), respectively. The RDE is 450 mg QD LSZ102 with 400 mg QD ribociclib for both ribociclib regimens. Preliminary PK showed the exposure of LSZ102 and ribociclib in combination at the RDE were largely comparable with exposure of the corresponding single agents. Conclusion: The combination of LSZ102 and ribociclib was well-tolerated and demonstrated antitumor activity in heavily pre-treated pts with ER+ ABC many of whom had progressed after fulvestrant and/or CDK4/6 inhibitor therapy. Citation Format: Komal Jhaveri, Dejan Juric, Sara Cresta, Yoon-Sim Yap, Francois P Duhoux, Catherine Terret, Rachel Layman, Nicole Kundamal, Serena Liao, Yan Ji, Adam Crystal, Giuseppe Curigliano. A phase 1/1b study of LSZ102, an oral selective estrogen receptor degrader (SERD), in combination with ribociclib in patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC) who had progressed after endocrine therapy (ET) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD7-09.

Understanding the benefits and challenges of first-line cyclin-dependent kinases 4 and 6 inhibitors in advanced breast cancer among postmenopausal women.

Endocrine therapy (ET) has been regarded for many years as the standard treatment for patients with hormone receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer (ABC) without visceral crisis. However, the efficacy of single-agent ET is constrained by the development of resistance, attributed to alterations in several intracellular signaling pathways, including those related to cell cycle dysregulation. The cyclin-dependent kinases 4 and 6 (CDK4/6) are principal regulators of cell cycle progression from the G1-phase into the DNA synthesis (S)-phase. In vitro inhibition of CDK4/6 activity has potent antiproliferative properties against luminal breast cancer cell lines, which are enhanced when combined with traditional ET. This has led to a substantial interest in targeting this pathway to overcome endocrine resistance in the clinic. Three selective CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) have been approved as first-line therapy in combination with an aromatase inhibitor, or fulvestrant in the case of ribociclib in patients with ER+/HER2- ABC. To date, there is no clue as to which subgroup of patients might benefit most from these combinations. Here, we outline some of the established approaches to overcome endocrine resistance, with special emphasis on the unique mechanism of action of CDK4/6 inhibitors.

386TiP - RIbociclib plus goserelin with hormonal therapy versus physician choice chemotherapy in premenopausal or perimenopausal patients with HR+, HER2– inoperable locally advanced or metastatic breast cancer: RIGHT choice study

BackgroundA high percentage of breast cancer patients in the Asia-Pacific (∼42%) and Middle East (∼50%) regions are aged 50 years or younger. Although a high proportion of younger patients with endocrine-responsive metastatic disease are treated initially with cytotoxic chemotherapy (CT) in routine general practice, data from phase III trials have shown higher response rates and longer progression-free survival with endocrine therapy (ET) in combination with CDK4/6 inhibitor versus single agent ET. Due to lack of direct evidence, trials in pre-/perimenopausal advanced breast cancer are thus necessary to assess the efficacy of ET in combination with CDK4/6 inhibitor vs CT in aggressive or high tumor burden setting where CT is clinically indicated. Trial designThe RIGHT Choice study (NCT03839823) is a randomized, open-label, multination phase 2 study with a target enrollment (approximately 55 sites in 13 countries in the Asia-Pacific and Middle East regions) of 222 pre-/perimenopausal women aged 18-59 years who have not received prior systemic ET or CT for advanced disease. Patients must have advanced HR+, HER2– breast cancer not amenable to curative therapy (ie, symptomatic visceral metastases, rapid progression of disease or impending visceral compromise, or markedly symptomatic nonvisceral disease where combination chemotherapy is clinically indicated). Tumors must be estrogen receptor-positive ≥10%; and ECOG performance status ≤2. Exclusion criteria include pregnancy or lactation, and postmenopausal status. Patients will be randomized to receive ribociclib (600mg, 3 weeks on/1 week off) in combination with letrozole or anastrozole plus goserelin or to investigator’s choice of combination CT (docetaxel + capecitabine, paclitaxel + gemcitabine, or capecitabine + vinorelbine). The primary endpoint is progression-free survival. Secondary endpoints include time to treatment failure, overall response rate, clinical benefit rate, time to response, overall survival, patient global health status, and safety. Healthcare resource utilization will be evaluated as an exploratory endpoint. Clinical trial identificationNCT03839823. Editorial acknowledgementMedical editorial assistance was provided by Rob Camp, PhD, of Healthcare Consultancy Group, LLC, and funded by Novartis Pharmaceuticals Corporation. Legal entity responsible for the studyNovartis Pharmaceuticals. FundingNovartis Pharmaceuticals. DisclosureS.S. Malwinder: Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: AstraZeneca. H.A. Azim: Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: Hekma. Y. Eralp: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Speaker Bureau / Expert testimony, Non-remunerated activity/ies: BMS; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Pfizer; Non-remunerated activity/ies: Nobel; Research grant / Funding (institution): AstraZeneca; Leadership role: Istanbul Breast Cancer Research Group (IMAG). S. Im: Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Amgen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Roche; Advisory / Consultancy: Hanmi; Advisory / Consultancy: Pfizer. Y.S. Yap: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche. T. Delgar Alfaro: Full / Part-time employment: Novartis. M. Gao: Full / Part-time employment: Novartis. Y. Lu: Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Merck, Sharp & Dohme; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Eisai; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: EuroPharma. All other authors have declared no conflicts of interest.

Abstract CT140: Circulating tumor cells as a tool to guide first line therapy in metastatic breast cancer: subgroup analyses of the STIC CTC Phase III utility trial

Abstract Background: Endocrine therapy (ET) is the preferred 1st line therapy in ER+ HER2- metastatic breast cancer (MBC) patients, but not all benefit from such strategy for which predictive biomarkers are lacking. Prior studies showed that circulating tumor cells (CTC) count is the strongest prognostic factor beyond PS in that population. The STIC CTC trial (NCT01710605) assessed whether CTC count could drive the choice between frontline ET or chemotherapy (CT, with or without ET maintenance). Methods: For this multicenter phase 3 non-inferiority trial, main inclusion criteria were: ER+ HER2- MBC with no prior therapy, PS≤2, no contra-indication to ET or CT, informed consent. Patients were randomized 1:1 between clinically-driven choice (single agent ET if clinicallow, CT if clinicalhigh, as decided by physician based on clinical factors, blinded to CTC results) or a CTC-driven choice [ET if CTClow (&amp;lt;5 CTCs/7.5mL), CT if CTChigh (≥5 CTCs/7.5mL)]. The primary objective was treatment efficacy ([PFS hazard ratio (HR)], non-inferiority being established if the upper bound of the PFS HR 2-sided 90%CI is &amp;lt;1.25; secondary objectives included subgroup analyses (CTC status, patient characteristics) and OS. Results: In this trial, 778 patients were randomized between both strategies. Of all patients, 71.0%, 26.6% and 2.4% were considered as endocrine-sensitive, with secondary or with primary endocrine resistance, respectively. In both arms (clinically- and CTC-driven), prognostic evaluation by physician/CTCs and allocated treatments were as follows: (i) clinicallow/CTClow 46.5% and 48.6% of patients, all treated with ET. (ii) clinicalhigh/CTChigh 14.0% and 13.0%, all treated with CT. (iii) clinicallow/CTChigh 26.1% and 24.2%, treated with ET or CT respectively. (iv) clinicalhigh/CTClow 13.4% and 14.0%, treated with CT or ET respectively. CTC-driven strategy met the primary endpoint, yielding a non-inferior PFS (median: 17 months; 95%CI [15.4-20.3] vs 18 months 95%CI[13.9-23.3]). In the 2 discordant subgroups, preplanned analyses showed the following results: in the clinicallow/CTChigh subgroup, patients treated with CT had a significantly longer PFS than those treated with ET (15.6 months, 95%CI [12.2-22.7] vs 10.5 months, 95%CI [7.3-15.4], log rank p=0.002). In the clinicalhigh/CTClow subgroup, patients treated with CT had a non-significant PFS advantage over patients treated with ET. Pooling these two subgroups of patients (N=292) with discordant treatment recommendations (depending on clinician or CTC count standpoint), an exploratory analysis showed that patients treated with CT frontline had significantly longer PFS (HR=0.66; 95%CI [0.51-0.85]) and OS (HR=0.65; 95%CI [0.43-0.98]); 2-year OS were 82.9% versus 74.7% in patients treated with CT (±maintenance ET) or ET, respectively. Conclusion: This trial demonstrates the utility of CTC count to select 1st line therapy in ER+ HER2- MBC patients, especially in those for whom single agent ET is the recommended therapy based on clinical factors. With this modern prognostic biomarker, the STIC CTC trial is the first one to identify potential ER+ HER2- MBC patients who might derive more benefit from frontline CT followed by maintenance ET than from frontline ET, challenging current standards. Funding: French Ministry of Health (PSTIC 2011); Menarini SB; Institut Curie. Citation Format: Francois-Clement Bidard, William Jacot, Sylvain Dureau, Etienne Brain, Thomas Bachelot, Hugues Bourgeois, Anthony Goncalves, Sylvain Ladoire, Herve Naman, Florence Dalenc, Joseph Gligorov, Marc Espie, Christelle Levy, Jean-Marc Ferrero, Delphine Loirat, Paul Cottu, Veronique Dieras, Marie-Emmanuelle Legrier, Frederique Berger, Catherine Alix-Panabieres, Jean-Yves Pierga. Circulating tumor cells as a tool to guide first line therapy in metastatic breast cancer: subgroup analyses of the STIC CTC Phase III utility trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT140.

Abstract SY31-02: Clinical utility trials for CTC and ctDNA in ER+ advanced breast cancer

Abstract Background: In ER+ HER2- metastatic breast cancer (MBC) patients, current first line treatment options are either endocrine therapy (ET, given either as single agent or, more recently, in combination with cdk4/6 inhibitor) or chemotherapy (CT). Given its good risk/benefit ratio, endocrine therapy (ET) is the preferred 1stline therapy in these patients, but not all benefit from such strategy for which predictive biomarkers are lacking. During first line ET, resistance may also appear following the emergence of ESR1-mutated subclones. On grounds of prior clinical validity studies, the clinical utility of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) as a tool to improve the outcome of 1st line ER+ HER2- MBC patients has been / is investigated in large phase 3 trials. CTC clinical utility trial: In the STIC CTC phase III trial (NCT01710605, coordinated by Institut Curie), the baseline CTC count (CellSearch, Menarini SB) was compared to the clinician's choice to treat patients with either single agent ET or frontline CT. N=778 ER+ HER2- MBC have been randomized between the CTC-driven choice to the clinician-driven choice. #60% of patients had a concordant prognostic evaluation. In the 2 subgroups (#40% of patients) with discordant treatment recommendations (depending on clinician or CTC count standpoint), frontline CT yielded significantly longer PFS. An unplanned analysis also suggested that CT was associated with a longer OS. Relying on CTC count as a modern prognostic biomarker, the STIC CTC trial was the first to identify potential ER+ HER2- MBC patients who might derive more benefit from frontline CT than from single agent ET, challenging current standards and deserving further studies. ctDNA clinical utility trial: The phase III PADA-1 trial (NCT03079011, coordinated by Unicancer UCBG and GYNECO) is testing the clinical utility of real time ESR1mut detection (at baseline, at 1 month and then every 2 months) through ctDNA analysis in N=1000 ER+ HER2- MBC patients treated with aromatase inhibitor (AI) and palbociclib. Patients with rising ESR1mut in circulating tumor DNA (i.e. increasing or appearing mutations) during first line AI-palbociclib therapy are randomized in a second step between switching to Fulvestrant-palbociclib or keeping the same regimen (AI-palbociclib until disease progression, a cross-over being then proposed). ESR1mut are tracked in circulating DNA from up to 4ml of plasma by a ddPCR-based assay targeting E380, L536, Y537 and D538 hotspots (i.e. &amp;gt;90% of known ESR1 activating mutations) with #0.1% sensitivity (Bidard et al, AACR 2018 #3867). Whereas the study is ongoing, preliminary results confirmed that ESR1mut is a rare event in untreated AI-"sensitive" ER+ HER2- MBC patients and primarily associated with a prior use of AI in the adjuvant setting. Interestingly, in most MBC patients with ESR1mut detected at baseline, ESR1mut became undetectable after 1 month of AI-Palbociclib therapy, suggesting that this combination may retain early antitumor efficacy. Discussion: Demonstrating clinical utility is paramount for new cancer biomarkers such as CTC and ctDNA. Large prospective interventional trials are however required, such as those discussed here. Citation Format: Francois-Clement Bidard. Clinical utility trials for CTC and ctDNA in ER+ advanced breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY31-02.

Abstract 1014: Characterization of breast cancer cells resistant to letrozole and palbociclib combination therapy and the potential of dinaciclib to treat such resistance

Abstract Treatment of estrogen receptor positive (ER+) breast cancer have included single-agent endocrine therapy, such as with aromatase inhibitors (AIs) and, more recently, AIs in combination with the cyclin-dependent kinase 4/6 inhibitor palbociclib. While combination therapy is effective, drug resistance is a well-known phenomenon and breast cancer cells can acquire resistance to aromatase inhibitor and palbociclib individually. In anticipation of patient who may become resistant to combination therapy with aromatase inhibitor (letrozole) and palbociclib, this current study has 1) developed MCF7Ca cells resistant to both letrozole and palbociclib (MCF7Calet+palb); 2) characterized them in comparison to drug naïve (MCF7Ca) and letrozole alone-resistant (LTLTCa) cells; and 3) explored potential treatments. Characterization of MCF7Calet+palb cells by phase contrast microscopy, mammosphere assays, and invasion assays, indicate that they have more basal/mesenchymal morphology, produce more mammospheres (an indicator of cancer stem cells; 150±10 vs. 80±10 in MCF7Ca and 123± 8 in LTLTCa cells), and are more invasive (1200±50 cells vs. 791±15 in MCF7Ca cells). The more aggressive phenotype of MC7Calet+palb correlated with changes in protein expression. Compared to the other cell lines, MCF7Calet+palb expressed significantly lower fold expression levels of cell cycle cyclin D1 (0.2±0.1), phosphorylated CDK9 (0.5±0.1), and phosphoRb and total Rb (0.4±0.2), but higher levels of phosphoCDK1 and CDK2 (1.4±0.1 and 3.1±0.6). Regarding growth pathway proteins, MCF7Calet+palb comparably had increased HER2 and phosphorylated Akt (6.2±1.3 and 3.3±1.2, resp.) as LTLTCa vs. MCF7Ca cells, but had even more reduced levels of ERα (0.04 vs. 0.1±0.4 in LTLTCa and 1±0.01 in MCF7Ca). Cancer stem cell marker breast cancer resistance protein (BCRP) was increased further in MCF7Calet+palb cells (2.11-fold). Based on these results, the effect of dinaciclib, a broader range CDK inhibitor, was studied. In MTT assays, dinaciclib was shown to be effective in inhibiting cell viability in all three cell types. Dinaclicib’s IC50s were 1.4 nM (MC7Ca) 9.5 nM (LTLTCa) and 12.4 nM in MCF7Calet+palb cells, while palbociclib IC50s were 1.5 μM, 11.2 μM, and 118 μM, respectively. Dinaciclib also significantly reduced mammosphere formation 0.01-fold and cell invasion/migration by 0.3-fold vs. untreated. Lastly, preliminary exome sequencing data suggested highly mutated FGFRL1, ARL11, and FCGBP genes, among others, when MCF7Calet+palb cells were compared to MCF7Ca cells. Overall, these results suggest that acquired resistance to combination therapy with letrozole and palbociclib induces genetic, molecular, and phenotypic changes in breast cancer cells, and that dinaciclib may be an effective treatment to either treat and/or prevent this resistance. Citation Format: Armina Kazi, Emily Shukdinas, Saranya Chumsri, Gauri J. Sabnis. Characterization of breast cancer cells resistant to letrozole and palbociclib combination therapy and the potential of dinaciclib to treat such resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1014.

Triplet therapy (continuous ribociclib, everolimus, exemestane) in HR+/HER2− advanced breast cancer postprogression on a CDK4/6 inhibitor (TRINITI-1): Efficacy, safety, and biomarker results.

1016 Background: The combination of CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) provides consistent improvement in PFS and response rates compared with single-agent ET as first- or subsequent-line therapy in HR+, HER2− advanced breast cancer (ABC), but the optimal regimen postCDK4/6i progression, including the role of continued CDK 4/6 blockade, is unclear. Methods: TRINITI-1 is a Phase I/II, open-label trial (NCT02732119) of triplet therapy: ribociclib (RIB; CDK4/6i) + everolimus (EVE; mTORi) + exemestane (EXE; ET) in men or postmenopausal women with HR+, HER2− ABC that progressed on prior CDK4/6i and up to 3 lines of therapy (≥ 1 ET and ≤ 1 chemotherapy regimen). Phase I determined RP2D; Phase II assessed efficacy/safety of RIB 300 or 200 mg + EVE 2.5 or 5 mg + EXE 25 mg/day. Here we present the first results in the entire patient population who received this triplet regimen and the correlation of biomarkers with outcomes. Results: As of October 24, 2018, 95 patients were evaluable (ET refractory and postCDK4/6i) in Phases I (n = 17) and II (n = 78). Continuous RIB + EVE + EXE demonstrated clinical benefit at week 24 in 39 patients (41.1%), exceeding the predefined primary end point threshold (&gt; 10%). ORR was 8.4% by investigator assessment, median PFS was 5.7 months, and 1-year PFS was 33%. AEs were consistent with known safety profile of RIB, EVE, and EXE. Most common AEs were neutropenia (all grades, 41.7%; grade 3/4, 31.3%), stomatitis (41.7%; 3.1%), and fatigue (35.4%; 1.0%). No grade 3/4 QTc prolongation was noted. ctDNA genotyping revealed patients with certain tumor alterations, eg ESR1, had shorter median PFS vs wild-type: 3.5 vs 6.9 mo (HR 1.76, 95% CI 1.01–3.05). Additional genomic results, including PIK3CA, will be presented. Conclusions: TRINITI-1 met its primary efficacy end point and is the first trial to demonstrate clinical benefit and tolerability of continuous triplet therapy with ET + mTORi + CDK4/6i in patients with ET-refractory HR+, HER2− ABC postCDK4/6i progression. Tumor genomic profile might impact the clinical outcome with triplet therapy and warrants additional research to guide rational therapy selection. Clinical trial information: NCT02732119.

Abstract P6-18-03: Biomarker analysis of CDK 4/6 and endocrine pathways in hormone-receptor positive (HR+) advanced breast cancer (ABC) bone only disease patients: A joint analysis of PALOMA-2 and PALOMA-3 studies

Abstract Background: Palbociclib (PAL) in combination with endocrine therapy (ET) is a preferred treatment option for untreated and previously treated patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2 (HER2)–negative ABC. Patients with bone only disease could derive prolong disease control with single agent ET. Further understanding the predictive markers for sensitivity to ET alone and P+ET in both endocrine sensitive and resistant settings could help guide clinical treatment sequencing decision. We performed biomarker (BM) analysis of baseline tumor tissues in both PALOMA-2 (P2) and PALOMA-3 (P3) in bone only (BO) vs non-bone (NBO) only patients. Methods: Postmenopausal women (N=666) with no prior systemic therapy for ER+/HER2-ABC were randomized 2:1 to receive PAL+LET or matching placebo (PBO)+LET in P2. In P3 women (N=521) who progressed on prior endocrine therapy were randomized 2:1 to receive PAL+ FUL vs matching PBO+FUL. All pts including those with BO disease had to consent to provide tumor tissues to participate the current study. EdgeSeq Oncology Biomarker Panel (HTG Molecular Diagnostics; Tucson, AZ) was used for mRNA profiling. Cox regression analysis was used to evaluate the association of BO disease with treatment effect as well as the association of gene expression with treatment effect in BO vs NBO pts. Results: Treatment effect in the BM population from each study was consistent with that observed in the respective ITT population. In ITT population, BO disease was reported in 151 (23%) pts of P2 with mPFS 36.2mo PAL+LET arm (n=103) vs 11.2mo LET arm (n=48), HR=0.40 (0.26-0.62) and in 124 (24%) pts of P3 with mPFS 14.3mo PAL+FUL arm (n=86) vs 9.2mo FUL arm (n=38), HR=0.64(0.38-1.06). BO disease was reported in 107 (24%) pts in P2 and 81 (27%) pts in P3 BM population. In P2, longer mPFS was seen with PAL+ LET vs PBO+LET in BO vs NBO disease (30.6 mo vs 11.2 mo; HR=0.42 (0.25-0.69) in BO pts and 22.1 mo vs 13.8 mo HR=0.67 (0.52-0.88) in NBO pts) although the interaction effect was not statistically significant. Similar results were also observed in P3 with longer mPFS in PAL+FUL vs PBO+FUL in BO vs NBO disease (16.6 mo vs 11.2 mo HR=0.79 (0.40-1.56) in BO pts and 11.1mo vs 3.5 mo HR=0.47 (0.34-0.66) in NBO pts) with insignificant interaction effect. In both studies, BO pts had higher incidence of luminal A disease (BO vs NBO: P2=62% vs 47%; P3=54% vs 40%) and lower rate of luminal B disease (P2=19% vs 33%; P3: 26% vs 33%). In both studies, baseline ESR1, Cyclin E and CDK 4 gene expression level were comparable between BO vs NBO pts. Elevated CDK4 gene expression level was associated with resistance to LET in P2 and lower Cyclin E gene expression predicts the effect of PAL in P3. Conclusion: mPFS was significantly prolonged in BO pts with the addition of PAL to ET. BO disease was more frequently associated with luminal A subtype in ABC setting. CDK4 expression level was similar to NBO disease pts but associated with resistance to single agent LET. Citation Format: Finn RS, Turner NC, Liu Y, Rugo HS, Loibl S, Diéras V, Slamon DJ, André F, Gelmon K, DeMichele A, Loi S, Zhang Z, Giorgetti C, Gauthier E, Huang Bartlett C, Cristofanilli M. Biomarker analysis of CDK 4/6 and endocrine pathways in hormone-receptor positive (HR+) advanced breast cancer (ABC) bone only disease patients: A joint analysis of PALOMA-2 and PALOMA-3 studies [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 P6-18-03.

The role of abemaciclib in treatment of advanced breast cancer.

Until recently, the mainstay of treatment in the majority of hormone receptor (HR)-positive, human epidermal growth factor 2 receptor (HER2)-negative advanced breast cancer (ABC) has consisted of single-agent endocrine therapy (ET). However, as understanding of endocrine resistance has grown, newer targeted agents have come to the fore. Inhibition of cyclin-dependent kinase complexes 4 and 6 (CDK4/6) combined with ET has shown significant activity in HR+ HER2− ABC, with impressive results in terms of progression-free survival (PFS) when compared with ET alone. This review summarizes the seminal findings pertaining to CDK4/6 inhibition in this population, specifically focusing on abemaciclib, contrasted with palbociclib and ribociclib. Potential directions for future studies are discussed, as a way of addressing outstanding issues such as establishing optimal treatment sequencing and agent combinations, appropriate patient selection to derive maximal benefits, predictive biomarkers and the employment of CDK4/6 inhibition beyond the ABC setting.