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Introduction Triple negative breast cancer (TNBC) is a heterogeneous breast cancer subtype which continues to portend a particularly poor prognosis compared to other breast cancer subtypes. Immune checkpoint inhibitor (ICI) therapies have emerged as promising options for locally advanced and metastatic TNBC. However, clinical trials have demonstrated mixed results with respect to ICI response. Given varied outcomes and the potential for immune-related adverse events associated with ICIs, there is critical need for identification of accurate biomarkers of response and improved strategies to counteract ICI resistance and/or toxicity. Methods Advanced immunoprofiling of peripheral blood mononuclear cells (PBMCs) and plasma from 7 metastatic TNBC patients with variable responses to anti-PD1 or anti-PDL1 therapy was performed. Samples were analyzed from blood draws obtained: (i) prior to first administration, (ii) while receiving ICI treatment, and (iii) at the time of conformed clinical progression or response to therapy. Response was determined by standard radiological assessment. Immunoprofiling included high parameter flow cytometry, single cell transcriptomics (10x genomics) and secretome analysis (Isoplexis). Single cell RNA profiles from 63,984 cells were analyzed. Results High parameter flow cytometry identified higher circulating levels of a subpopulation of activated CD4+ T cells with a phenotype of CXCR3low CD62Llow CD45RAhigh and CD57high expression in responders versus non-responders. Higher effector function of CD4+ T cells was corroborated by significantly elevated plasma concentrations of IL-2 (p=0.02) and IL-5 (p< 0.0001) among responders. Single cell transcriptomic analysis revealed clusters of B and T cells with distinct activation patterns that were associated with radiographic response. Strikingly, genes involved in B cell activation and T cell-B cell conjugation such as CD81 were found to be highly upregulated among CD4+ T cells from responders. Conclusions Our results are consistent with previous reports describing an association of increased B cell activity in TNBC with improved overall survival. We identified a subpopulation of CD4+ T cells with effector functions consistent with type 2 helper T cells that may not only target cancer cells by direct cytotoxic function, but also promote increased B cell anti-tumor activity. Our study provides insight into specific mechanisms of immune cell interplay that may drive response to ICI therapy. These cell populations and their associated pathways may represent potential biomarkers of response and/or targets for resistance reversal. Citation Format: Avia D. Wilkerson, Patricia A. Rayman, Paul G. Pavicic Jr, Hana Husic, Vladimir Makarov, Ivan Juric, Timothy Chan, Alberto J. Montero, Marcela Diaz-Montero. A multiomic approach to the identification of immune signatures of anti-PD1/PDL1 therapy responders in metastatic triple negative breast cancer: new implications in the role of helper T-cell and B-cell interplay [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-04-04.

Background Metastatic hormone receptor positive (HR+)/human epidermal growth factor receptor-2 negative (Her2−) breast cancer remains a significant cause of cancer-related mortality. First-line treatment with endocrine therapy (ET) with a cyclin-dependent kinases 4 and 6 inhibitor (CDK4/6i) has largely become the standard systemic therapy. Following progression, no prospective randomized data exist to help guide second-line treatment. Materials and Methods This study used a nationwide electronic health record (EHR)-derived de-identified database, specifically analyzing 1210 patients with HR+/Her2− metastatic breast cancer (MBC) who were treated in the first-line setting with a CDK4/6i from the years 2015-2020. The aim of this study was to assess what therapies were given after first-line progression on CDK4/6i and to observe treatment patterns over time. Determination of second-line treatment efficacy, specifically assessing real-world progression-free survival (rwPFS) and overall survival (OS) was performed. Results A total of 839 patients received a documented second-line therapy after progression on first-line CDK4/6i treatment. Chemotherapy was chosen for 29.7% of patients, and the use of chemotherapy decreased over time. Three hundred two (36.0%) of patients continued a CDK4/6i. Data were adjusted for age, race, Eastern Cooperative Oncology Group (ECOG) performance status, stage at breast cancer diagnosis, and insurance payer type. Continuation of the CDK4/6i was associated with improved rwPFS (HR 0.48, 95% CI 0.43-0.53, P < .0001) and OS (HR 0.30, 95% CI 0.26-0.35, P < .0001) compared to chemotherapy. A majority of these patients continued the same CDK4/6i in the second-line setting, as was given in the first-line setting. Conclusion While prospective data are needed, analysis of real-world data suggests a survival benefit for continuation of a CDK4/6i beyond frontline progression for patients with HR+/Her2− MBC.

Figure S1. Correlative Angiogenesis Biomarkers. A, levels of circulating endothelial cells in patients in schedule A and B at baseline (Pre-treatment). B, circulating endothelial precursor cells (EPCs) at baseline in patients in schedule A and B. C, baseline plasma angiogenic activity (PAA) at baseline in patients in schedule A and B.

Purpose: To evaluate the safety, MTD, pharmacokinetics/pharmacodynamics, and early clinical activity of ixabepilone given either weekly or every 3 weeks in combination with daily sunitinib in patients with advanced solid tumors.Experimental Design: Eligible patients received either weekly (schedule A) or every 3 weeks (schedule B) ixabepilone at escalating doses (schedule A: 7.5, 15, or 20 mg/m2; schedule B: 20, 30, or 40 mg/m2), and oral sunitinib (37.5 mg daily), starting on day 8 of cycle 1. Dose-limiting toxicities (DLT) were assessed during cycle 1.Results: The ixabepilone and sunitinib combination was fairly well tolerated. DLTs were observed in 3 subjects (1 in schedule 3A and 2 in schedule 3B). The most common grade 3–4 hematologic and nonhematologic adverse events were leukopenia and fatigue, respectively. Four patients (3 in schedule A) achieved a partial response, while 13 patients had stable disease. Nine of 17 heavily pretreated colorectal cancer patients had clinical benefit. Coadministration of sunitinib with ixabepilone on a weekly (but not every 3 week) schedule was associated with a significant increase in the half-life and a significant decrease in the clearance of ixabepilone. Correlative studies demonstrated a significant association between higher baseline plasma angiogenic activity (PAA) and clinical benefit in schedule A patients. Weekly, but not every 3 weeks, ixabepilone led to a significant decrease in PAA postbaseline.Conclusions: Coadministration of ixabepilone with sunitinib has acceptable toxicity and encouraging clinical activity in heavily pretreated patients, particularly in patients with metastatic colorectal cancer. Clin Cancer Res; 22(13); 3209–17. ©2016 AACR.

BackgroundCardiovascular disease (CVD) is the leading cause of death in men with prostate cancer (PC). Accumulated stress plays an important role in CVD development. The cumulative burden of chronic stress and life events can be measured using allostatic load (AL).MethodsThe initial cohort included males aged 18 years and older diagnosed with PC (2005-2019). AL was modeled as an ordinal variable (0-11). Fine-Gray competing risk regressions measured the impact of precancer diagnosis AL and postdiagnosis AL in 2-year major cardiac events (MACE). The effect of AL changes over time on MACE development was calculated via piecewise Cox regression (before, and 2 months, 6 months, and 1 year after PC diagnosis).ResultsWe included 5261 PC patients of which 6.6% had a 2-year MACE. For every 1-point increase in AL before and within 60 days after PC diagnosis, the risk of MACE increased 25% (adjusted hazard ratio [aHR] =1.25, 95% confidence interval [CI] = 1.18 to 1.33) and 27% (aHR = 1.27, 95% CI = 1.20 to 1.35), respectively. Using AL as a time-varying exposure, the risk of MACE increased 19% (aHR = 1.19, 95% CI = 1.11 to 1.27), 22% (aHR = 1.22, 95% CI = 1.14 to 1.33), 28% (aHR = 1.28, 95% CI = 1.23 to 1.33), and 31% (aHR = 1.31, 95% CI = 1.27 to 1.35) for every 1-point increase in AL before, 2 months after, 6 months after, and 1 year after PC diagnosis, respectively.ConclusionAL and its changes over time are associated with MACE in PC patients, suggesting a role of a biological measure of stress as a marker of CVD risk among men with PC.

Background: CDK 4/6 inhibitors (CDKI) with Endocrine therapy (ET) is mainstay treatment for hormone receptor-positive (HR+) Her2- metastatic breast cancer (MBC). Despite excellent efficacy, most patients develop resistance to CDKI limiting its utility. CDK4/6 are thought to act by upregulating VEGF causing tortuous angiogenesis and promoting cancer progression. Recent studies have shown aggressive tumors possess a higher density and tortuous vasculature. In this study, we evaluated if vascular radiomic features computationally extracted from liver CT scans pre- and post CDKI treatment could predict patient survival and treatment response. Method: From a registry of 350 patients on treatment with CDKI at institution 1(S1), 51 pts with HR+, Her2-, MBC patients with evidence of liver mets and disease progression (PFS) data were identified. 30 pts discontinued treatment due to progression or death, with a median time to progression of 195 days. Pre-treatment and first post-treatment CT exams were analyzed from 25 and 34 patients, respectively. Median time between scans was 128 days. To validate the prognostic value of our signature, a cohort of 29 patients with available OS data was identified from institution 2 (S2). A publicly available pre-trained deep learning model was applied to isolate liver metastases and vessels. Next, fast marching algorithm was applied to reduce vessels to their centerlines and divide the vasculature into constituent branches. 7 quantitative metrics were computed measuring vascularity of metastases and 3-D shape of hepatic vessels. First, the number (f1) and percentage (f2) of hepatic vessels arising from the tumor were computed. Vessel tortuosity - measuring the degree of twisting across a vessel - was computed separately for each branch. The mean (f3), standard deviation (f4), maximum (f5), skewness (f6), and kurtosis (f7) tortuosity values were calculated to summarize these measurements at patient level. The features were individually assessed at pre- and post-treatment for association with PFS at S1 in univariable Cox proportional hazards models. Features found to be associated in S1 were evaluated for association with OS in S2. Results: On the initial post-treatment scan, features of both tumor vascularization (f6 - HR=1.115 [1.039-1.196]; f7 - HR=10.646 [2.539-44.641]), as well as two features of vessel tortuosity (f3 - HR=0.011 [0.001-0.199]; f4 - HR=0.545 [0.313-0.949]) were significantly associated with PFS. Both tortuosity features were also significantly associated with OS in S2 (f3 - HR=0.085 [0.009-0.780]; f4 - HR=0.331 [0.130-0.842]). In addition the percentage (f7 - HR=6.445 [2.001-20.753]]),of vessels feeding the lesions was also significant in S2 while the number (f6 - HR=1.070 [0.966-1.184]), of vessels was not. No vessel metrics from the pre-treatment baseline exam were significantly associated with OS. Conclusions: Radiomic analysis of tumor vascularity and vessel tortuosity on CT scans post-CDK treatment was associated with patient survival and treatment response. Table 1.Association of vessel features with PFS in Institution 1(S1)and OS in Institution 2(S2)S1- Pretreatment CT (n=25)S1 - Post-Treatment CT (n=34)S2 - Post-treatment CT - Validation (n=29)f1Tortuosity - Mean0.9912702470.852294696–f2Tortuosity - St. Dev0.7563942230.273115373–f3Tortuosity - Max0.1387051870.0022517550.02931473f4Tortuosity - Skewness0.254463710.0318270370.02022882f5Tortuosity - Kurtosis0.3058266760.108967601–f6Number of vessels feeding lesions0.419096650.0025747910.19306052f7Percentage of vessels feeding lesions0.0517942660.0012205950.00179103 Citation Format: Vidya Sankar Viswanathan, Nathaniel Braman, Priyanka Reddy, Siddharth Kunte, Jame Abraham, Alberto J Montero, Anant Madabhushi. Post-treatment vascularity and vessel shape are associated with survival and response to CDK4/6 inhibitors in hormone receptor-positive metastatic breast cancer (MBC) [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 P5-13-27.

Background: HER2-targeted therapies have led to marked improvements in survival for patients with HER2-positive breast cancer. Despite the gains obtained with current HER2-targeted therapies, an unmet medical need remains for patients with HER2-expressing (high or low expression) advanced breast cancer that has progressed after prior treatments. Zanidatamab is a novel HER2-targeted bispecific antibody that has multiple mechanisms of action, including immune clearance of HER2-expressing tumor cells through antibody-dependent cellular phagocytosis. Zanidatamab has been shown to be well-tolerated and has demonstrated antitumor activity, both as monotherapy and in combination with chemotherapy, across HER2-expressing solid tumors in a Phase 1 study. ALX148 is a high affinity CD47-blocking fusion protein with an inactive human immunoglobulin Fc region designed to enhance the activity of anticancer therapies, including antibodies, with minimal added hematologic toxicity. Treatment with zanidatamab in combination with ALX148 has the potential to augment the immune clearance of HER2-expressing cancer cells by blocking the CD47-SIRPa interaction that inhibits phagocytosis of the same cancer cells. In a Phase 1 study, ALX148 demonstrated antitumor activity when combined with trastuzumab in patients whose disease had progressed on prior HER2-targeted therapies. Here, we describe a Phase 1b/2 study to investigate the safety and antitumor activity of a chemotherapy-free combination of zanidatamab plus ALX148 in advanced HER2-expressing cancers, including breast cancer. Methods: ZWI-ZW25-204 is a Phase 1b/2, 2-part, open-label, multicenter study to evaluate the safety and antitumor activity of zanidatamab administered in combination with ALX148 in patients with locally advanced/inoperable and/or metastatic HER2-expressing cancer. Part 1 of this study will evaluate safety and tolerability and will establish the recommended doses (RDs) of zanidatamab plus ALX148. It will include patients with either HER2-positive (defined per ASCO/CAP guidelines) or HER2-low (defined as immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization (ISH) negative) breast cancer. Part 2 will evaluate the antitumor activity of zanidatamab plus ALX148 (at their combination therapy RDs) in 3 expansion cohorts: HER2-positive breast cancer (Cohort 1), HER2-low breast cancer (Cohort 2) and other HER2-overexpressing advanced malignancies (Cohort 3). Other key eligibility criteria include: prior use of approved agents known to confer clinical benefit, disease progression on or after the most recent systemic therapy, measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Patients will receive zanidatamab and ALX148, each administered intravenously once every 2 weeks in a 28-day treatment cycle. Response assessments will be performed every 8 weeks. Primary endpoints include safety and tolerability assessments (Part 1) and confirmed objective response rate per RECIST 1.1 (Part 2). Secondary endpoints in Part 2 include disease control rate, clinical benefit rate, duration of response, progression-free survival, overall survival, safety, pharmacokinetics, and immunogenicity assessments. The study is currently open for enrollment in the United States and may enroll up to 93 patients (NCT: 05027139). Citation Format: Sara A. Hurvitz, Jorge Chaves, Adam Brufsky, Alberto J. Montero, Bruno Fang, Kay Yeung, Manish R. Patel, Ritesh Parajuli, Adam Omidpanah, Elaina Gartner, Abraham Fong, Sophia Randolph, Funda Meric-Bernstam. Zanidatamab in combination with ALX148 in advanced human epidermal growth factor receptor 2 (HER2)-expressing cancers, including breast cancer: A phase 1b/2, multicenter, open-label, dose-finding and cohort-expansion study (ZWI-ZW25-204) [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 OT1-14-01.

Background: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with a higher risk of locoregional and distance recurrence. Consequently, this population was considered poor candidate for breast conservation (BCT). Our study aim was to determine whether BCT plus radiotherapy (RT) was equivalent to mastectomy for TNBC after adjustment of selection bias of demographic and clinical characteristics. Methods: The National Cancer Database was queried for women diagnosed as primary unilateral invasive clinical T1-2N0-2 TNBC from 2004-2016. Patients who underwent mastectomy or breast conservation (partial mastectomy plus radiation) were included. A 1:1 propensity match with replacement was performed to compare breast conservation vs. mastectomy. Overall survival was analyzed using stratified multivariable Cox proportional hazard regression analysis.Results: Of 59,599 clinical T1-2N0-2 TNBC patients, 26,325 (44.2%) underwent mastectomy and 33,274 (55.8%) were treated with BCT. BCT patients were older (median age 59 vs. 54, p Citation Format: Lifen Cao, Christopher W Towe, Megan E Miller, Alberto J Montero, Robert Shenk. Breast conservation plus radiotherapy provides superior survival benefit than mastectomy in triple negative breast cancer: A propensity matched national cancer database analysis [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 P3-18-02.

There is a male predominance of acute myeloid leukemia (AML) incidence, but survival data are conflicting. The objective of this study is to carry out a comprehensive analysis of sex differences in AML, and to investigate the impact of sex disparities in survival.The cohort included patients ≥18 years diagnosed with AML (2010-2022). Demographics, treatment patterns, treatment adverse events, and survival were analyzed. The population was described and compared by sex, and sex-based risks and associations were obtained via Cox proportional-hazards regression.In total, 1020 AML patients were analyzed (57.4% males), with lower risk of death for females (aHR = 0.41, 95% CI 0.26-0.66). Among females, BMT (aHR = 0.51, 95% CI 0.27-0.97), hospitalization record (aHR = 0.65, 95%CI 0.45-0.93), and higher appointment completion rates (aHR = 0.98, 95% CI 0.98-0.98) were associated with lower risk of death. Overall, and similarly in males, higher age at diagnosis (aHR = 1.03, 95% CI 1.02-1.04) and a TP53 mutation (aHR = 2.24, 95% CI 1.69-2.97) were associated with higher risk of death.Sex differences exist in both AML incidence and overall survival. Treatment and health care factors should be addressed by caregivers and public policies developed to reduce mortality rates and mitigate existing sex differences.

Breast cancer; Cancer Càncer de mama; Càncer Cáncer de mama; Cáncer The METRIC study (NCT#0199733) explored a novel antibody–drug conjugate, glembatumumab vedotin (GV), targeting gpNMB that is overexpressed in ~40% of patients with triple-negative breast cancer (TNBC) and associated with poor prognosis. The study was a randomized, open-label, phase 2b study that evaluated progression-free survival (PFS) of GV compared with capecitabine in gpNMB-overexpressing TNBC. Patients who had previously received anthracycline and taxane-based therapy were randomized 2:1 to receive, GV (1.88 mg/kg IV q21 days) or capecitabine (2500 mg/m2 PO daily d1–14 q21 days). The primary endpoint was RECIST 1.1 PFS per independent, blinded central review. In all, 327 patients were randomized to GV (213 treated) or capecitabine (92 treated). Median PFS was 2.9 months for GV vs. 2.8 months for capecitabine. The most common grade ≥3 toxicities for GV were neutropenia, rash, and leukopenia, and for capecitabine were fatigue, diarrhea, and palmar-plantar erythrodysesthesia. The study did not meet the primary endpoint of improved PFS over capecitabine or demonstrate a relative risk/benefit improvement over capecitabine. Funding provided by Celldex Therapeutics, Inc.

Background: Hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (Her2-) breast cancers represent the majority of metastatic breast cancers (mBC) among women and are often treated with sequential courses of endocrine therapy (ET) prior to the eventual need for chemotherapy (CT). Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) block cell cycle progression and decrease proliferation of breast cancer cells. Currently, there are three available CDK4/6i: palbociclib, ribociclib and abemaciclib. Each has been shown to improve progression-free survival (PFS) when given with ET in the frontline setting, compared to ET alone. After progression on CDK4/6i, no standard of care exists for the next line of systemic therapy, and there are no prospective data to help guide clinical practice. Analysis of real-world data may provide insight into optimal second-line treatment for women who have progressed on CDK4/6i therapy. Methods: The nationwide Flatiron Health electronic health record-derived de-identified database was utilized for this analysis. We evaluated patient data collected from 2015-2020 for women with HR+/Her2- mBC who received CDK4/6i as frontline therapy and received a documented second-line systemic therapy. The objectives of this study were to describe what therapies were given as second-line treatment and estimate the real-world PFS (rwPFS) of those therapies. rwPFS was defined as time between initiation of second-line therapy until clinician-recorded progression (or death). Patients (pts) who did not progress or die were considered censored at the end of follow-up or end of second-line therapy. Results: A total of 1,210 pts with HR+/Her2- mBC received CDK4/6i with ET in the frontline setting, including 29.1% with de novo metastatic disease. Average age at diagnosis of metastatic disease was 64.4 years (range 28-84). A majority of pts received palbociclib in the frontline setting (88.2%), and 68.8% received an aromatase inhibitor (AI) as the frontline ET partner. 839 pts subsequently received second-line therapy (Table 1). CDK4/6i was continued as part of second-line treatment in 308 (36.7%) pts. 249 (29.7%) pts received CT as second-line treatment. The proportion of pts who continued CDK4/6i increased from years 2015-2020 (p=0.035), and the proportion who received CT decreased over time (p TABLE 1. Second-Line Therapy Used. F, fulvestrant; T, tamoxifenSECOND-LINE THERAPYOverall (N=839)AI23 (2.7%)CDK4/6i4 (0.5%)CDK4/6i + AI97 (11.6%)CDK4/6i + F160 (19.1%)CDK4/6i + F + AI35 (4.2%)CDK4/6i + F + T3 (0.4%)CDK4/6i + T3 (0.4%)CT249 (29.7%)F70 (8.3%)F + AI14 (1.7%)mTOR99 (11.7%)PARP4 (0.5%)PI3K16 (1.9%)T11 (1.3%)Clinical Trial51 (6.1%) Citation Format: James M Martin, Elizabeth A Handorf, Alberto J Montero, Lori J Goldstein. Analysis of systemic therapies following progression on frontline CDK4/6-inhibitor therapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-15.

Background. Given the significant clinical activity of the anti-PD1 inhibitor pembrolizumab as either a single agent or in combination with cytotoxic chemotherapy in the treatment of patients with metastatic triple-negative breast cancer (mTNBC), as well as the favorable cytotoxic and immunomodulatory properties of carboplatin and nab-paclitaxel, we identified a strong rationale to treat patients with mTNBC with the combination of carboplatin (C), nab-paclitaxel (N) and pembrolizumab (P) (CNP). Material and Methods. We undertook a prospective, single-arm pilot study of 30 patients with mTNBC treated at two institutions. Inclusion criteria included: radiographically measurable mTNBC, ECOG performance status of 0-1, Conclusions. CNP demonstrated significant activity in patients with mTNBC. Studies are underway to identify pathologic and genomic correlates of clinical response to CNP. Citation Format: Joseph Baar, Jame Abraham, G. Thomas Budd, Paula Silverman, Alberto Montero, Halle Moore, Pingfu Fu, Vinay Varadan, Kara Ladaika, Lauren Hricik. Pilot study of carboplatin, nab-paclitaxel and pembrolizumab for metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-16.

Background: Everolimus in combination with exemestane (EVE+EXE) was initially FDA approved to treat metastatic hormone receptor-positive breast cancer (mHRBC) in patients previously treated with nonsteroidal aromatase inhibitors based on the BOLERO-2 trial. However, none of the patients in the BOLERO-2 trial received prior CDK4/6 inhibitors, which have become standard of care for mHRBC. There is limited data to support the use and clinical benefit of EVE+EXE in mHRBC patients previously treated with CDK4/6 inhibitors. Methods: We reviewed patients ≥18 years old with mHRBC treated with EVE+EXE at our institution from January 1, 2012, to April 1, 2020. Patients were excluded if they received EVE+EXE ≤30 days. Data collected included patient and tumor characteristics, prior therapies in the metastatic setting, adverse drug events, and clinical outcomes. The primary objective was to compare progression free survival (PFS) for EVE+EXE between patients with and without prior exposure to CDK4/6 inhibitors. Secondary outcomes included overall survival (OS) and safety. Group comparisons were performed by two-sample t test or Wilcoxon rank sum test for continuous variables and Pearson’s chi-square test or Fisher’s exact test for categorical variables. Log-rank test was used to compare the PFS and OS between groups. Results: One-hundred ninety two patients were included in the study; 79 patients had received prior CDK4/6 inhibitor based therapies, while 113 patients did not. Baseline patient characteristics such as histology, menopause status, de novo metastatic disease, presence of lung or liver metastases, and bone only disease were similar between groups. There was a median of 2 lines of treatment in the metastatic setting prior to receiving EVE+EXE in both groups. Fewer patients received prior chemotherapy in the metastatic setting in those who received prior CDK4/6 inhibitors (32.9% vs 49.6%, p=0.032). In patients who received a prior CDK4/6 inhibitor, median PFS was 3.9 months (95% CI: 3.5 to 4.8) compared to 5.5 months (95% CI: 4.0 to 6.3) in those who did not receive a prior CDK4/6 inhibitor (HR for progression, 1.46; 95% CI: 1.08 to 1.97, p=0.013). Overall survival between groups was not significantly different. A total of 32 (16.7%) patients discontinued EVE+EXE due to intolerance or adverse drug events. Conclusion: Patients who received a prior CDK4/6 inhibitor had a lower median PFS benefit from EVE+EXE compared to those who did not. Citation Format: Hanjie Mo, Catherine E Renna, Halle CF Moore, Jame Abraham, Megan L Kruse, Alberto J Montero, Susan B LeGrand, G Thomas Budd. Efficacy of everolimus and exemestane for the treatment of metastatic hormone receptor-positive breast cancer in patients previously treated with CDK4/6 inhibitors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-18.

Background: In patients (pts) with ER+/HER2− metastatic breast cancer (MBC) following progression on prior endocrine and CDK4/6i therapy, the EMERALD trial demonstrated significantly prolonged progression-free survival (PFS) and a manageable safety profile for elacestrant versus standard of care endocrine therapy (SoC). Benefit was observed in all pts and in pts with ESR1 mutant MBC (ESR1-mut). EMERALD is the only oral SERD monotherapy pivotal trial where all pts were pretreated with CDK4/6 inhibitor (CDK 4/6i). Here, we examine the impact of duration of prior CDK4/6i on PFS. Methods: EMERALD (NCT03778931) is a randomized, open-label, phase 3 trial that enrolled pts with ER+/HER2- MBC who previously had 1-2 lines of endocrine therapy, mandatory CDK4/6i, and ≤1 chemotherapy; prior treatment with fulvestrant was allowed. Patients were randomized 1:1 to elacestrant (400 mg orally daily) or SoC (investigator’s choice of aromatase inhibitor or fulvestrant). If randomized to the control arm, patients who received prior fulvestrant were to receive an aromatase inhibitor, and vice versa. If two CDK4/6i were used in the metastatic setting (n=40), the cumulative duration was calculated. Results: A total of 478 pts were randomized (228 with ESR1-mut) between Feb 2019 – Oct 2020 (n=239, elacestrant; n=239, SoC). Overall survival was not yet mature, as of September 2nd 2022. Updated PFS results show statistically significant results in favor of elacestrant, both in all pts and in pts with ESR1-mut. The duration of prior CDK4/6i in the metastatic setting was positively associated with PFS, the longer the duration of prior CDK4/6i in the metastatic setting (n=465), the longer the PFS on elacestrant versus SoC (Table 1). Updated safety data were consistent with previously reported results. Most of the adverse events (AEs), including nausea, were grade 1 and 2, and only 3.4% and 0.9% of the pts discontinued trial therapy because of an AE on elacestrant and SoC, respectively. A low percentage of pts received an antiemetic; 8.0%, 3.7%, and 10.3%, on elacestrant, fulvestrant, and AI, respectively. No hematological safety signal was observed and none of the patients in either of the two treatment arms had sinus bradycardia. Conclusions: EMERALD is the first phase 3 trial to demonstrate a significant PFS improvement versus SoC in all pts and in the subgroup with ESR1 mutations in pts with ER-positive/HER2-negative MBC with 1-2 prior lines of endocrine treatment ± one line of chemotherapy. Elacestrant demonstrated longer PFS versus SOC that was positively associated with the duration of prior treatment with CDK4/6i, which was more pronounced in pts with ESR1-mut MBC. In this 2nd and 3rd line setting, elacestrant was well tolerated with significantly longer PFS versus SoC, highlighting its potential role as a therapeutic option for pts with ER+/HER2- MBC. Table 1: PFS estimates in the elacestrant and SoC arms based on different cut-off points for the duration of prior CDK4/6i. Citation Format: Aditya Bardia, Francois-Clement Bidard, Patrick Neven, Guillermo Streich, Alberto J. Montero, Frederic Forget, Marie-Ange Mouret-Reynier, Joo Hyuk Sohn, Donatienne Taylor, Kathleen K. Harnden, Hung Khong, Judit Kocsis, Florence Dalenc, Patrick Dillon, Sunil Babu, Simon Waters, Ines Deleu, Jose Angel García-Sáenz, Emilio Bria, Marina Elena Cazzaniga, Philippe Aftimos, Javier Cortés, Giulia Tonini, Tarek Sahmoud, Nassir Habboubi, Krzysztof Grzegorzewski, Virginia Kaklamani. GS3-01 EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: Updated results by duration of prior CDK4/6i in metastatic setting [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-01.

PURPOSE Patients with pretreated estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies. METHODS This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable ESR1 mutations. RESULTS Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). ESR1 mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; P = .002) and patients with ESR1 mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; P = .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively). CONCLUSION Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with ESR1 mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer.

Despite the achieved advancement in pharmacological cancer treatments, the majority of postmenopausal women with hormone receptor-positive metastatic breast cancer (mBC) will experience disease progression. Research into alternative therapies with improved efficacy and reduced side effects has led to the development of a new class of oral anticancer medications, the cyclin-dependent kinase (CDK) 4/6 inhibitors, which include palbociclib, ribociclib, and abemaciclib. Nonetheless, there is growing evidence that the effectiveness of oral anticancer medications is sub-optimal, being influenced by low adherence, sociodemographic factors, and adverse effect profiles. In addition, there is a disconnect between the high price tags of CDK 4/6 inhibitors and their observed effectiveness, raising questions about their value. Currently, the existing knowledge base on the effectiveness and cost-effectiveness of newer oral anticancer medications in understudied populations with possible health disparities is scant. This commentary discusses what is known about palbociclib's clinical effectiveness, safety, and adherence and suggests the need for further studies of real-world effectiveness and cost-effectiveness to help establish the value of newer oncologic drugs, such as palbociclib. DISCLOSURES: No funding supported the writing of this article. The authors have nothing to disclose.

Background: Invasive lobular breast cancer (ILC) is the second most common histological type of invasive breast cancer and accounts for 10-15% of all breast cancer cases. It is commonly strongly hormone receptor positive and, in general, is considered to be less chemo-sensitive compared with invasive ductal carcinoma (IDC). The aim of this study was to compare survival outcomes among ILC patients treated with adjuvant endocrine therapy (ET) compared with chemoendocrine therapy (CET). We also sought to assess utilization of Oncotype Dx testing and distribution of Recurrence Score results among ILC patients treated at our institution. Methods: We conducted an IRB approved retrospective study at Cleveland Clinic Taussig Cancer Institute of patients with non-metastatic ILC. Patient diagnosed with ILC and treated from January 2004 through December 2017 were identified from our tumor registry. Patient characteristics including demographics, pathologic features, hormone replacement therapy (HRT) use, Oncotype Dx recurrence score, treatment details and recurrence data were obtained through medical chart review. Recurrence-free and overall survival (OS) were compared between ET and CET using Kaplan-Meier method and Cox proportional hazard model with consideration of differences on age and prognostic factors. The outcomes between age and pathological stage propensity score matched treatment groups were also compared. Results: A total of 638 patients (Mean age 61.9±11.7, 99.1% estrogen receptor positive, 82.6% progesterone receptor positive) were identified. 406 (63.6%) patients received ET and 232 (36.4%) patients received CET. Compared to ET, patients who received CET were significantly younger (Mean 56.3 vs 65.0 years) and more likely to be premenopausal (40.1% vs 14.6%), however they had significant worse prognostic features including pathological stage (stage III: 38.9% vs 2.1%), grade (≥ II: 69.0% vs 55.9%) and Oncotype Dx score (≥18: 72.4% vs 36.2%). Patients were followed for median (IQR) time of 4 (2.0, 6.4) years for survival outcomes. Although recurrence-free survival (local or distant) was worse in CET (5-year recurrence-free: 81.9% vs 96.5%), age and clinical prognostic features adjusted recurrence risk was similar as ET (Adjusted HR and 95% CI: 0.83, 0.36-1.92) and risk of death was also similar (Adjusted HR and 95% CI: 0.68, 0.31-1.50). Only 222 patients had Oncotype Dx score (35%), with 59% falling in the low risk range, 39% intermediate risk range and 2% high risk range. The Oncotype Dx recurrence score was not associated with recurrence or death. The recurrence-free (5-year: 97.4% vs 90.4%, p=0.37) and OS (At 5-year OS: 94.3% vs 89.4%, p=0.08) were also similar between age and pathological stage matched CET and ET groups. Conclusion: Use of chemoendocrine therapy did not result in improved survival outcomes for patients with ILC compared to those treated with endocrine monotherapy in the adjuvant setting. The majority of ILC patients did not have Oncotype Dx testing sent however when it was ordered, most cases resulted in the low-intermediate risk range, suggesting limited benefit of chemotherapy as reflected by survival outcome results observed. Citation Format: Mathew Thomas, Hong Li, Jame Abraham, Halle CF Moore, G Thomas Budd, Alberto J Montero, Megan L Kruse. Comparison of survival outcomes between treatment with endocrine therapy and chemoendocrine therapy in patients with invasive lobular carcinoma [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 P2-14-13.

Background: IDO1 is a mediator of tumor immune suppression through alteration of tryptophan metabolism. Indoximod (1-methyl-tryptophan) is an IDO1 pathway inhibitor. There is preclinical evidence that indoximod acts synergistically with chemotherapy such as taxanes (Uyttenhove, 2003) in an immune dependent fashion. Previous studies demonstrated the safety and activity of indoximod combined with docetaxel in patients with advanced solid tumors, including breast cancer (Soliman, 2014). A phase 2 clinical trial was designed to study the efficacy of indoximod plus taxanes in metastatic breast cancer (MBC) patients (pts). Method: This is a phase II randomized, 1:1 placebo controlled clinical trial, that enrolled MBC pts in multiple centers in the US and Poland. Eligibility criteria included ER+ or ER- HER2- MBC, ability to receive taxane therapy, PS 0-1, normal organ function and absence of autoimmune disease. Pts were randomized to taxane (either weekly paclitaxel 80mg/m2 3 on 1 off or q3wk docetaxel at 75mg/m2 per treating physician’s discretion) + placebo (TP) or taxane + indoximod 1200mg PO BID (TI) as first line treatment for MBC. Primary endpoint was PFS. The sample size of 154 patients was designed to detect a HR of .64 with one sided α=.1 and β=.2 after 95 events. Archival tumor tissue was stained with IHC for IDO1 expression when available. Aperio digital pathology positive pixel algorithm was used for scoring, with manual verification. Median value was used as cut-off for IDO positivity. Results: 164 pts were randomized and treated (85 TI, 79 TP). Demographics and tumor features are shown in table 1. Treatment discontinuation was due to disease progression (60%), adverse events (10%), other (30%). Objective response rate was 40% in TI and 37% in TP arm (p=.74). The median PFS was 6.0 (95% CI, 4.5, 8.1) months in the TI arm and 8.4 (95% CI, 5.6, 9.8) in the TP arm, HR of 1.14 (0.81, 1.60). The median OS was 21.6 months (CI 95%, 16, 39.1) in the TI arm and 21.2 (CI 95%, 19.1, 32.1) in the TP arm. The median follow up was 17.4 (range 0.1, 39.4) months. Grade ≥3 treatment emergent adverse events were observed in 60% of patients in both arms with neutropenia, fatigue, anemia, diarrhea being most common but not significantly different between arms. An exploratory analysis of IDO staining with outcomes in 42 samples (22 in TI and 20 TP) suggested a difference in median PFS in pts with high IDO expression assigned to TI vs. TP (10.3 vs 4 months, p=.047). No other prognostic or predictive associations were observed based on IDO status in the analysis. Conclusions: The combination of indoximod with a taxane in 1st line HER2- MBC was safe and did not result in added toxicity. In an unselected population, no improvement in clinical outcomes was observed for the combination over taxane alone. However, higher tumor IDO expression may select for MBC pts who benefit more from indoximod and should be investigated as a predictive biomarker in future studies. Demographics and tumor featuresIndoximodPlaceboOverallParameterStatistic(N=85)(N=79)(N=164)Age (years)n8579164median (min, max)58 (29,76)57 (29,85)58 (29,85)GenderMalen (%)1 (1.2)2 (2.5)3 (1.8)Femalen (%)84 (98.8)77 (97.5)161 (98.2)RaceWhiten (%)71 (83.5)66 (83.5)137 (83.5)African Americann (%)12 (14.1)10 (12.7)22 (13.4)Asiann (%)1 (1.2)01 (0.6)Othern (%)1 (1.2)3 (3.8)4 (2.4)ECOG status0n (%)41 (48.8)43 (54.4)84 (51.5)1n (%)44 (52.2)36 (44.3)80 (46.6)Hormone Receptor StatusNegativen (%)23 (27.1)23 (29.1)46 (28.0)Positiven (%)62 (72.9)56 (70.9)118 (72.0)Choice of TaxaneDocetaxeln (%)62 (72.9)59 (74.7)121 (73.8)Paclitaxeln (%)23 (27.1)20 (25.3)43 (26.2) Citation Format: Veronica Mariotti, Shou-Ching Tang, Patrick Dillon, Alberto Montero, Andrew Poklepovic, Susan Melin, Ibrahim Nuhad, Petros Nikolinakos, Eugene Kennedy, Hyo Han, Roohi Ismail-Khan, Daniel Bruetman, Oana Danciu, Paul Gilman, Boguslawa Karaszewska, Krzysztof Lesniewski-Kmak, Timothy Panella, Dhimant Patel, Malgorzata Suszko-Kazarnowicz, Fabio Volterra, Hatem Soliman. Results of a phase II double-blinded, randomized, placebo-controlled clinical trial of Indoximod, an Indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, in combination with Taxane chemotherapy in metastatic breast cancer (MBC) [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 PD1-04.

The Institute of Medicine defines quality in healthcare as the degree to which health services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge. This concept is highly relevant for cancer care that involves patients with complex diseases in the setting of rapidly evolving treatment landscape that requires provision of appropriate services in a patient-centric and technically competent manner. This chapter uses the Donabedian model to review the structural, process, and outcome-based quality domains that lay the foundation for a robust system to measure, monitor, and improve quality of care at cancer centers. The infrastructure and personnel, systems, and culture needed for ensuring provision of high-quality cancer care are reviewed.

Purpose: Approximately 20% of all breast cancers (BC) are HER2 amplified. In the APT trial, weekly paclitaxel/ trastuzumab in node negative HER2+ BC with tumors Methods: In the National Cancer Database (2004-2017), patients with a primary diagnosis of pT1N0M0 HER2+ BC, were separated into two groups: (i) HER2 monotherapy, i.e. trastuzumab, and (ii) chemo-HER2 therapy. A 3:1 propensity match was performed to balance patient selection bias between the two different cohorts. Long-term overall survival (OS) was compared between both groups. Results: A total of 23, 281 patients met the criteria. 22,268 (96.7%) received chemo-HER2 therapy and 1,013 (4.4%) received HER2 monotherapy. Propensity match identified 1,995 patients who received chemo-HER2 therapy, and 666 who received HER2 monotherapy. After match, adjuvant chemo-HER2 therapy was associated with a modest survival advantage over HER2 monotherapy (5-year OS 94.1% vs. 90.6%, P=0.041). Conclusions: Even though there is a modest OS advantage favoring adjuvant chemo-HER2 therapy in pT1N0 HER2+ BC, HER2 monotherapy was associated with 5-year OS >90%. Therefore, in select patients who have contraindications for cytotoxic chemotherapy, or decline adjuvant chemotherapy, adjuvant trastuzumab monotherapy appears to be a reasonable alternative.

Background: Routine sentinel lymph node biopsy (SLNB) has been recommended against by Choosing Wisely© Foundation due to its low value in clinical node negative, hormone receptor positive breast cancer patients age≥70 years old. We used the National Cancer Database (NCDB) to examine the effect of SLNB omission and outcomes in this population. We hypothesized that SLNB would be beneficial in this population.Methods: The National Cancer Database was queried for women diagnosed with primary unilateral invasive clinical stage T1N0M0 hormone receptor positive, HER-2 negative breast cancer from 2012-2017. Patients age ≥ 70 years old with Charlson Score ≥1 who underwent partial mastectomy and received hormonal therapy were included in the study cohort. Patients received neoadjuvant therapy or underwent upfront axillary lymph node dissection (ALND) were excluded. A 1:3 propensity match with replacement was performed to compare SLNB omission vs. SLNB group controlling age, race, comorbidities, insurance and facility. Overall survival was analyzed using stratified multivariable Cox proportional hazard regression analysis.Results: Of 14,150 patients, 1,928 (13.6%) omitted SLNB and 12,222 (86.4%) underwent SLNB, including 1,545/12,222 (12.6%) who proceeded to ALND. Central portion tumor location (OR=1.77, P=0.001), clinical T1c (OR= 2.49, P Citation Format: Lifen Cao, Megan E Miller, Luke D Rothermel, Alberto J Montero, Christopher W Towe, Robert Shenk. Less is not necessarily more: A propensity matched national analysis on effect and outcome of sentinel lymph node biopsy omission [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 PD7-08.

Background Neoadjuvant chemotherapy (NCT) is considered more effective in downstaging hormone receptor-positive (HR+) breast cancer than neoadjuvant endocrine therapy (NET), particularly in node-positive disease. This study compared breast and axillary response and survival after NCT and NET in HR+ breast cancer. Methods Based on American College of Surgeons Oncology Group (ACOSOG) Z1031 criteria, women age 50 years or older with cT2-4 HR+ breast cancer who underwent NET or NCT and surgery were identified in the National Cancer Database 2010–2016. Chi-square and logistic regression analysis determined differences between the NCT and NET groups and therapy response, including downstaging and pathologic complete response (pCR, ypT0/is and ypN0). Results Of 19,829 patients, 14,025 (70.7%) received NCT and 5804 (29.3%) received NET. The NET patients were older (mean age, 68.9 vs. 60.3; P < 0.001) and had greater comorbidity (1+ Charlson–Deyo score, 21% vs. 16%; P < 0.001). Therapy achieved T downstaging (any) for 58% of the patients with NCT versus 40.5% of the patients with NET, and in-breast pCR was achieved for 9.3% of the NCT versus 1.3% of the NET patients (P < 0.001). Approximately half of the mastectomy procedures could have been potentially avoided for the patients with in-breast pCR (53.6% of the NCT and 43.8% of the NET patients). For the cN+ patients, N downstaging (any) was 29% for the NCT patients versus 18.3% for the NET patients (P < 0.001), and nodal pCR was achieved for 20.3% of the NCT versus 13.5% of the NET patients (P < 0.001). Among those with nodal pCR, axillary lymph node dissection (ALND) still was performed for 56% of the patients after NCT and 45% of the patients after NET. Conclusions Although the response rates after NCT were higher, NET achieved both T and N downstaging and pCR. Neoadjuvant endocrine therapy can be used to de-escalate surgery for patients who cannot tolerate NCT or when chemotherapy may not be effective based on genomic testing. Supplementary Information The online version contains supplementary material available at 10.1245/s10434-021-10459-3.

Background gpNMB is an internalizable transmembrane protein overexpressed in ˜40% of TNBC, and associated with a worse prognosis. Preclinical data implicates gpNMB in tumor invasion and metastasis. GV is a novel ADC designed to deliver monomethyl auristatin E (MMAE) to gpNMB-overexpressing cells. Prior phase 1/2 studies suggested promising activity of GV in gpNMB-overexpressing TNBC. Methods In the METRIC trial (NCT#01997333), patients (pts) with mTNBC were randomized 2:1 to GV (1.88 mg/kg IV q21 days) or capecitabine (2,500 mg/m2 PO daily d1-14 q21 days) until disease progression or intolerance. Key eligibility criteria included: gpNMB over-expression (>25% tumor cells positive by central immunohistochemistry of archival tissue); estrogen and progesterone receptor expression Results From Feb 2014 to Aug 2017, 327 women were randomized at 120 institutions to GV (n=218) or capecitabine (n=109). Pretreatment characteristics were well balanced between arms: median age of 55 years; 77% visceral disease; 2.4 years median duration of disease at study entry; 1 median prior anticancer regimen for metastatic disease. At the cut-off for final data analysis (Nov 30, 2017), 21 pts remained on treatment and 98 pts were alive. For GV vs. capecitabine based on independent central review, median PFS was 2.9 (95% CI: 2.8, 3.5) vs. 2.8 (95% CI: 1.6, 3.2) months (HR=0.95; p=0.76); median OS was 8.9 (95% CI: 7.9, 10.5) vs. 8.7 (95% CI: 6.9, 10.8) months (HR=1.06; p=0.73); ORR was 16% (95% CI: 11.1, 22.4) vs. 15% (95% CI: 8.6, 23.5); and median DOR was 5.6 (95% CI: 3.0, 7.8) vs. 4.2 (95% CI: 3.0, 12.2) months. A post-hoc subgroup analysis suggested the greatest benefit from GV was in potentially taxane-sensitive disease (i.e., not previously rechallenged or >6 months progression-free interval following last taxane). The incidence of grade ≥ 3 treatment-related adverse events (TRAEs) was 58% in the GV arm and 37% in the capecitabine arm. The most common grade ≥ 3 TRAEs were neutropenia (27%), rash (15%), and leukopenia (9%) in the GV arm, and diarrhea (14%) and palmar-plantar erythryodysesthesia (8%) in the capecitabine arm. There was 1 fatal TRAE of neutropenic sepsis in the GV arm and none in the capecitabine arm. Conclusion The METRIC study evaluating GV in mTNBC did not meet the primary efficacy endpoint of improved PFS over capecitabine. While anticancer activity was seen with GV, it was comparable to capecitabine with no therapeutic advantage of GV in terms of ORR, PFS, or OS. The safety profile of GV was consistent with prior experience with no new safety signals identified. Citation Format: Vahdat LT, Forero-Torres A, Schmid P, Blackwell K, Telli ML, Melisko M, Holgado E, Moebus V, Cortes J, Fehrenbacher L, Montero AJ, Ma C, Nanda R, Wright GS, He Y, Bagley RG, Halim A, Turner CD, Yardley DA. METRIC: A randomized international phase 2b study of the antibody-drug conjugate (ADC) glembatumumab vedotin (GV) in gpNMB-overexpressing, metastatic, triple-negative breast cancer (mTNBC) [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 P6-20-01.

Background Radiotherapy is the recommended treatment after breast‐conserving surgery (BCS) for early‐stage breast cancer (BC). However, there is no clear evidence whether radiotherapy after BCS improves the survival of elderly women diagnosed with early‐stage hormone receptor‐positive (HR+) BC. The aim of this study was to investigate the survival benefit associated with radiotherapy plus hormonal therapy vs hormonal therapy alone after BCS for early‐stage HR+ BC patients. Methods Using the Surveillance, Epidemiology, and End Results linked with Medicare data, we identified elderly (65 years and older) women diagnosed with early‐stage HR+ BC (2006‐2011) who received hormonal therapy with or without radiotherapy after BCS. A log‐rank test, Cox proportional hazards models, and propensity score matching were used to estimate the overall survival (OS) benefit associated with radiotherapy after BCS. Results Of the 5688 patients, there were 303 deaths from any cause. One hundred and eighty‐five (61%) of these deaths occurred in the hormonal therapy group, and 118 (39%) deaths occurred in the radiotherapy plus hormonal therapy group. The mean survival time in the radiotherapy plus hormonal therapy group was 5.32 ± 1.86 years compared with 4.92 ± 1.86 years in the hormonal therapy group. Based on the adjusted and propensity score matching analysis, patients in the adjuvant radiotherapy group had a lower risk of death compared with those who did not receive radiotherapy. Radiotherapy plus hormonal therapy decreased the risk of death by 32%. The effect estimates were similar in the adjusted and matched cohorts. Conclusions Radiotherapy plus hormonal therapy resulted in a significant improvement in the OS of elderly women diagnosed with HR+ BC.

Importance Indoleamine 2,3-dioxygenase 1 (IDO1) causes tumor immune suppression. The IDO1 pathway inhibitor indoximod combined with a taxane in patients with ERBB2-negative metastatic breast cancer was tested in a prospective clinical trial. Objective To assess clinical outcomes in patients with ERBB2-negative metastatic breast cancer treated with indoximod plus a taxane. Design, setting, and participants This phase 2 double-blinded randomized 1:1 placebo-controlled clinical trial enrolled patients at multiple international centers from August 26, 2013, to January 25, 2016. Eligibility criteria included ERBB2-negative metastatic breast cancer, ability to receive taxane therapy, good performance status, normal organ function, no previous immunotherapy use, and no autoimmune disease. The study was discontinued in June 2017 because of lack of efficacy. Data analysis was performed from February 2019 to April 2020. Interventions A taxane (paclitaxel [80 mg/m2] weekly 3 weeks on, 1 week off, or docetaxel [75 mg/m2] every 3 weeks) plus placebo or indoximod (1200 mg) orally twice daily as first-line treatment. Main outcomes and measures The primary end point was progression-free survival (PFS); secondary end points were median overall survival, objective response rate, and toxic effects. A sample size of 154 patients would detect a hazard ratio of 0.64 with 1-sided α = .1 and β = .2 after 95 events. Archival tumor tissue was stained with immunohistochemistry for IDO1 expression as an exploratory analysis. Results Of 209 patients enrolled, 169 were randomized and 164 were treated (85 in the indoximod arm; 79 in the placebo arm). The median (range) age was 58 (29-85) years; 166 (98.2%) were female, and 135 (79.9%) were White. The objective response rate was 40% and 37%, respectively (indoximod vs placebo) (P = .74). The median (range) follow-up time was 17.4 (0.1-39.4) months. The median PFS was 6.8 months (95% CI, 4.8-8.9) in the indoximod arm and 9.5 months (95% CI, 7.8-11.2) in the placebo arm (hazard ratio, 1.2; 95% CI, 0.8-1.8). Differences between the experimental and placebo arms in median PFS (6.8 vs 9.5 months) and overall survival (19.5 vs 20.6 months) were not statistically significant. Grade 3 or greater treatment-emergent adverse events occurred in 60% of patients in both arms. Conclusions and relevance This randomized clinical trial found that, among patients with ERBB2-negative metastatic breast cancer, addition of indoximod to a taxane did not improve PFS compared with a taxane alone. Trial registration ClinicalTrials.gov Identifier: NCT01792050.

BACKGROUND: Interleukin-12 (IL-12) is a potent immunoregulatory cytokine that plays a key role in the crosstalk between innate (dendritic, macrophage, and natural killer) and adaptive (T and B) cells promoting anti-tumor immune responses. DNA plasmid-based IL-12 delivered to accessible tumors by intratumoral injection and electroporation (TAVO-EP) has been shown to induce activation of innate and adaptive tumor-infiltrating and peripheral immune cells, regression of treated and distant untreated lesions (abscopal effect), and expression of PD-L1 in patients with melanoma or triple-negative breast cancer (TNBC), without the systemic toxicity that has limited therapeutic use of IL-12 historically. The combination of TAVO-EP and pembrolizumab has demonstrated durable responses in melanoma patients with immunologically “cold” tumors or with prior progression on anti-PD1 therapy. Early clinical data indicate similar potential for eliciting strengthened immunogenic responses in TNBC. KEYNOTE-890 (OMS-I141) is a Phase 2 study in patients with metastatic TNBC to evaluate the safety and efficacy of TAVO-EP + pembrolizumab in the second-line or later (2L+) treatment setting (Cohort 1) or TAVO-EP + pembrolizumab + chemotherapy in the first-line (1L) setting (Cohort 2). Cohort 1 data are presented in a separate abstract. Enrollment in Cohort 2 is ongoing. METHODS: Cohort 2 of this Phase 2, open-label, multicenter study will be assessing the safety and efficacy of TAVO-EP in combination with pembrolizumab and chemotherapy as a first-line treatment for metastatic TNBC. Eligible patients are adults with metastatic TNBC (ER and PR staining Citation Format: Melinda Telli, Bianca Devitt, Katharine Cuff, Shaveta Vinayak, Rita Nanda, Alberto J. Montero, Rina Hui, David A. Canton, Christopher Twitty, Sunny Xie, Donna Bannavong, Bridget O'Keeffe, Sandra Aung, Rohit Joshi. Trial in progress: Phase 2 study of intratumoral plasmid interleukin-12 (tavokinogene telseplasmid; TAVO™) plus electroporation in combination with pembrolizumab with or without chemotherapy in patients with inoperable locally advanced or metastatic triple-negative breast cancer (KEYNOTE-890/OMS-I141) [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 OT2-01-03.

Background: Endocrine therapy(ET) plus CDK4/6 inhibitor (i) is the mainstay for the management of estrogenreceptor-positive (ER+)/HER2- mBC. However, most patients (pts) with ER+ mBCeventually experience disease progression, including development of ESR1mutations (mESR1). Elacestrant, an oral SERD, demonstrated preclinical activity,and clinical activity in a phase 1 trial in ER+ mBC, including responses in ptswith prior fulvestrant, CDK4/6i, and mESR1tumors (Bardia JCO 2021).. Methods: EMERALD(NCT03778931), a multicenter, international, randomized, open-label, controlledphase 3 trial, enrolled postmenopausal pts with ER+/HER2- mBC who had received 1-2prior lines of ET and ≤1 line of chemotherapy in the mBC setting and had prior progressionon a ET plus CDK4/6i. Pts were randomized 1:1 to elacestrant (400 mg orallydaily) or standard of care (SOC; investigator’s choice of fulvestrant or anaromatase inhibitor). Stratification factors included mESR1 status (by central lab), priorfulvestrant exposure, and presence of visceral disease. The study had 2 primary endpoints of progression-free survival (PFS), by blindedindependent review committee, in pts withtumors harboring mESR1 and in all pts (mESR1 or mESR1 notdetected). Secondary endpoints included: overall survival (OS), safety, tolerability,and quality of life. An alpha-value of 0.0475 was used to determine statisticalsignificance (2-sided using the truncated Hochberg procedure).. Results: EMERALD enrolled 477 pts(228 with mESR1) between Feb 2019 - Oct 2020, with 239 pts randomized toreceive elacestrant vs 238 pts to SOC. Demographics and disease characteristicswere well-balanced across treatment arms [median age: 63 yrs vs 63.5 yrs; 2prior lines: 46% vs 40.8%; prior CDK4/6i: 100% in both arms]. The study met bothprimary endpoints. There was a 30% reduction in the risk of progression ordeath in the elacestrant arm in all pts (HR=0.697 [95% CI: 0.552, 0.88]; P=0.0018),and a 45% (HR=0.546 [95% CI: 0.387, 0.768]; P=0.0005) reduction in therisk of progression or death in pts with mESR1.For both endpoints, results in key prespecified subgroups, including visceral metastases,number of prior lines of therapy, pretreatment with fulvestrant, and geographicalregion, were consistent with the overall outcome. The PFS rate at 12 months was 22.32% (95% CI: 15.24%, 29.40%)with elacestrant vs 9.42% (95% CI: 4.02%, 14.81%) with SOC in all pts, and26.76% (95% CI: 16.17%, 37.36%) vs 8.19% (95% CI: 1.26%, 15.12%) in the mESR1 subgroup. The prespecified interim OS analysis plannedat the time of the final PFS analysis (allocated2-sided alpha level of 0.0001) demonstrated a trend in favor of elacestrant inall pts (HR=0.751 [95% CI: 0.542, 1.038]; P=0.0821) and in pts with mESR1(HR=0.592 [95% CI: 0.361, 0.958]; P=0.0325). The final OS analysisis expected next year. Common (>10%) treatment-related adverse events (AEs) withelacestrant vs SOC included: nausea (25.3% vs 8.7%), vomiting (11% vs 2.6%), and fatigue (11% vs 7.9%), mostlygrade 1/2. Treatment-emergent AEs leading to discontinuation of elacestrant orSOC were infrequent in both arms (6.3% and 4.4%). Grade ≥3 treatment-relatedAEs in the elacestrant arm vs SOC were 7.2% vs 3.1%, mainly driven by nausea(2.1% vs 0.9%). There were no treatment-related deaths in either group.. Conclusions:Elacestrant is the first oral SERD to demonstrate a statistically significantand clinically meaningful improvement of PFS vs SOC in a randomized phase 3study in pts with ER+/HER2- mBC in the 2nd/3rd-linesetting, including those whose tumors harbor mESR1. Elacestrant was well tolerated and hasthe potential to become the new standard of care for pts with ER+/HER2- mBC. Citation Format: Aditya Bardia, Patrick Neven, Guillermo Streich, Alberto J. Montero, Frédéric Forget, Marie-Ange Mouret-Reynier, Joo Hyuk Sohn, Peter Vuylsteke, Kathleen K. Harnden, Hung Khong, Judit Kocsis, Florence Dalenc, Virginia Kaklamani, Patrick Dillon, Sunil Babu, Simon Waters, Ines Deleu, José García-Sáenz, Emilio Bria, Marina Cazzaniga, Janice Lu, Philippe Aftimos, Javier Cortes, Shubin Liu, Dirk Laurent, Maureen G. Conlan, Francois-Clement Bidard. Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial [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 GS2-02.

In 1996, Jim Allison demonstrated that blocking the immune regulatory molecule CTLA-4 with anit-CTLA4 antibody led to enhance tumor responses in mice. It would take an additional 15 years for human studies to confirm the potency and clinical efficacy of anti-CTLA4, ultimately leading to US FDA approval of the first checkpoint inhibitor, ipilimumab. Now with a plethora of immune-modulating agents demonstrating single agent safety and benefit across many tumor types, investigation on the optimal combination of immune-based therapies has begun in earnest. While there are many challenges, a central one is how to select which combination for which patient is the best. Here we review the current approaches that a practitioner can use to achieve this therapeutic goal.

Purpose Patients who are diagnosed with stage IV metastatic melanoma have an estimated 5-year relative survival rate of only 17%. Randomized controlled trials of recent US Food and Drug Administration–approved immune checkpoint inhibitors—pembrolizumab (PEM), nivolumab (NIVO), and ipilumumab (IPI)—demonstrate improved patient outcomes, but the optimal treatment sequence in patients with BRAF wild-type metastatic melanoma remains unclear. To inform policy makers about the value of these treatments, we developed a Markov model to compare the cost-effectiveness of different strategies for sequencing novel agents for the treatment of advanced melanoma. Materials and Methods We developed Markov models by using a US-payer perspective and lifetime horizon to estimate costs (2016 US$) and quality-adjusted life years (QALYs) for treatment sequences with first-line NIVO, IPI, NIVO + IPI, PEM every 2 weeks, and PEM every 3 weeks. Health states were defined for initial treatment, first and second progression, and death. Rates for drug discontinuation, frequency of adverse events, disease progression, and death obtained from randomized phase III trials were used to determine the likelihood of transition between states. Deterministic and probabilistic sensitivity analyses were conducted to evaluate model uncertainty. Results PEM every 3 weeks followed by second-line IPI was both more effective and less costly than dacarbazine followed by IPI then NIVO, or IPI followed by NIVO. Compared with the first-line dacarbazine treatment strategy, NIVO followed by IPI produced an incremental cost effectiveness ratio of $90,871/QALY, and first-line NIVO + IPI followed by carboplatin plus paclitaxel chemotherapy produced an incremental cost effectiveness ratio of $198,867/QALY. Conclusion For patients with treatment-naive BRAF wild-type advanced melanoma, first-line PEM every 3 weeks followed by second-line IPI or first-line NIVO followed by second-line IPI are the most cost-effective, immune-based treatment strategies for metastatic melanoma.