Pretreated Triple-negative Breast Cancer Research Articles

Dose escalation and expansion results from the phase I study of F0024, a trophoblast cell-surface antigen 2 (TROP2) antibody-drug conjugate (ADC), in patients (pts) with advanced solid tumors.

e13131 Background: F0024 is an antibody-drug conjugate (ADC) targeting Trop-2, an intracellular calcium signaling transducer overexpressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. We assessed its safety and efficacy in patients with advanced solid tumors, mainly in triple negative breast cancer (TNBC). Methods: PTs with unresectable solid tumors refractory to/relapsed from standard treatment received F0024 on days 1 and 8 of 21-day treatment cycles. Primary objectives include maximum tolerated dose (MTD) identification, safety, and tolerability and secondary objectives include efficacy, pharmacokinetics, and incidence of anti-drug antibodies against F0024. Pts were eligible regardless of TROP2 level. Results: As of October 8, 2023, 62 pts were treated with≥1 dose of F0024. 21 pts were treated during dose escalation at 2.5 (n = 1), 5.0 (n = 3), 7.5 (n = 3), 10 (n = 4), 12 (n = 8), and 15 (n = 2) mg/kg and 41 pts with TNBC were treated in dose expansion at 10.0 (n = 30) and 12.0 (n = 11) mg/kg. 32 pts (51.6%) discontinued (20 (32.2%) due to disease progression per RECIST v1.1). Treatment emergent adverse events (TEAEs) regardless of causality were reported in 61 of 62 pts (98.4%; 34 pts [54.8%] experienced ≥grade 3, 9 pts [14.5%] had serious adverse events). Treatment related adverse events (TRAEs) were reported in 61 of 62 pts (98.4%; 32 pts [51.6%] experienced ≥grade 3, 4 pts [6.5%] had serious adverse events). The most common grade 3 TRAE were neutropenia (45.2%), leukopenia (33.9%), febrile neutropenia (4.8%), anemia (4.8%), and maculo-papular rash (4.8%). A total of 17 responses have been observed at the dose of 5.0 mg/kg or greater. 34 TNBC pts were dosed at 10 and 19 were dosed at 12 mg/kg with exposure to a median of 11.5 (1.0-26.0) and 4.0 (1.0-21.0) doses. 11 partial responses were achieved in 29 efficacy-evaluable TNBC pts at 10 mg/kg leading to an overall response rate (ORR) of 37.9% (95% CI 20.7% - 57.7%). The disease control rate of 10 mg/kg is 79.3% (95% CI 60.3%-92.0%). 5 escalation pts and 25 expansion pts remain on trial. Updated trial details/results will be presented. Conclusions: In this first-in-human study of F0024, treatment was generally well tolerated and MTD was not yet reached up to 12 mg/kg. F0024 demonstrated encouraging preliminary antitumor activity in heavily pretreated TNBC pts, especially in 10 and 12 mg/kg. Clinical trial information: NCT05174637 .

Enfortumab vedotin (EV) in triple-negative breast cancer (TNBC) and HR+/HER2- breast cancer (BC) cohorts of EV-202.

1005 Background: EV, a Nectin-4–directed antibody–drug conjugate, is approved for use in urothelial cancer. Nectin-4 is expressed in several solid tumors, including BC. EV monotherapy was evaluated in TNBC and HR+/HER2- BC in EV-202 (NCT04225117). Methods: In this open-label, multicohort, phase 2 trial, eligible adults had locally advanced or metastatic (la/m) solid tumors, measurable disease, and ECOG PS 0–1. In BC cohorts, patients (pts) had prior taxanes or anthracyclines, ≥1 standard-of-care cytotoxic regimen and ≤2 lines (L) of cytotoxic therapy for la/mBC, and prior PD-1/L1 inhibitor (TNBC) or endocrine treatment (tx) with a CDK4/6 inhibitor (HR+/HER2- BC). Nectin-4 expression was not required but was assessed retrospectively. Pts received EV 1.25 mg/kg intravenously days 1, 8, and 15 of each 28-d cycle until discontinuation criteria (eg, disease progression, unacceptable toxicity) were met. Primary endpoint was confirmed objective response rate (ORR); ≥10 (TNBC) or ≥12 (HR+/HER2- BC) responders out of 40 evaluable pts were needed to claim promising antitumor activity. Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety/tolerability. Antitumor activity was investigator-assessed per RECIST v1.1. Results: In the TNBC cohort, 42 female pts received EV as of Mar 3, 2023 (median follow-up, 11.8 mo). Median age was 53 y, 64% had ≥2L systemic tx for metastatic BC, and 33% had prior sacituzumab govitecan. ORR was 19.0%. Grade ≥3 tx-related adverse events (TRAEs) in >1 pt were decreased neutrophil count (n=3, 7%), decreased white blood cell count (n=2, 5%), and increased aspartate aminotransferase (n=2, 5%). Selected TRAEs of special interest were skin reactions (n=25, 60%), peripheral neuropathy (n=11, 26%), and hyperglycemia (n=2, 5%). In the HR+/HER2- BC cohort (median age, 57.0 y), 45 female pts received EV as of Dec 3, 2022 (median follow-up, 11.2 mo). Most (73%) had ≥3L systemic tx for metastatic BC. ORR was 15.6%. Grade ≥3 TRAEs in >1 pt were maculopapular rash (n=7, 16%), pruritus and increased aspartate aminotransferase (both n=3, 7%), and abdominal pain and erythema (both n=2, 4%). Selected TRAEs of special interest were skin reactions (n=28, 62%), peripheral neuropathy (n=12, 27%), and hyperglycemia (n=5, 11%). Additional efficacy data for both cohorts are in the table. Conclusions: EV showed antitumor activity in heavily pretreated TNBC. Safety in both cohorts was manageable and consistent with previous reports. Clinical trial information: NCT04225117 . [Table: see text]

Predictive biomarkers of response and survival following immunotherapy with a PD-L1 inhibitor benmelstobart (TQB2450) and antiangiogenic therapy with a VEGFR inhibitor anlotinib for pretreated advanced triple negative breast cancer

In our phase Ib trial (ClinialTrials.gov Identifier: NCT03855358), benmelstobart (TQB2450), a novel humanized IgG1 antibody against PD-L1, plus antiangiogenic multikinase inhibitor, anlotinib, demonstrated promising antitumor activities in pretreated triple negative breast cancer (TNBC) patients. We conducted explorative analyses of genomic biomarkers to explore the associations with treatment response and survival outcomes. Targeted next generation sequencing (NGS) was undertaken toward circulating tumor DNA (ctDNA) collected from peripheral blood samples prior to the start of treatment and after disease progression. A total of 31 patients received targeted NGS and functional driver mutations in 29 patients were analyzed. The most frequent mutations were TP53 (72%), MLL3 (28%), and PIK3CA (17%). At a blood-based tumor mutational burden (bTMB) cutoff of 6.7 mutations per megabase, patients with low bTMB showed better response to anlotinib plus TQB2450 (50% vs. 7%, P = 0.015) and gained greater PFS benefits (7.3 vs. 4.1 months, P = 0.012) than those with high bTMB. At a maximum somatic allele frequency (MSAF) cutoff of 10%, a low MSAF indicated a better objective response (43% vs. 20%) as well as a significantly longer median PFS (7.9 vs. 2.7 months, P < 0.001). Patients with both low MSAF and low bTMB showed a notably better objective response to anlotinib plus TQB2450 (70% vs. 11%, P < 0.001) and a significantly longer median PFS (11.0 vs. 2.9 months, P < 0.001) than patients with other scenarios. Our findings support future studes and validation of MSAF and the combined bTMB-MSAF classification as predictive biomarkers of immune checkpoint inhibitor-based regimens in advanced TNBC patients.

HER2-Low Breast Cancer: a New Subtype?

Breast cancer (BC) guidelines subdivide the disease into three main groups, namely hormone receptor (HR)-positive HER2-negative, HER2-positive, and triple-negative BC (TNBC). The natural history of the HER2-positive subtype has changed since the introduction of HER-targeted therapies, which demonstrated benefit only in case of HER2 overexpression (IHC, score 3+) or gene amplification. Such observation may depend on direct drug inhibition of HER2 downstream signaling, which is needed for survival and proliferation in HER2-addicted BC. Clinically focused categories cannot comprehensively describe biology, as almost half of the currently defined HER2-negative BCs show some degree of IHC expression and have been recently renamed as HER2-low. Why? As technological breakthroughs enable the synthesis of antibody-drug conjugates (ADCs), target antigens may be viewed not only as a biological switch to be turned on-off by targeted drugs but also as an anchor for ADC docking and tethering. As trastuzumab deruxtecan (T-DXd) has already proven in the clinical trial DESTINY-Breast04, even fewer HER2 available receptors on cancer cells may be sufficient for a clinical benefit. So, for HR-negative HER2-low subtype (~40% of TNBCs), though only 58 patients had been enrolled in DESTINY-Breast04, the observed benefit, together with the dismal prognosis of TNBC, warrants the use of T-DXd. Notably, another topoisomerase-based ADC, sacituzumab govitecan, has already been granted approval for pretreated TNBC (ASCENT). As no head-to-head comparison has been performed, the choice relies on regulatory approvals at the time of patient assessment, critical appraisal of available evidence, and careful evaluation of possible cross-resistance with sequential use of ADCs. As for HR-positive HER2-low disease (~60% of HR-positive tumors), DESTINY-Breast04 provides solid evidence for T-DXd prioritization in either second or third treatment lines. Although the remarkable activity observed in this setting favorably compares with outcomes observed in treatment-naive patients, the ongoing DESTINY-Breast06 will clarify the role of T-DXd in this population.

Efficacy of sacituzumab govitecan based regimen in triple-negative breast cancer: A systematic review.

e13068 Background: Sacituzumab govitecan (SG) is an drug-antibody conjugate composed of anti-trophoblast cell-surface antigen 2 (Trop-2) IgG1 Kappa antibody with SN-38 through a hydrolysable linker. SG has a promising efficacy safety profile in triple negative breast cancer (TNBC) and was given regular approval for nonresectable locally advanced or metastatic disease with 2 or more previous line of therapies. This review aims to explore the efficacy and safety of SG-regimens for the treatment of TNBC. Methods: We conducted a literature search using three databases (PubMed, Embase, and ClinicalTrials.gov). Our search strategy included MeSH and keywords for breast cancer and SG including trade and generic names from the date of inception to January 15, 2022. Initial databases yielded 275 articles. After exclusion, two clinical trials on the use of SG in pretreated TNBC were included. Results: Among a total of 963 enrolled patients, 379 patients were evaluated. Majority of the patients received SG dose of 10 mg/kg. Bardia et al. studied the efficacy of SG in TNBC pts (n = 235) in phase III (ASCENT) trial achieved an overall response rate (ORR) of 31%. The median overall survival (OS) was 11.8 months (95% CI 10.5-13.8) and a median progression-free survival (PFS) was 4.8 months (95% CI, 4.1-5.8).Similarly, in another study Bardia et al. studied SG in TNBC pts (n = 144) in phase I/II (basket) trial and observed ORR of 33.3%. The median overall survival (OS) was 13 months (95% CI, 11.2 to 14) and a median progression-free survival (PFS) was 5.6 months (95% CI, 4.8 to 6.6). (Table) Diarrhea and Nausea was the most common adverse effect reported by the patient whereas neutropenia was the most common grade 3 adverse effect. Conclusions: SC showed promising outcomes in terms of ORR for the treatment of TNBC. [Table: see text] [Table: see text]

Abstract P3-09-13: Identification of a tumor biomarker in advanced triple-negative breast cancer that predicts response to bintrafusp alfa (M7824), a bifunctional fusion protein targeting transforming growth factor-β and programmed death ligand 1

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Identification of biomarkers that are predictive of response to investigational therapies will help identify patients that are more likely to clinically benefit from treatment. Bintrafusp alfa (M7824) is an innovative first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. In this expansion cohort of a global, phase 1, open-label trial (NCT02517398), an extensive tumor biomarker analysis was conducted to identify potential markers correlating with efficacy in patients with advanced TNBC treated with bintrafusp alfa. Methods: Patients received infusions of bintrafusp alfa 1200 mg every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal. Tumor archival material was collected from each patient for biomarker analysis. All biomarker analyses were exploratory. PD-L1 expression and immune phenotype were determined by immunohistochemistry. Tumor samples were also processed for RNA sequencing (RNAseq) and resulting data were analyzed to identify potential associations between gene expression and efficacy of bintrafusp alfa treatment. Results: As of August 24, 2018, 33 patients with heavily pretreated TNBC were treated with bintrafusp alfa (54.5% of patients received ≥4 prior regimens). The objective response rate was 9.1% (n=3) and the disease control rate was 15.2% in a total of 5 patients. PD-L1 expression levels in tumor cells and in the tumor microenvironment were generally low in this cohort with the majority of patients having 0% PD-L1+ tumor cells and/or ≤10% PD-L1+ immune cells in their tumor microenvironment. Moreover, several patients had an immune desert phenotype. PD-L1 expression was not associated with response to treatment. Importantly, exploratory analysis of RNAseq data (n=26 passing quality control) identified differential expression of the high mobility group AT-hook 2 (HMGA2) gene with 32.0-fold higher expression (as computed by DESeq2; q=2.23e−13) in patients who experienced disease control (response or stable disease) compared to those who had progressive disease. HMGA2 is a transcriptional regulator whose expression is upregulated by TGF-β signaling. Furthermore, HMGA2 is known to be an important factor in mediating TGF-β-induced epithelial-mesenchymal transition. In The Cancer Genome Atlas dataset, approximately 12% of subjects annotated as TNBC have high expression of HMGA2. Clinical efficacy and safety data for this expansion cohort are presented in a separate abstract. Conclusions: We identified high expression of HMGA2 as a potential predictive biomarker of response in TNBC patients treated with bintrafusp alfa. HMGA2 assay development is on-going to confirm this finding in a future clinical trial. Citation Format: George Locke, Yue Zhang, Laureen S Ojalvo, Christoph Helwig, Alex Rolfe, Olaf Christensen, Isabelle Dussault. Identification of a tumor biomarker in advanced triple-negative breast cancer that predicts response to bintrafusp alfa (M7824), a bifunctional fusion protein targeting transforming growth factor-β and programmed death ligand 1 [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 P3-09-13.

Abstract P3-09-06: Bintrafusp alfa (M7824), a bifunctional fusion protein targeting transforming growth factor-β and programmed death ligand 1, in advanced triple-negative breast cancer: Preliminary results from a phase 1 cohort

Abstract Background: Approximately 10%-20% of breast cancers (BCs) are classified as triple-negative breast cancer (TNBC). TNBC lacks targeted treatment options and has a poor prognosis. Bintrafusp alfa (M7824) is an innovative first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. We report interim results in patients with advanced TNBC treated with bintrafusp alfa in an expansion cohort of an ongoing, open-label, phase 1 trial (NCT02517398). Methods: Eligible patients had confirmed TNBC (ER: IHC &amp;lt;1%; PR: IHC &amp;lt;1%; HER2: FISH non-amplified, IHC 0/1+, or IHC 2+ and FISH non-amplified) that progressed during or after first-line chemotherapy with an ECOG performance status of ≤1 and measurable disease by RECIST 1.1. Prior treatment with immune checkpoint inhibitors was not permitted. Patients received bintrafusp alfa 1200 mg every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal. The primary endpoint was confirmed best overall response (BOR) as assessed by independent review committee (IRC) according to RECIST 1.1. Key secondary endpoints included investigator-assessed BOR and safety. Exploratory endpoints included an extensive integrated biomarker evaluation of patient samples. These data are presented in a separate, submitted abstract. Results: As of August 24, 2018, 33 patients with heavily pretreated TNBC (54.5% of patients had ≥4 prior regimens) were enrolled in this study of bintrafusp alfa. Patients received a median of 3 doses of bintrafusp alfa (range, 1-24). Confirmed responses as assessed by IRC and investigator occurred in 3 patients (1 complete response and 2 partial responses as assessed by IRC; ORR, 9.1% [95% CI, 1.9%-24.3%]); disease control was achieved in a total of 5 patients (15.2% [95% CI, 5.1%-31.9%]) by both IRC and investigator read. The median progression-free survival per IRC was 1.3 months (95% CI, 1.2-1.4 months), and the median overall survival was 7.8 months (95% CI, 2.1-12.8 months). Importantly, a biomarker related to TGF-β biology was identified via RNAseq analysis of tumor samples with 32.0-fold higher expression in patients who experienced disease control (response or stable disease) compared with those who had progressive disease (biomarker results for this expansion cohort are presented in a separate abstract). PD-L1 expression was not associated with response to treatment. In the entire cohort, 6 patients (18.2%) experienced ≥1 grade 3 treatment-related adverse event (TRAE), including anemia (n=3), asthenia, decreased appetite, generalized rash, hypophysitis, and increased transaminases (all n=1). No grade 4 TRAEs were reported. Three patients discontinued treatment due to TRAEs, including 1 death that was assessed by the investigator as related to treatment. Dyspnea, hemolysis, and thrombocytopenia were reported as grade 5 TRAEs in this patient, who had extensive disease at trial entry and was noted to have multiple pulmonary emboli, progressive disease, and expanding pleural effusion after 3 doses. No autoantibodies mediating hemolysis or thrombocytopenia were identified on workup. Conclusions: In summary, bintrafusp alfa was well tolerated, with a safety profile consistent with expectations in this heavily pretreated, advanced TNBC cohort. We identified high expression of a potential predictive biomarker of response in patients with advanced TNBC treated with bintrafusp alfa. Detailed biomarker data are presented in the separate abstract and warrant further investigation of bintrafusp alfa in TNBC. Citation Format: Alexander Spira, Ahmad Awada, Nicolas Isambert, David Lorente Estellés, John Nemunaitis, Nicolas Penel, Laureen S Ojalvo, Christoph Helwig, Christian Borel. Bintrafusp alfa (M7824), a bifunctional fusion protein targeting transforming growth factor-β and programmed death ligand 1, in advanced triple-negative breast cancer: Preliminary results from a phase 1 cohort [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 P3-09-06.

Abstract P2-09-11: Intratumoral tavokinogene telseplasmid and electroporation in pre-treated inoperable locally advanced or recurrent triple-negative breast cancer

Abstract Introduction: Triple negative breast cancer (TNBC) accounts for approximately 15% of breast cancer diagnoses and is associated with a higher risk of recurrence and more aggressive course in the metastatic setting. Emerging data suggest that some patients with TNBC benefit from immune-based therapies targeting the anti-programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) axis, but success has been limited in poorly immunogenic tumors. Thus, combination therapies that drive an influx of CD8+ tumor infiltrating lymphocytes (TILs) and/or upregulate PD-L1 expression are required to increase response rates to these therapeutics. Intratumoral injection of plasmid IL-12 (tavokinogene telseplasmid; tavo) followed by electroporation (IT-tavo-EP) is a gene therapy approach that drives local expression of the proinflammatory cytokine, interleukin-12 (IL-12). Local expression of IL-12 is hypothesized to result in increased TILs and enhanced expression of proinflammatory cytokines, resulting in conversion of poorly-immunogenic/low TIL TNBC tumors into highly inflamed immunologically active lesions while demonstrating a high safety profile. Methods: OMS-I140 is a phase I, non-randomized, open-label study of IT-tavo-EP in patients with inoperable locally advanced, metastatic and/or treatment-refractory TNBC (NCT02531425). Eligible patients have pre-treated TNBC and at least 2 anatomically distinct cutaneous or subcutaneous lesions accessible for injection and electroporation, with or without other regional or distant metastases. 10 patients are planned for enrollment. IT-tavo-EP is administered on Days 1, 5 and 8 of a single 28-day cycle. Tavo is injected intratumorally (based on tumor volume) at a concentration of 0.5 mg/mL and immediately followed by co-localized electroporation (6 pulses at 1500 V/cm with 1-second intervals). Tumor biopsies are obtained at baseline and post-treatment on day 28 of both treated and untreated lesions to determine if this therapy can promote a pro-inflammatory molecular and histologic signature. Pain scores and adverse events are recorded. Results: To date, nine patients have completed study therapy. Reported treatment-related adverse events include pain associated with electroporation (grade 1) in 8 patients and fatigue (grade 1) in 1 patient. Median pain score (range 0-10) immediately after treatment was 2 (range 0-10) and 5 minutes post-treatment was 0 (range 0-6). In some patients, treatment-related increases in CD8+ TIL density have been observed by intratumoral chromogenic staining. Further immune profiling is being conducted to characterize the tumor microenvironment pre- and post-therapy. A subset of patients with treatment refractory TNBC received anti-PD-1 monotherapy as their immediate next therapy with clinical response observed. Updated data will be presented. Conclusions: Our data suggest that IT-tavo-EP is a safe and tolerable TIL stimulating therapy in TNBC. Further study of IT-tavo-EP in combination with pembrolizumab in pretreated metastatic TNBC is planned. Citation Format: Telli ML, Zablotsky K, Le MH, Canton D, Browning E, Bannavong D, Gargosky S, Wapnir I. Intratumoral tavokinogene telseplasmid and electroporation in pre-treated inoperable locally advanced or recurrent triple-negative breast cancer [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 P2-09-11.

Abstract PD5-07: Comprehensive profiling of poor-risk paired primary and recurrent triple-negative breast cancers reveals immune phenotype shifts

Abstract Background: Prognosis for triple-negative breast cancer (TNBC) patients remains poor, due in part to the lack of effective targeted therapies in the advanced setting. Emerging clinical data indicates reduced efficacy of immune checkpoint inhibitors in heavily pre-treated TNBC, but the underlying mechanisms are poorly understood. To better understand the immune phenotypic evolution of paired TNBCs, we studied the genomic and transcriptomic profiles of tumors from patients undergoing treatment for TNBC. Methods: We analyzed primary and recurrent TNBCs from 55 poor-risk patients, including 44 paired primary-metastatic samples and 11 paired metastatic tumors. FoundationOne® and RNAseq was successful on 89 specimens and 97 specimens, respectively. In addition to somatic alterations, FoundationOne® provided tumor mutational burden (TMB). From RNAseq, we ascertained the TNBC molecular subtypes, and the mRNA expression of immune-related genes. Stromal tumor-infiltrating lymphocytes (stromal TILs), recurrence-free survival, and overall survival were also studied. Results: From FoundationOne® sequencing, a mutational landscape typical of TNBCs was observed across both primary and recurrent disease specimens, with TP53 mutated in 82.0% of specimens, and BRCA1 and BRCA2 mutated in 4.5% and 16.9% of specimens, respectively. Sample profiles revealed minimal shifts in copy number alterations and TMB over time, however, notable TNBC subtype shifts were observed between primary and recurrent tumors. These included an increase in the Lehmann/Pietenpol-defined basal-like 1 phenotype (BL1, 12.8% to 20.9%), an increase in the mesenchymal phenotype (M, 12.8% to 20.9%), and a significant decrease in the immunomodulatory phenotype (IM, 27.1% to 2.3%). Similarly, tumors exhibited a downward shift in gene expression delineating the Burstein-defined basal-like immune-activated phenotype (BLIA, 37.0% to 14.3%). Composite expression of immunomodulatory gene signatures representative of Th1/Th2 responses, IFNg-related inflammation, M1/M2 macrophage activation and suppression, etc., was decreased in the recurrent tumors compared to the primaries (p = 0.01), and histopathology-derived percent stromal TILs were significantly decreased in the recurrent TNBCs (p = 0.02). However, higher stromal TILs (≥30%) were not associated with improved overall survival when measured in primary specimens (p = 0.15), or with the time from relapse to death when measured in recurrent specimens (p = 0.65) in this cohort of immunotherapy-naïve patients. Conclusion: In this retrospective study of paired TNBCs, significant transcriptomic phenotype shifts were observed as patients progressed, while only minor genomic shifts were seen. Selective immune profiling showed significantly reduced TILs and immune-activating gene expression signatures in recurrent TNBCs, which may explain the lack of efficacy of immunotherapeutic agents in heavily pretreated TNBCs. Further studies are ongoing to understand the proteomic landscape shifts in TNBCs over time and to identify novel targeted agents appropriate for recurrent disease. Citation Format: Yuan Y, Yost SE, Chang C-W, Yoh KE, Johnson RM, Schmolze D, Liang J, Hutchinson KE. Comprehensive profiling of poor-risk paired primary and recurrent triple-negative breast cancers reveals immune phenotype shifts [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 PD5-07.

Abstract P6-16-08: The impact of genomic mutation on metastatic breast cancer treatment: A retrospective clinical trial

Abstract Background: Next-Generation Sequencing (NGS) has made genomic mutation-driven cancer medicine feasible. Recognizing the importance of pathway and biomarker-driven personalized therapy for patients with metastatic breast cancer (MBC), we frequently submit tumor tissue for FoundationOne® genomic sequencing. Here we report the results and clinical impact of this test in 44 patients with MBC. Patients and Methods: An institution IRB protocol was established for this retrospective clinical trial performed at the City of Hope Comprehensive Cancer Center from January 2014 to May 2016 with available tumor genomic DNA mutation results through FoundationOne® testing. Patients' clinical characteristics including age, race, treatment history, clinical outcome and genomic mutation profiles were reviewed. Results: We identified 44 patients with MBC submitted for FoundationOne® genomic profiling: 24 triple negative breast cancer (TNBC), 16 estrogen receptor positive (ER+) and 4 human epidermal growth factor receptor 2 positive (HER2+). A total of 23 patients received over 3 lines of chemotherapies prior to FoundationOne® testing. Actionable mutations were identified in 42 of the 44 patients and 23 patients (52%) initiated mutation-driven targeted therapies. Of these 23 patients treated, a total of 17 had accessible responses and 6 patients did not have accessible responses due to short exposure (&amp;lt;2 weeks) and transition to hospice. The remaining 19 patients failed to initiate targeted therapy: 7 transitioned to palliative care/hospice, 5 were placed on other chemotherapy by treating physician, 4 had exhausted all of the targeted therapies recommended, and 3 chose not to start on treatment. Of the 7 responders, 2 received pazopanib and 5 received everolimus containing regimen. Durable response was observed in 3 cases: two patients carried PIK3CA alterations and were treated with everolimus, and the other responder had FGFR1 amplification and was treated with pazopanib. Comparing the genomic mutation profiling with The Cancer Genome Atlas (TCGA) database which contains primary breast cancer, the heavily pretreated TNBC tumors carried higher percentage of PIK3CA mutations (29% vs. 8%, p&amp;lt;0.01). Conclusion: Targeted genomic sequencing through FoundationOne® can identify effective therapy that has not generally been used based on pathology type. NGS should be performed early in patients with good performance status. This approach should be utilized in a setting where genomic mutation driven therapeutic trials are available. Contact information: Yuan Yuan MD PhD, Department of Medical Oncology &amp; Molecular Therapeutics; City of Hope Comprehensive Cancer Center; Duarte, CA 91030; Email: yuyuan@coh.org. Citation Format: Yuan Y, Yost S, Yuan Y-C, Liu Z, Frankel P, Nicola S, Mortimer J. The impact of genomic mutation on metastatic breast cancer treatment: A retrospective clinical trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-16-08.

Abstract CT337: Phase I/Ib study of the PARP inhibitor (PARPi) olaparib (O) with carboplatin (C) in triple negative breast cancer (TNBC) at low genetic risk (NCT00647062)

Abstract Background: PARPi O demonstrates single agent activity in breast and ovarian cancer (Br/OvCa) pts with germline BRCA1/2 mutation (gBRCAm), and with BRCA-like phenotype. Subsets of TNBC are known to respond to therapies targeting DNA repair mechanisms. We hypothesize that O and C combination can be safely tolerated in TNBC pts and may result in benefit. Methods: Pts with recurrent or unresectable TNBC, BRCAPro score &amp;lt;10% or absent gBRCAm, and normal end-organ function were eligible. An open-label 3x3 dose escalation included daily oral O capsule formulation (200mg then 400 mg q12h, d1-7) with C/AUC3-5 on d2 q21d (dose level [DL]1-3). No more than 8 O/C cycles were given, followed by daily O until progression. Pts were evaluated for toxicity every 3 weeks by CTCAEv3.0, and every two cycles for response using RECISTv1.0. Results: 25 women (median age 52 [39-76]) were treated. All pts except one received prior therapy (median 5 [0-12]; prior platinum in 3pts). DLT was thrombocytopenia (DL 2: O 400mg/C AUC4 [1/6pts] and DL3: O 400mg/C AUC 5 [2/3pts]). MTD was reached at DL3 (C/AUC 5 with O 400mg capsule q12h d1-7 q21d). The expansion dose was O 400mg q12h d1-7, C/AUC 4. Gr 3/4 AEs included neutropenia (36%), thrombocytopenia (12%), and anemia (12%). 2 pts required C dose reduction and early discontinuation due to delayed marrow recovery. 13 pts (52%) needed peg-filgrastim, 6 (24%) blood transfusion, and 3 (12%) erythropoietin on at least one cycle. Responses (N=22 evaluable) included 1 CR (46+ mo), 2 PR (3, 5 mo), and 8 with SD ≥4 mo (36%; median 5 [4-7]), for a disease control rate of 50%. The pt who achieved CR had a strong family history of Br/OvCa. Peripheral blood mononuclear cells preC1, d3 or d7, and prior to C2 were collected for PAR incorporation ELISA. Paired tumor biopsies (pre/post-cycle1) were obtained from expansion cohort patients for biomarker proteomics and apoptosis endpoints; results will be presented. Conclusions: RP2D O capsule formulation 400 mg q12h d1-7 with C AUC4 q21d is tolerable in heavily pretreated TNBC pts. Interactive marrow suppression was observed. Citation Format: Victoria L. Chiou, Elise C. Kohn, Christina M. Annunziata, Lori Minasian, JoAnne Zujewski, Minshu Yu, Jay Ji, James Doroshow, Nicolas Gordon, Nicole Houston, Jung-Min Lee. Phase I/Ib study of the PARP inhibitor (PARPi) olaparib (O) with carboplatin (C) in triple negative breast cancer (TNBC) at low genetic risk (NCT00647062). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT337. doi:10.1158/1538-7445.AM2014-CT337

21IN - Is there a Role for New Cytotoxic Agents in TNBC?

ABSTRACT Triple-negative breast cancer (TNBC), which accounts for 15% to 20% of all cases of breast cancer, is characterized by having estrogen-receptor (ER)-negative and progesterone-receptor (PR)-negative and has no overexpression of human epidermal growth factor receptor 2 (HER2). It is an aggressive subtype of breast cancer marked by higher rates of visceral and central nervous system metastases and poor disease-free survival compared with hormone receptor-positive sybtypes. In recent years, an increasing appreciation and identification of somatic mutations and other genetic aberrations that drive human malignancies have led us within reach of personalized cancer medicine. However, after a high expectation with iniparib, a non optimal PARP inhibitor, final data from a randomized phase III trial did not demonstrate this drug to improve outcomes in combination with chemotherapy in patients with advanced TNBC and bevacizumab is the only “targeted” agent which has shown to improve outcomes in combination with chemotherapy in patients with metastatic TNBC. Thus, chemotherapy continues to be the standard of care in these patients. Although taxanes and anthracyclines are still the most important compounds for patients with metastatic TNBC, the majority of them will progress and patients will need new chemotherapeutic drugs. Thus, new cytotoxic drugs are being studied in patients with TNBC in late-line. Among them, new antimicrotubule agents such as eribulin mesylate have shown to increase survival versus the treatment of physicians choice and seems to be active also in this tumor type. Other agents which seem to play a role are vinflunine and KNTR-102, a new polymeric conjugate of irinotecan, both in phase III trials. NKTR-102 has shown an impressive response rate in patients with very heavily pretreated TNBC, including taxanes, anthacyclines and capecitabine. Disclosure J. Cortes: Consultant: Roche, Novartis, Celgene Honoraria: Roche, Celgene, Novartis, Cephalon/Teva