Recurrent Triple-negative Breast Cancer Research Articles

Abstract OT1-03-05: TROPION-Breast02: Phase 3, open-label, randomized study of first-line datopotamab deruxtecan versus chemotherapy in patients with locally recurrent inoperable or metastatic TNBC who are not candidates for anti-PD-(L)1 therapy

Abstract Introduction: Despite recent treatment advances, the prognosis for patients diagnosed with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) remains poor. Single-agent chemotherapy has been the mainstay of treatment for metastatic TNBC for many years, with very limited treatment options for patients who are not candidates for anti-PD-1/PD-L1 therapy; consequently, there remains an urgent unmet need. Trophoblast cell surface protein 2 (TROP2) is a type I transmembrane glycoprotein highly expressed on various solid tumors, including breast. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) composed of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to an exatecan derivative (DXd) – a highly potent topoisomerase I inhibitor payload – via a stable, tumor-selective, tetrapeptide-based cleavable linker. Dato-DXd has previously been evaluated in TROPION-PanTumor01 (NCT03401385) – an ongoing Phase I clinical trial across multiple advanced solid tumors, including heavily-pretreated, metastatic TNBC. As of the July 30, 2021 cut-off date, the objective response rate (ORR) by blinded independent central review (BICR) was 34% (15/44) in all patients with TNBC and 52% (14/27) in those patients treatment-naïve to topoisomerase I inhibitor-based ADC therapies, with measurable disease (per RECIST 1.1) at baseline. Furthermore, a manageable safety profile was reported, with no new safety signals identified; low grade nausea and stomatitis were most frequent, with neutropenia and diarrhea being uncommon. The aim of the phase 3 TROPION-Breast02 trial is to evaluate the efficacy and safety of Dato-DXd versus investigator’s choice of chemotherapy (ICC) in patients with TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy. Methods: TROPION-Breast02 (NCT05374512) is an ongoing Phase 3, open-label, randomized study of Dato-DXd versus ICC in first-line treatment of patients with locally recurrent inoperable or metastatic TNBC. Approximately 600 patients will be randomized 1:1 to receive either Dato-DXd 6 mg/kg IV every three weeks or ICC (paclitaxel, nab-paclitaxel, carboplatin, capecitabine, or eribulin mesylate). Patients ≥18 years with histologically/cytologically confirmed TNBC who have not received prior chemotherapy or targeted systemic therapy for metastatic or locally recurrent inoperable disease are eligible for inclusion. Patients are also required to have an ECOG PS of 0 or 1 and be eligible for treatment with one of the ICC options per investigator assessment. Patients must have ≥1 measurable lesion per RECIST v1.1 not previously irradiated, along with a formalin-fixed and paraffin-embedded tumor sample available. Those with a previously treated neoplastic spinal cord compression or clinically inactive brain metastases can be included. Key exclusion criteria are history of another primary malignancy; persistent toxicity from previous anti-cancer treatments; uncontrolled infections; current/prior interstitial lung disease/pneumonitis or clinically severe pulmonary function compromise; clinically significant corneal disease; and prior treatment with topoisomerase I inhibitors, TROP2-targeted therapy, or the same chemotherapy agent chosen for on-study ICC. The dual primary endpoints are progression free survival (PFS) per RECIST 1.1 by BICR, and OS. Secondary endpoints include ORR, duration of response, PFS by investigator assessment, time to deterioration for patient-reported outcomes, time to first subsequent therapy, time to second subsequent therapy, time to second progression or death, pharmacokinetics and immunogenicity of Dato-DXd, and safety. Recruitment for this study is ongoing as of June 2022. Citation Format: Rebecca Dent, David W. Cescon, Thomas Bachelot, Kyung Hae Jung, Zhi-Ming Shao, Shigehira Saji, Tiffany A. Traina, Petra Vuković, Darlington Mapiye, Micah Maxwell, Peter Schmid, Javier Cortés. TROPION-Breast02: Phase 3, open-label, randomized study of first-line datopotamab deruxtecan versus chemotherapy in patients with locally recurrent inoperable or metastatic TNBC who are not candidates for anti-PD-(L)1 therapy [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 OT1-03-05.

Pembrolizumab (Keytruda)


 CADTH recommends that Keytruda be reimbursed by public drug plans, in combination with chemotherapy, for the treatment of adult patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) who have not received prior chemotherapy for metastatic disease and whose tumours express programmed death-ligand 1 (PD‐L1) (combined positive score [CPS] ≥ 10) as determined by a validated test if certain conditions are met.
 Keytruda should only be covered for adult patients with centrally confirmed TNBC who have PD-L1–positive tumours (CPS ≥ 10), have not received treatment for locally recurrent or metastatic TNBC, and are in relatively good health (i.e., have a good performance status, as determined by a specialist). Patients with unstable central nervous system (CNS) metastases or those who have clinical contraindications to immunotherapy are not eligible for reimbursement.
 Keytruda should only be reimbursed if prescribed in combination with chemotherapy and given by a clinician who is experienced in treating breast cancer and the cost of Keytruda is reduced.

Real-World Survival and Treatment Regimens Across First- to Third-Line Treatment for Advanced Triple-Negative Breast Cancer.

Metastatic triple-negative breast cancer (mTNBC) is an aggressive subtype of breast cancer with poor survival. Currently, the literature lacks comprehensive real-world evidence on locally recurrent and mTNBC patients. To validate the optimal treatment for patients with mTNBC, real-world evidence in combination with data from clinical trials must be evaluated as complementary. The objective of the study is to examine outcomes and treatment patterns of patients with advanced triple-negative breast cancer (TNBC) utilizing real-world data of patients from all oncology sites across Denmark. This is a retrospective, non-interventional, multi-site, population-based observational study conducted across all oncology departments in Denmark. We included all women diagnosed with metastatic or locally recurrent TNBC from January 1, 2017, to December 31, 2019, using the national Danish Breast Cancer Group database. The primary endpoints were overall survival (OS) and progression-free survival (PFS) in the first to third treatment line. The study included 243 women diagnosed with metastatic or recurrent TNBC. The median OS (mOS) was 11.6 months after the first line of treatment, 6.5 months after the second line, and 6.5 months after the third line. De novo mTNBC was associated with shorter OS (mOS: 8.3 vs 14.2 months), and those with a relapse within 18 months of primary diagnosis had shorter OS than those with a relapse after 18 months (mOS: 10.0 vs 18.2). In the first line, taxane was the preferred choice of treatment for patients with de novo mTNBC, whereas capecitabine was preferred for patients with recurrent TNBC. This real-world, nationwide study demonstrated poor OS among patients with metastatic or recurrent TNBC, with a mOS of 11.6 months (95% CI, 9.9-17.3). Patients who presented with de novo mTNBC or who had a relapse of their breast cancer within 18 months of primary diagnosis had shorter OS. The study was registered and approved by the Danish Capital Regions research overview (P-2021-605).

74P The safety, tolerability, and preliminary antitumor activity of sitravatinib plus tislelizumab in patients (pts) with locally recurrent or metastatic triple-negative breast cancer (TNBC): A multi-cohort, phase II trial

This is a multi-cohort, phase II trial to evaluate the safety and preliminary antitumor activity of 70 mg (cohort A) or 100 mg (cohort B) sitravatinib QD plus tislelizumab in pts with locally recurrent or metastatic TNBC, and their combination with nab-paclitaxel in untreated locally recurrent inoperable or metastatic TNBC pts (cohort C). The preliminary result of cohort A has been reported with ORR of 38.1% (Lei Fan. JCO 2022 40:16_suppl). This analysis aims to report the updated analysis in cohort A and the interim results in cohort B.

Tissue Selection for PD-L1 Testing in Triple Negative Breast Cancer (TNBC).

Atezolizumab in combination with nab-paclitaxel has been introduced for the treatment of locally advanced or recurrent triple negative breast cancer (TNBC). Patient selection relies on the use of immunohistochemistry using a specific monoclonal PD-L1 antibody (clone SP142) in a tightly controlled companion diagnostic test (CDx) with a defined interpretative algorithm. Currently there are no standardized recommendations for selecting the optimal tissue to be tested and there is limited data to support decision making, raising the possibility that tissue selection may bias test results. We compared PD-L1 SP142 assessment in a collection of 73 TNBC cases with matched core biopsies and excision samples. There was good correlation between PD-L1-positive core biopsy and subsequent excision, but we found considerable discrepancy between PD-L1 negative core biopsy and matched excision, with a third of cases found negative on core biopsies converting to positive upon examination of the excision tissue. In view of these findings, we developed a workflow for the clinical testing of TNBC for PD-L1 and implemented it in a central referral laboratory. We present audit data from the clinical PD-L1 testing relating to 2 years of activities, indicating that implementation of this workflow results in positivity rates in our population of TNBC similar to those of IMpassion130 clinical trial. We also developed an online atlas with a precise numerical annotation to aid pathologists in the interpretation of PD-L1 scoring in TNBC.

Significance of the effects of chemotherapy on programmed death-ligand 1 expression in triple-negative breast cancer.

Atezolizumab has been approved as an antibody against programmed death-ligand 1 (PD-L1)-positive immune cells in patients with advanced or recurrent triple-negative breast cancer. However, the optimal timing to examine PD-L1 expression remains controversial. We retrospectively researched PD-L1 positivity rates in biopsy, surgical and recurrent specimens from patients with triple-negative breast cancer treated with neoadjuvant chemotherapy. We also examined alterations in PD-L1 and their meaning. In total, 35 triple-negative breast cancer biopsy specimens obtained before neoadjuvant chemotherapy, 20 corresponding specimens obtained after neoadjuvant chemotherapy and 5 corresponding recurrent specimens were obtained. We examined PD-L1 immunohistochemistry on tumor cells and tumor-infiltrating immune cells using SP142 antibody. In comparison with specimens obtained before neoadjuvant chemotherapy, PD-L1 expression randomly changed in immune cells after neoadjuvant chemotherapy, but PD-L1 expression was significantly reduced in tumor cells. Pre-neoadjuvant chemotherapy specimens with low PD-L1 expression (PD-L1 scores of ≤1 for both immune cells and tumor cells) were linked to better disease-free survival (P<0.001) and overall survival (P<0.001) than the other specimens. This is the first study to evaluate PD-L1 expression both before and after chemotherapy in breast cancer and examine its relationship with prognosis. The results suggest that the PD-L1 level may be useful for predicting the prognosis of patients with triple-negative breast cancer who do not have pathological complete responses to neoadjuvant chemotherapy.

The safety, tolerability, and preliminary antitumor activity of sitravatinib plus tislelizumab in patients with locally recurrent or metastatic triple-negative breast cancer.

1070 Background: Anti-PD-1 antibody plus chemotherapy has been demonstrated promising anti-tumor activity in patients with locally recurrent or metastatic triple negative breast cancer (TNBC). However, this regime only limited to TNBC patients with PD-L1 positive. As antiangiogenic agents could enhance the response to immune checkpoint inhibitors, we conducted this phase 2 study to assess the efficacy and safety of novel chemotherapy-free regimen of sitravatinib (targets receptor TKI against TYRO3, AXL, MERTK and VEGF family of receptors) in combination with tislelizumab (anti-PD-1 antibody) in patients with locally recurrent or metastatic TNBC regardless of PD-L1 status. Methods: Patients with locally recurrent or metastatic TNBC were included and divided into two cohorts. Patients received 70 mg (cohort A) or 100 mg (cohort B) sitravatinib QD PO and 200 mg tislelizumab IV Q3W until disease progression or intolerable toxicity. The primary endpoints included overall response rate (ORR) (cohort A and B) and rate of grade ≥3 treatment-related adverse events (AEs) (cohort B). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), 1-year overall survival rate and safety/tolerability. In cohort A, the first statistical analysis would be performed when 12 patients were enrolled; if ≥1 of 12 patients were with confirmed response during the first stage, additional 9 patients would be enrolled to the second stage based on Simon's two-stage design. We would deem cohort A to be statistically superior to a historical control of 8% under the settings if &gt; 3 of 21 patients responded (one-sided a = 0.1 and power of 80%). Patients’ recruitment in cohort B would begin after completing the recruitment in cohort A. Results: Herein we reported the preliminary results in cohort A. Four patients were with confirmed response during the first stage, and additional nine patients were enrolled to the second stage. A total of 21 patients with 0-3 lines of prior chemotherapy were included from April 2021 to September 2021. The median age was 51 (32-66) years and 20 (95%) patients had ECOG PS 0. At data cut off 13 Jan 2022, 19 patients were alive, 11 are still on treatment. The confirmed ORR was 38.1% (95% CI, 18.1%-61.6%) based on current 21 efficacy evaluable patients. DCR was 95.2% (95% CI, 76.2%-99.9%), and median PFS was 7.0 (95% CI, 3.7 - not reached) months. 4/21 (19%) of patients experienced grade 3 treatment-related AEs. Grade 3 AEs reported in ≥5% of patients were aspartate aminotransferase increased (9.5%) and palmar-plantar erythrodysaesthesia syndrome (9.5%). No patients experienced grade 4 AEs. Conclusions: Sitravatinib combined with tislelizumab demonstrated clinically meaningful anti-tumor activity and had a manageable safety profile. Clinical trial information: NCT04734262.

Apatinib plus etoposide as second-or higher-line treatment in recurrent or metastatic triple-negative breast cancer: A single-arm, open label, prospective, phase II clinical trial.

e13069 Background: Due to the lack of targeted therapies, the standard of care for advanced triple-negative breast cancer (TNBC) was still chemotherapy, yet its effectiveness remains unsatisfied. Therefore, an urgent need exists to find a novel treatment option for patients with TNBC. The effect and safety profile of apatinib and etoposide have been demonstrated in several clinical trials for the treatment of late-stage TNBC respectively. In the present study, we aimed to investigate the potential effect of combination therapy of apatinib plus etoposide in recurrent or metastatic TNBC. Methods: Patients with late-stage TNBC who failed at least one line of chemotherapy were recruited in our study. Eligible patients were treated with in a 3-week cycle until disease progression or unacceptable toxicity for up to a maximum of 6 cycles. Apatinib could be declined to 250mg according to patients’ condition. Patients who completed their treatment were followed every 8 weeks and their disease progress was assessed scans according to RECIST 1.1. The primary endpoint was progress-free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Safety was also evaluated. Results: From August 2018 to September 2021 a total of 40 patients were enrolled in this study. Their median age was 56-year old (range, 27-76) and had received a median of 3 (range, 2-6) previous lines chemotherapy. Until January 2022, among all eligible patients, 30 PFS events were observed. The median PFS was 6 months (95% CI, 3.77̃8.23) and the median OS was 24.53 months (95% CI, 10.23-38.83). Meanwhile, 4 patients achieved partial response, 21 patients achieved stable disease, the ORR was 10% and the DCR was 62.5% In addition, the most common adverse events were hypertension (65%), nausea (47.5%), vomiting (42.5%), and hand–foot syndrome (32.5%). The most common grade ≥ 3 adverse events were hypertension (5%) and proteinuria (5%). Conclusions: The results of the study exhibited a promising clinical effect of the combination therapy of apatinib plus etoposide and acceptable toxicity in recurrent or metastatic TNBC as second-or higher-line treatment. And more results will be updated with the progress of this clinical trial. Clinical trial information: ChiCTR1800018497.

Phase 1b/2 study of GX-I7 plus pembrolizumab in patients with refractory or recurrent (R/R) metastatic triple-negative breast cancer (mTNBC): The KEYNOTE-899 Study.

1081 Background: GX-I7 (efineptakin alfa) is a hybrid Fc-fused long-acting recombinant human IL-7 which plays an essential role in the development and homeostasis of T-cells. GX-I7 can potentially enhance the anti-tumor effect of pembrolizumab via induction of T-cell activity. Here, we report results of phase 1b/2 study of GX-I7 plus pembrolizumab in patients with R/R mTNBC. Methods: Eligible patients had R/R mTNBC that failed up to 3rd lines of chemotherapy in the metastatic setting. Phase 1b patients received GX-I7 in 5 dose levels ranging from 360 µg/kg to 1,440 µg/kg every 9 (Q9W) or 12 (Q12W) weeks plus pembrolizumab 200 mg Q3W (n=51). Phase 2 is an expansion cohort where 33 patients were treated with the recommended phase 2 dose (RP2D). The primary objective was to determine the RP2D for phase 1b and to assess the objective response rate (ORR) for phase 2. Results: The study included 84 patients (phase 1b, n=51; phase 2, n=33) and 53.6% (45/84) of patients have received 2nd to 3rd lines of previous therapy. In phase 1b, one dose-limiting toxicity (DLT; grade 3 skin rash) was reported in the 1,440 µg/kg cohort and GX-I7 1,200 µg/kg Q9W was selected as RP2D. The ORRs were 15.7% [95% confidence interval (CI): 7.0 – 28.6] for phase 1b (n=51) and 21.2% [95% CI: 9.0 – 38.9] for phase 2 (n=33). Median PFS was 2.4 months (95% CI: 2.1 – 2.7) at the median follow-up of 10.4 months for all patients combined (n=84). GX-I7 induced up to 3.6-fold (range 1.2 – 8.1) increase in absolute lymphocyte counts (including CD4+ and CD8+ T cell) in all dose levels. The most common treatment-related adverse events (AEs) of any grade were injection site reaction (50.0%), ALT increased (39.3%), pyrexia (38.1%) and rash (35.7%). The additional correlative study data will be presented. Conclusions: GX-I7 in combination with pembrolizumab demonstrated a manageable safety profile with promising anti-tumor activity in patients with R/R metastatic TNBC. Clinical trial information: NCT03752723. [Table: see text]

Leveraging patient engagement to optimize a phase 3 clinical trial design, study participation and recruitment for women diagnosed with triple-negative breast cancer (TNBC).

1073 Background: The importance of Patient Engagement (PE) on clinical trial design is well established. PE in oncology medicines development can serve many purposes including obtaining input on trial design/procedures, identifying recruitment challenges and barriers to participation, and understanding retention strategies. Designing a clinical trial with procedures that have been confirmed as acceptable to participants is also likely to improve patient adherence to treatments. Triple-Negative Breast Cancer (TNBC) is a virulent subtype associated with early onset and increased risk of early recurrence and accounts for 15% to 20% of breast cancers. In addition, a higher risk exists in premenopausal and Black women. Chemotherapy is the mainstay of curative therapy recommended by guidelines. The aim was to obtain insights from patients to inform key aspects of a clinical study design including choice of chemotherapy regimen, study feasibility and recruitment strategies. Methods: Two groups of US women (N = 20) ages 28-54; (race 55% Caucasian, 30% African American, 10% Hispanic, 5% Native American) diagnosed with Stage IIb-IV TNBC and in active or completed treatment were recruited to participate in two in person IRB approved sessions. Trained 3rd party facilitators used qualitative methods to elicit patient feedback. Preliminary research included interviews with key stakeholders, including TNBC advocacy group leaders and a review of online patient communities. Patients reviewed a study design with an investigational agent every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel) or placebo plus chemotherapy. Results: Patient reaction to the choice of taxane chemotherapy in the standard of care arm was neutral to negative. Approximately 50% of the patients identified taxane treatment as a barrier to participation. All patients requested flexibility in treatment choices, clear information about required tests and visits, and more diversity in recruitment materials. Black and Hispanic women impacted by TNBC did not feel they had equal access to clinical trials due to race, rural location, and other factors. Patient insights reinforced the decision to add another standard-of-care option (carboplatin plus gemcitabine) as a treatment arm to the trial design and was confirmed with investigators. Patient feedback was incorporated into the trial along with additional strategies to support recruitment of diverse patients in the clinical study. Conclusions: On November 13, 2020 the FDA approved this regimen in the label for pembrolizumab in combination with chemotherapy, as the 1st line treatment in women with locally recurrent or metastatic TNBC. Both patients and physicians perceived that a flexible chemotherapy backbone was a benefit.

Fatty acid oxidation protects cancer cells from apoptosis by increasing mitochondrial membrane lipids.

Overcoming resistance to chemotherapies remains a major unmet need for cancers, such as triple-negative breast cancer (TNBC). Therefore, mechanistic studies to provide insight for drug development are urgently needed to overcome TNBC therapy resistance. Recently, an important role of fatty acid β-oxidation (FAO) in chemoresistance has been shown. But how FAO might mitigate tumor cell apoptosis by chemotherapy is unclear. Here, we show that elevated FAO activates STAT3 by acetylation via elevated acetyl-coenzyme A (CoA). Acetylated STAT3 upregulates expression of long-chain acyl-CoA synthetase 4 (ACSL4), resulting in increased phospholipid synthesis. Elevating phospholipids in mitochondrial membranes leads to heightened mitochondrial integrity, which in turn overcomes chemotherapy-induced tumor cell apoptosis. Conversely, in both cultured tumor cells and xenograft tumors, enhanced cancer cell apoptosis by inhibiting ASCL4 or specifically targeting acetylated-STAT3 is associated with a reduction in phospholipids within mitochondrial membranes. This study demonstrates a critical mechanism underlying tumor cell chemoresistance.

164O Health-related quality of life (HRQoL) with pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as 1L treatment for advanced triple-negative breast cancer (TNBC): Results from KEYNOTE-355

KEYNOTE-355 (NCT02819518) evaluated pembro + chemo vs pbo + chemo in previously untreated patients (pts) with locally recurrent inoperable or metastatic TNBC. Pembro + chemo improved the PFS and OS in pts with PD-L1 combined positive score (CPS) ≥10 disease. We present results for patient-reported outcome (PRO) measures among pts with PD-L1 CPS ≥10.

Incidence and impact of brain metastasis in patients with hereditary BRCA1 or BRCA2 mutated invasive breast cancer

Patients with hereditary mutations in BRCA1 or BRCA2 (gBRCA1/2) and breast cancer have distinct tumor biology, and encompass a predilection for brain metastasis (BM). We looked into baseline risk of BMs among gBRCA1/2 patients. Patients with gBRCA1/2, stage I-III invasive breast cancer seen between 2000–2017 with parenchymal BMs. Among gBRCA1 with distant breast cancer recurrence, 34 of 76 (44.7%) were diagnosed with brain metastases compared to 7 of 42 (16.7%) patients with gBRCA2. In the comparator group, 65 of 182 (35.7%) noncarrier triple-negative breast cancer (TNBC) and a distant recurrence experienced BM’s. In a competitive risk analysis using death as a competing factor, the cumulative incidence of BMs was similar between gBRCA1 and noncarrier TNBC patients. The time from primary breast cancer diagnosis to detection of BMs was similar between gBRCA1 and noncarrier TNBC patients (2.4 vs 2.2 years). Survival was poor after BMs (7.8 months for gBRCA1 patients vs. 6.2 months for TNBC noncarriers). Brain was a more common site of initial distant recurrence in gBRCA1 patients versus TNBC noncarriers (26.3% vs. 12.1%). Importantly, the presence of BMs, adversely impacted overall survival across groups (HR 1.68 (95% CI 1.12–2.53), hazard ratio for death if a patient had BMs at the time of initial breast cancer recurrence vs. not). In conclusion, breast cancer BMs is common and is similarly frequent among gBRCA1 and noncarrier patients with recurrent TNBC. Our study highlights the importance of improving the prevention and treatment of BMs in patients with TNBC, gBRCA1 carriers, and noncarriers.

Abstract P2-14-04: Updated data from FUTURE-C-PLUS: Combination of famitinib with camrelizumab plus nab-paclitaxel as first-line treatment for advanced, immunomodulatory triple-negative breast cancer, an open-label, single-arm, phase 2 trial

Abstract Background Camrelizumab and nab-paclitaxel demonstrated promising anti-tumour activity in refractory metastatic immunomodulatory triple-negative breast cancer (TNBC) in FUTURE trial. Anti-angiogenic agents have been reported to facilitate immune infiltration. Famitinib is a tyrosine kinase inhibitor targeting VEGFR-2, PDGFR and c-kit. The FUTURE-C-PLUS trial (NCT04129996) which added famitinib to camrelizumab and nab-paclitaxel is a single-arm, phase 2 trial evaluating this novel triplet combinatorial strategy in patients with advanced immunomodulatory TNBC. Study design and the primary endpoint ORR has been reported previously (Zhi-ming Shao, et al. ASCO 2021, Abstract 1007). Here, we reported the updated results of this trial. Method Briefly, this study enrolled women aged 18-70 years, with previously untreated, histologically confirmed, unresectable, locally advanced, recurrent or metastatic immunomodulatory TNBC. Immunomodulatory TNBC was defined as CD8 expression on at least 10% of cells using immunohistochemistry analysis. Eligible patients received the triple therapy. Study design has been reported previously in ASCO 2021. Results Between Oct 2019 and Oct 2020, 48 patients were enrolled and treated. 39 (81.3%, 95% CI 70.2-92.3) patients had a confirmed objective response which has been reported in ASCO 2021. At this updating data cutoff (June 30, 2021), the median progression-free survival was 11.9 months (95% CI, 7.3-16.5) with the median follow-up was 14.0 months. While overall survival data were not mature yet, a promising overall survival rate was observed at 12 months (84•2%, 95% CI 73.4-95.0) and 18 months (73.6%, 95% CI 52.0-95.2). In the 39 responders, median duration of response was also not mature. The disease control rate was 95.8% (46/48). The most common treatment-related grade 3 or 4 adverse events were neutropenia (16 [33.3%]), anemia (5 [10.4%]), febrile neutropenia (5 [10.4%]), and thrombocytopenia (4 [8.3%]). No treatment-related deaths were reported. Conclusions These data, combined with those from our previous reports, provide further evidence for the triplet combination of famitinib, camrelizumab and nab-paclitaxel as an active therapy in advanced Immunomodulatory TNBC. To our knowledge, this is the best objective response rate reached in first-line treatment of advanced TNBC. A randomized controlled FUTURE-Super trial (NCT04395989) is keeping recruiting patients to further validate those findings. Citation Format: Li Chen, Yi-Zhou Jiang, Songyang Wu, Jiong Wu, Genhong Di, Guangyu Liu, Keda Yu, Lei Fan, Junjie Li, Yifeng Hou, Zhen Hu, Canming Chen, Xiaoyan Huang, Ayong Cao, Xin Hu, Shen Zhao, Xiaoyan Ma, Xiaoyu Zhu, Jianjun Zou, Wentao Yang, Zhonghua Wang, Zhi-ming Shao. Updated data from FUTURE-C-PLUS: Combination of famitinib with camrelizumab plus nab-paclitaxel as first-line treatment for advanced, immunomodulatory triple-negative breast cancer, an open-label, single-arm, phase 2 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 P2-14-04.

The Economic Burden of Recurrence in Triple-Negative Breast Cancer Among Working Age Patients in the United States.

Triple-negative breast cancer (TNBC) is associated with a high recurrence risk. However, the magnitude of direct and indirect costs associated with recurrence is lacking in the literature. Adults 18-65years old diagnosed with TNBC were identified from the OptumHealth Reporting and Insights claims database (1999-2017) and stratified by recurrence. For patients with recurrence, theindex date was defined as 30days before recurrence; for patients without recurrence, it was randomly assigned based on the distribution of time between first treatments and index dates of the recurrence cohort. All-cause and breast cancer-related healthcare resource utilization (HRU), direct and indirect costs, and work loss up to 1 year were compared between cohorts using generalized linear models. Kaplan-Meier analyses and Cox proportional hazards models compared the risk of leaving the workforce. Among the 2340 patients analyzed, mean age was 54years and > 75% of patients had stage 0-2 cancer. Among the 1170 patients with recurrence, 236 were categorized as having metastatic recurrence and 934 as having locoregional recurrence. Relative to patients without recurrence, those with recurrence had significantly higher all-cause and breast cancer-related HRU. For instance, adjusted incidence rates (IRs) for all-cause inpatient admissions were 3.67 and 10.19 times higher for patients with locoregional and metastatic recurrence, respectively (p < 0.001). Adjusted all-cause healthcare costs were $8575/month higher for metastatic recurrence and $3609/month higher for locoregional recurrence vs. patients without recurrence (p < 0.001). Adjusted IRs for work loss days were approximately two times higher for locoregional and metastatic recurrence vs. without recurrence (p < 0.001). Patients with locoregional recurrence incurred $335/month more indirect costs vs. patients without recurrence; those with metastatic recurrence incurred $769/month more (p < 0.05). Patients with recurrence had a 63% higher rate of leaving the work force (p = 0.003). The incremental direct and indirect economic burden associated with recurrent TNBC is substantial relative to non-recurrence.

Periostin Exon-21 Antibody Neutralization of Triple-Negative Breast Cancer Cell-Derived Periostin Regulates Tumor-Associated Macrophage Polarization and Angiogenesis.

Simple SummaryDespite remarkable advances in breast cancer treatment, few strategies other than standard cytotoxic chemotherapy are available for patients with triple-negative breast cancer (TNBC) due to the lack of therapeutic target molecules. TNBC is still the most aggressive subtype, with a high risk of recurrence and metastasis within 2 years after initial treatment. Thus, there is an unmet medical need to develop new treatments for metastatic and recurrent TNBC patients. In this study we tested a new antibody, targeting extracellular periostin protein alternative splicing variants, which are induced by conventional chemotherapy or during the process of endothelial mesenchymal transition. This antibody reduced periostin-secreting TNBC in a mouse xenograft model, accompanied by a decrease in the number of M2 tumor-associated macrophages and tumor vessels. Periostin alternative splicing variants might be a specific and safe therapeutic target in patients with TNBC.Periostin (Pn) is involved in multiple processes of cancer progression. Previously, we reported that Pn expression is correlated with mesenchymal tumor markers and poor prognosis in triple-negative breast cancer (TNBC). In the TNBC xenograft model, chemotherapy increased expression of a Pn alternative splicing variant (ASV) with exon 21, and administration of the neutralizing antibody against Pn with exon 21 (Pn-21 Ab) overcame chemoresistance with a reduction in the mesenchymal cancer cell fraction. In the present study, the role of Pn ASV with exon 21 in TNBC progression has been addressed. We first established a stable cell line carrying a fluorescence-based splicing reporter. Pn-positive TNBC has higher expression of genes related to tumor-associated macrophage (TAM) recruitment and ECM-receptor interaction than Pn-negative cells. In a xenograft model, only Pn-positive cells initiated tumor formation, and the Pn-21 Ab suppressed tumor cell growth, accompanied by decreased M2 TAM polarization and the number of tumor vessels. These data suggest that cancer cell-derived Pn ASV educates TAMs and regulates angiogenesis, which in turn establishes a microenvironmental niche that is supportive of TNBC.

Autoimmune hemolytic anemia, rare immune-related adverse event after combination atezolizumab and paclitaxel treatment in recurrent triple-negative breast cancer: A case-report

Autoimmune hemolytic anemia, rare immune-related adverse event after combination atezolizumab and paclitaxel treatment in recurrent triple-negative breast cancer: A case-report

A narrative review of immune checkpoint inhibitors in early stage triple negative breast cancer

: Triple negative breast cancer (TNBC) is an aggressive disease characterized by heterogeneous molecular and immunological characteristics that portends worse overall survival compared to other breast cancer subtypes. Until now, chemotherapy has remained the cornerstone of TNBC treatment despite recent efforts to explore new molecularly targeted therapeutic targets and personalized treatments. Given TNBC has a more immunogenic tumor microenvironment than other breast cancer subtypes, there is hope that immunotherapy will emerge as a new pillar of treatment in TNBC. Based on the IMPASSION130 and KEYNOTE-355 studies, the combination of nab-paclitaxel plus atezolizumab, and chemotherapy plus pembrolizumab, respectively, have been approved by the Food and Drug Administration for locally recurrent, unresectable, or metastatic TNBC in the first line setting. Several studies have now been published demonstrating programmed cell death-1 protein (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors given alongside neoadjuvant taxane and anthracycline-based chemotherapy with or without a platinum agent significantly improves pathologic complete response rate. The choice of chemotherapy given in cooperation with PD-1/PD-L1 checkpoint inhibitor seems to determine the amount benefit derived from immunotherapy. However, longer term follow-up is required to ascertain whether immunotherapy, specifically PD-1/PD-L1 blockade, will improve event-free survival and overall survival. Future studies are underway investigating the role of immunotherapy in the adjuvant setting and in patients with residual disease after neoadjuvant therapy. Other unanswered questions remain including the total duration of immunotherapy, and which patient population would benefit from these expensive and sometimes toxic therapies. This narrative review aims to provide insight on the current landscape of immune checkpoint inhibitors in early TNBC.

Abstract OT-29-01: Tenacity: A phase 2, multicenter, open-label, single-arm study of AL101 monotherapy in patients with notch-activated triple negative breast cancer

Abstract Background: There is an urgent need to identify new therapeutic strategies for triple-negative breast cancer (TNBC), a sub-type associated with poor prognosis. The Notch pathway is activated during mammary gland development and has been implicated as a key driver in breast cancer (Collu, 2007). The frequency of Notch mutations or gene rearrangements was reported at 5 to 16% in TNBC tumors and over-expression of Notch was associated with worse overall survival (Robinson, 2011; Stoeck, 2014; Wang, 2015). AL101 is a potent and selective inhibitor of gamma secretase-mediated Notch signaling. In preclinical models, AL101 exerts its antitumor activity through direct inhibition of cell proliferation and indirectly via inhibition of tumor angiogenesis. In TNBC patient-derived xenograft (PDX) tumor models, the presence of activating Notch mutations/fusions correlated with robust response to AL101 monotherapy (ASCO 2019, Abstr 1064). AL101 has been studied in three Phase 1 studies in more than 200 subjects with various cancers (ASCO 2018, Abstr 2515) and is currently being studied in a Phase 2 study for patients with Adenoid Cystic Carcinoma with Notch activating mutations (ACCURACY- NCT03691207). Preliminary data reported from this trial showed clear signs of clinical activity along with a favorable safety profile (ESMO 2019, Abstr 3568). Trial design: The TENACITY study is an open-label, international, multicenter, single arm Phase 2, Simon two-stage optimal design for targeted therapy study of AL101 monotherapy in subjects with Notch-activated recurrent or metastatic TNBC who have received ≤ 3 lines of prior therapy. Patients with stable, asymptomatic CNS metastases are eligible. Notch activation will be determined by Next Generation Sequencing (NGS) of tumor DNA/RNA to detect somatic mutations and gene rearrangements. Target enrollment is 67 subjects. The design will include a lead-in cohort of 6 subjects to ascertain safety of AL101, 6 mg weekly (QW). After the 6th subject completes 4 weeks of therapy, safety will be assessed and subsequent dosage of AL101 will be determined (continue at 6 mg QW versus reduction to 4 mg QW). The primary endpoint is overall response rate (ORR), based on RECIST v1.1 as assessed by the treating investigator. The study design has 80% power with type I error level of 5% to detect an ORR of 23%. Key Secondary endpoints include progression free survival, clinical benefit rate, duration of response, overall survival and quality of life. Study will open to enrollment in July 2020. For further information on this trial, email chen.d@ayalapharma.com or visit clinicaltrials.gov (NCT04461600). Citation Format: Tiffany A Traina, Erin F Cobain, Ella Evron, Chen Duksin, Gary Gordon. Tenacity: A phase 2, multicenter, open-label, single-arm study of AL101 monotherapy in patients with notch-activated 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 OT-29-01.

Abstract GS3-01: Additional efficacy endpoints from the phase 3 KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy as first-line therapy for locally recurrent inoperable or metastatic triple-negative breast cancer

Abstract Background: Pembrolizumab (pembro) monotherapy showed durable antitumor activity and manageable safety in patients (pts) with metastatic triple-negative breast cancer (TNBC) in the KEYNOTE-012, -086, and -119 studies. In a prespecified interim analysis of KEYNOTE-355 (NCT02819518), pembro combined with chemotherapy (chemo) showed a statistically significant improvement in PFS versus chemo alone in pts with previously untreated locally recurrent inoperable or metastatic TNBC whose tumors expressed PD-L1 CPS ≥10 (HR for progression or death, 0.65, 95% CI, 0.49-0.86; one-sided P=0.0012 [prespecified statistical criterion was alpha=0.00411 at this interim analysis]). Additionally, pembro + chemo was generally well tolerated, with no new safety signals. Here, we examine PFS outcomes for each chemo partner and present key secondary endpoints from KEYNOTE-355. Methods: 847 pts with measurable disease per RECIST v1.1, ECOG PS 0-1, and ≥6 mo DFI were randomized 2:1 to pembro + chemo (nab-paclitaxel 100 mg/m2 days 1, 8, and 15 every 28 days; paclitaxel 90 mg/m2 days 1, 8, and 15 every 28 days; or gemcitabine 1000 mg/m2 + carboplatin AUC 2 days 1 and 8 every 21 days) or pbo + chemo for up to 35 administrations of pembro/pbo or until progression/intolerable toxicity. Steroid premedication for paclitaxel was given according to local guidelines and practices, and was not restricted by the protocol. Crossover between arms was not allowed. Pts were stratified by chemo type (taxane vs gemcitabine/carboplatin), PD-L1 status (CPS ≥1 vs &amp;lt;1), and prior (neo)adjuvant treatment with same-class chemo (yes vs no). Dual primary endpoints are PFS (RECIST v1.1, blinded independent central review) and OS in pts with PD-L1 positive tumors (CPS ≥10 and ≥1) and in all pts. Secondary endpoints include ORR, DCR (CR + PR + SD ≥24 weeks), and DOR. The PFS treatment effect was assessed in subgroups descriptively using HRs and 95% CIs; although subgroup analysis by on-study chemo were pre-specified, the trial was not powered to compare efficacy among treatment groups by different chemo regimens. Results: As of Dec 11 2019, median follow-up was 25.9 mo for pembro + chemo (n=566) and 26.3 mo for pbo + chemo (n=281). The HR for PFS favored pembro regardless of choice of chemo or CPS population (Table). Results for the key secondary endpoints of ORR, DCR, and DOR favored pembro + chemo, with the treatment effect increasing as CPS increased (Table). Conclusion: In subgroup analysis, PFS with pembro + chemo compared to pbo + chemo in pts with metastatic TNBC was improved regardless of chemo partner. A trend toward improved efficacy with PD-L1 enrichment with pembro + chemo was observed for ORR, DCR and DOR endpoints. These data further support the potential of pembro + chemo as a first-line treatment option for metastatic TNBC. CPS ≥ 10CPS ≥ 1All ptsPembro + ChemoPbo + ChemoPembro + ChemoPbo + ChemoPembro + Chemo|Pbo + ChemoN = 220N = 103N = 425N = 211N = 566N = 281PFS, mo median (95% CI)9.7 (7.6 - 11.3)5.6 (5.3 - 7.5)7.6 (6.6 - 8.0)5.6 (5.4 - 7.4)7.5 (6.3 - 7.7)5.6 (5.4 - 7.3)HR (95% CI)0.65 (0.49 - 0.86)0.74 (0.61 - 0.90)0.82 (0.69 - 0.97)PFS by on-study chemo, (n [%)) mo median(95% CI)Nab-Paclitaxel(63 [28.6%]) 9.9(36 [35.0%]) 5.5(130 [30.6%]) 6.3(74 [35.1%)) 5.3(173 [30.6%]) 7.5(95 [33.8%]) 5.4HR (95% CI)0.57 (0.34 - 0.95)0.66 (0.26 - 0.82)0.69 (0.51 - 0.93)Paclitaxel(33 [15.0%]) 9.6(11 [10.7%]) 3.6(62 [14.6%]) 9.4(22 [10.4%]) 3.8(82 [14.5%]) 8.0(32 [11.4%]) 3.8HR (95% CI)0.33 (0.14 - 0.76)0.46 (0.26 - 0.82)0.57 (0.35 - 0.93)Gemcitabine-Carboplatin(124 [56.4%]) 8.0(56 [54.4%]) 7.2(233 [54.8%]) 7.5(115 [54.5%]) 7.5(311 [54.9%]) 7.4(154 [54.8%]) 7.4HR (95% CI)0.77 (0.53 - 1.11)0.86 (0.66 - 1.11)0.93 (0.74 - 1.16)ORR, % (95% CI)53.2 (46.4 - 59.9)39.8 (30.3 - 49.9)45.2 (40.4 - 50.0)37.9 (31.3 - 44.8)41.0 (36.9 - 45.2)35.9 (30.3 - 41.9)DCR, % (95% CI)65.0 (58.3 - 71.3)54.4 (44.3 - 64.2)58.6 (53.7 - 63.3)53.6 (46.6 - 60.4)56.0 (51.8 - 60.1)51.6 (45.6 - 57.6)DOR, mo, median (range)19.3 (1.6+ - 29.8)7.3 (1.5 - 32.5+)10.1 (1.0+ - 29.8)6.5 (1.5 - 32.5+)10.1 (1.0+ - 29.8)6.4 ( 1.5 - 32.5+)"+" indicates there is no progressive disease by the time of last disease assessment. Citation Format: Hope S. Rugo, Peter Schmid, David W. Cescon, Zbigniew Nowecki, Seock-Ah Im, Mastura Md Yusof, Carlos Gallardo, Oleg Lipatov, Carlos Henrique Barrios, Jose Perez-Garcia, Hiroji Iwata, Norikazu Masuda, Marco Torregroza Otero, Erhan Gokmen, Sherene Loi, Zifang Guo, Jing Zhao, Vassiliki Karantza, Gursel Aktan, Javier Cortes. Additional efficacy endpoints from the phase 3 KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy as first-line therapy for locally recurrent inoperable or 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 GS3-01.