Pretreated Metastatic Breast Cancer Research Articles

Pyrotinib combined with metronomic etoposide in heavily pretreated HER2-positive metastatic breast cancer: a single-arm, phase II study

BackgroundExploration of novel combination mode of pyrotinib and chemotherapy for heavily pretreated HER2-positive metastatic breast cancer (MBC) and how to balance survival benefits and compliance are still urgent problems in clinical practice. The current single-arm prospective phase II study aimed to evaluate the efficacy and safety of pyrotinib in combination with metronomic oral etoposide in heavily pretreated HER2-positive MBC.MethodsHER2-positive MBC patients previously treated with trastuzumab were enrolled to receive oral pyrotinib 400 mg per day and metronomic oral etoposide 50 mg per day d1-21 every 28 days, until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), overall survival (OS), and safety.Results22 patients were enrolled with a median of 4 prior treatment regimens for MBC. During the follow-up of 20 evaluable patients, the median PFS was 9.0 months (95% CI, 7.6–10.4 months), and the median OS was 27.0 months (95%CI, 20.9–33.1 months). The ORR was 30% (6/20), the DCR was 80% (16/20), and the CBR was 65% (13/20). The most common grade 3 adverse events (AEs) included nausea (15%), vomiting (15%), diarrhea (5%), anemia (5%), and peripheral neuropathy (5%). No grade 4 or lethal AEs were observed.ConclusionThe combination of pyrotinib with metronomic oral etoposide has achieved promising clinical benefits in heavily pretreated HER2-positive MBC, with acceptable and manageable toxicity.Trial registrationRegistry number: NCT03923179. Registered April 18, 2019.

390P SARELIFE: An Italian, multicentric real-world study of sacituzumab govitecan (SG) in pretreated metastatic triple-negative breast cancer (mTNBC)

390P SARELIFE: An Italian, multicentric real-world study of sacituzumab govitecan (SG) in pretreated metastatic triple-negative breast cancer (mTNBC)

PD-1 inhibitor combined with SBRT, GM-CSF, and thymosin alpha-1 in metastatic breast cancer: A case report and literature review.

Triple-negative breast cancer is characterized by a worse prognosis compared with other breast cancer subtypes, especially in the case of pretreated metastatic triple-negative breast cancer (mTNBC). Because of the limited treatment options and suboptimal response rates, there is a pressing need to explore novel treatment protocols. A 48-year-old female patient diagnosed with mTNBC who had not responded to multiple lines of therapy (including surgery, chemotherapy, and radiotherapy) but demonstrated significant efficacy and abscopal effects after enrolling in our clinical trial. Triple-negative breast cancer with lung metastases. The clinical trial combined stereotactic body radiotherapy, immunotherapy, granulocyte-macrophage colony-stimulating factor, and thymosin alpha-1 to treat previously treated metastatic solid cancers. This combined treatment regimen implemented in this clinical trial yielded the patient's notable efficacy, accompanied by abscopal effects. The target lesion and the 3 observed lesions achieved a partial response according to the RECIST v1.1 criteria. reevaluation scans after 2 cycles of immunotherapy indicated a regression rate of -78.97% for the target lesion and -56.73% for the observed lesions. Hematological indexes were stable, and there was no apparent myelosuppression. Also, the tumor marker CA-199 exhibited a downward trend. During the course of treatment, the patient experienced a grade 2 skin reaction, which improved after receiving antiallergic treatment. No further adverse effects were observed. This treatment regimen may offer a promising treatment strategy for patients with mTNBC and other metastatic solid cancers.

A genetically engineered epothilone analog as a novel oral microtubule inhibitor: A clinical study of utidelone capsule for advanced breast cancer.

e13115 Background: Utidelone, a genetically engineered epothilone analog, is a potential best-in-class novel microtubule stabilizing agent. Utidelone injection was approved for advanced breast cancer in China in 2021. Utidelone is not susceptible to P-glycoprotein, leading to better oral bioavailability and successful development of an oral formulation-Utidelone Capsule (UTD2). As of now, there has been no oral microtubule stabilizing agent approved in China and the United States. UTD2 may benefit patients in various aspects including effectiveness, safety, better compliance, reduced medical cost, and facilitation of combination therapy, especially with other oral anti-cancer drugs. This is the first clinical study in China to investigate the efficacy and safety of UTD2 monotherapy for treatment of advanced breast cancer. Methods: This is an ongoing open-label, multi-center study (NCT05700084) consisting of three parts: dose escalation, bioavailability and food effect, and in combination with capecitabine for treatment of metastatic breast cancer. Here we report the preliminary results from single center for part I with determination of DLT and MTD as the primary objective, and efficacy, PK profile and safety in patients with pretreated metastatic breast cancer as the secondary objectives. Eligible patients are aged 18-70 years with confirmed advanced breast cancer refractory to prior standard therapies, and have an ECOG PS of 0-1, life expectancy ≥12weeks. Patients are treated with UTD2 monotherapy, at starting dose of 50 mg/m2/d-5day for two patients, with planned escalation (3+3) to 75 mg/m2/d-5day and 75 mg/m2/d-7day, then to 85 mg/m2/d-7day or down to 70 mg/m2/d-7day in a 21-day cycle. Results: As of 25th January 2024, 5 advanced breast cancer patients were enrolled, who had received prior treatment in advanced settings. Dose escalation is ongoing, and 75mg/m2/d-7day cohort is under evaluation. Four patients were evaluated for efficacy with an outcome of 2 PR (each for 50 and 75mg/m2/d-5day dose) and 2 SD (75mg/m2/d-5day dose) with treatment durations of 2 to 8 cycles. Most treatment-emergent adverse events (TEAEs) were Grade 1/2, manageable, and included peripheral sensory neuropathy (PN), dizziness and loss of appetite. There were two patients encountered Grade 3 TEAEs including one with PN and one with diarrhea/insomnia, that recovered through dose reduction or supportive treatment. No grade 4/5 adverse events and no treatment discontinuations due to AE were reported. There have been no DLTs and the MTD is not yet reached. Conclusions: These preliminary results suggested promising efficacy with a manageable safety profile of UTD2 in pretreated metastatic breast cancer patients. This study is still actively enrolling; further data will be provided at the time of presentation. Clinical trial information: NCT05700084 .

Comparison of expert treatment recommendations versus community healthcare providers: Analysis from an online decision support tool for metastatic breast cancer.

1053 Background: Management of metastatic breast cancer (MBC) is quickly evolving. Beyond hormone receptor (HR) status, a growing list of molecular markers are used to refine individualized systemic treatment (Tx). However, the number of options increases the complexity of Tx decision-making for healthcare professionals (HCPs). Here, we report an analysis of discordance between expert Tx recommendations vs HCPs from an online Interactive Decision Support Tool (IDST). Methods: Five breast cancer experts provided Tx recommendations for 59 unique MBC case scenarios where systemic therapy was indicated. Case scenarios were defined by key characteristics, including HR status, previous Tx, prior duration of response, and actionable biomarkers. After HCPs (n = 91) selected specific patient (pt) criteria and their intended Tx, the IDST showed the breast cancer experts’ recommendations, and HCPs were then asked whether seeing the recommendations changed their intended Tx plan. Experts’ recommendations were compared with that of HCPs to assess for concordance or discordance. Results: For first-line (1L) HR+/HER2- MBC, all experts (100%) recommended endocrine therapy with CDK4/6 inhibitor vs 38% of HCPs. For 1L HER2+ MBC, 62.5% concordance was observed with HCPs selecting expert recommended docetaxel, trastuzumab, and pertuzumab (THP). For 1L therapy for triple negative breast cancer (TNBC) based on BRCA1/2mutation and/or PD-L1 status, 44% of HCPs indicated they were uncertain of optimal Tx. Discordant findings were also observed for pretreated pts. For pretreated HR+/HER2- MBC, <50% of HCPs selected expert-recommended elacestrant for ESR1 mutant disease and chemotherapy (CT) if <12 months of prior response to 1L Tx vs 100% of experts. Moreover, 2 out of 5 HCPs agreed with experts in recommending T-DXd in pretreated HER2-low MBC. In pretreated HER2+ MBC, 100% of experts chose T-DXd vs 60% of HCPs if previous THP and no brain metastases, and 60% of experts vs 40% of HCPs chose T-DXd if brain metastases. In recurrent TNBC with no actionable biomarkers and ≥2 previous systemic CT, 7% of HCPs selected sacituzumab govitecan vs all experts selecting this Tx or CT not previously received. Overall, 50% and 29% of HCPs indicated expert recommendations changed or confirmed their practice, respectively. Conclusions: Data from an online IDST demonstrate discordance of expert recommendations and community HCPs Tx selection in MBC, which is made challenging by a number of variables that that must be assessed during the care continuum. Expert recommendations in the IDST often reinforced or changed HCP’s Tx plan, highlighting the need for ongoing education and the potential of an online tool to improve optimal Tx decisions for MBC, particularly when HCPs must consider current guidelines and tumor-specific biomarkers across multiple tumor types they may see.

Comparative survival analysis of patients with HER2-low and HER2-positive metastatic breast cancer with or without brain metastases treated with trastuzumab deruxtecan.

1036 Background: Breast cancer outcomes vary among HER2-amplified and HER2 low-expression patients, particularly in the presence of brain metastases (BM). Trastuzumab deruxtecan (T-DXd) is FDA approved for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low and HER2-positive (HER2+) patients (pts). This study aims to evaluate the impact of T-DXd treatment on overall survival among HER2 low and HER2-positive metastatic breast cancer (MBC) patients with and without brain metastases (BM). Methods: A retrospective analysis was conducted by using de-identified data available from seven US-based health systems part of Guardian Research Network (GRN). Patients treated with T-DXd from December 2019 to December 2023 with a diagnosis of HER2 low (immunohistochemistry [IHC] 1 + or IHC 2+/negative with HER2 FISH non-amplified) and HER2+ (IHC 3+ or HER2+ and FISH amplified MBC were included. Median overall survival (mOS), calculated from the initiation of T-DXd treatment, was assessed using Kaplan-Meier Curve analysis and Log-rank test. Results: A total of 380 MBC pts were identified. Among these 231 (61.1%) were stratified as having HER2 low and 149 (38.9%) HER2+ MBC. Pts with HER2+ disease had a higher prevalence of BM (n=70; 47%) compared to HER2-low pts (n=55;23.8%). The median age at BM diagnosis was 60.5 years, range: 21.6 to 87.1 years. Within the entire BM group (n=125), there were more pts with ER+ disease (81.9%) in the HER2 low group compared to HER2+ group (55.8%, p=0.01). The majority of these patients had multiple prior lines of therapy. HER2+ BM pts had a median overall survival (mOS) of 9.3 months [CI: 6.79-11.88, log rank p <0.001], compared to 4.3 months [CI: 1.89-6.82, log rank p <0.001] in the HER2-low pts. Without BM, HER2+ pts had a mOS of 10.7 months [CI: 0.71-20.82, log rank p <0.001], compared to 6 months [CI: 3.47-8.67, log rank p <0.001] in the HER2-low pts. Conclusions: In this retrospective study of heavily pretreated MBC patients with multiple prior lines of therapy, pts with HER2+ MBC with and without BM had a longer mOS compared to those with HER2- low disease, suggesting HER2 expression as a key determinant of T-DXd efficacy. Poor survival in MBC patients without BM was attributed to pre-treatment with multiple lines of therapy. Future research should explore combination therapies and predictive biomarkers while conducting clinical trials to optimize treatment strategies for HER2+ metastatic breast cancer patients.

Abstract PO1-20-12: CD8+ Tumor Infiltrating Lymphocytes Turn a Cold Tumor Hot in Metastatic Breast Cancer

Abstract Introduction: Turning “cold” tumors “hot” is considered essential for immune-oncology therapies to be effective. Bria-IMT is an allogenic human cancer cell line with antigen presenting cell activity (SV-BR-1-GM) designed to overcome the immune-suppressive tumor microenvironment. However, until now there has not been proof that “cold” tumors can become “hot” with this therapy. Using Zr-89 crefmirlimab berdoxam, a zirconium-89 labelled truncated antibody specific to human CD8α and developed for CD8 ImmunoPET, we image before and after Bria-IMT therapy administration to assess the baseline status as well as changes in CD8 cell presence after initiation of therapy. Here we present the first evidence that cold tumors can become hot on treatment with Bria-IMT combined with an anti-PD-1 checkpoint inhibitor (CPI), showing CD8+ cells increased over baseline using CD8 ImmunoPET. Case: After informed consent, a 61 year-old Hispanic female, enrolled in the ongoing randomized phase 2 Bria-IMT trial in advanced heavily pretreated metastatic breast cancer (MBC) (NCT03328026). Her history included MBC in May 2020, ductal type, grade 3, triple negative breast cancer (TNBC) with 6 prior lines of therapy including a Trop-2-directed antibody-drug conjugate and 6 lines of chemotherapy. Precision medicine testing identified no actionable targets. All prior therapies had progressive disease as their best response. The subject was randomized to start the CPI after 2 cycles of Bria-IMT to “train” the host immune system before proceeding with combination immune-oncology therapy. Baseline testing revealed the subject to be anergic to candida and SV-BR-1-GM inoculation. However, by cycle 3 delayed-type hypersensitivity to SV-BR-1GM developed. Interestingly the subject matched SV-BR-1-GM at 2 HLA loci: DRB3*02:02 and DRB1*11:04 which in previous publications is associated with greater clinical benefit. Tumor markers were stable or decreased slightly including CEA (25% decrease) and CA 15-3 (43% decrease). Circulating Tumor Cells (CTCs) and Cancer Associated Macrophage Like cells (CAMLs) also improved. Standard imaging at baseline showed 3 main sites of disease including a large right breast mass, multiple right axillary lymph nodes and a right lower lobe mass with CD8 ImmunoPET uptake in these areas similar to the blood pool. On the follow-up CT imaging, all of these lesions increased in size with newly appreciated pulmonary nodules. The right lower lobe mass showed increased CD8 ImmunoPET accumulation with an SUV of 5.8 (close to the liver background) as compared to an SUV of 2.2 at baseline. The lesions in the right breast and right axilla remained at blood pool levels. There was an increase in CD8 ImmunoPET uptake in bilateral inguinal lymph nodes reaching an SUV of 4.8 as compared to SUV 2.2 at baseline. In addition, there were non-enlarged lymph nodes in bilateral axillary regions that also showed increased radio-tracer accumulation reaching an SUV of 9.5 as compared to SUV 4.9 at baseline. Conclusion: This subject demonstrated a mixed response of metastatic lesions on CD8 ImmunoPET with encouraging changes in peripheral blood tumor markers and CTCs. The nonspecific nodal localization of CD8 ImmunoPET may indicate a systemic activation of CD8 positive lymphoid cells. This shows the value of CD8 ImmunoPET in identifying lesions that are progressing on treatment versus pseudo progression. It also provides support that the Bria-IMT + CPI combination immune-based therapy can result in an increase of CD8+ tumor infiltrating lymphocytes in breast cancer metastatic sites as well as an increase in lymphoid organs. This advance may aid in triaging patients, adjudicating pseudo-progression and predicting clinical benefit of immune based therapies. Citation Format: Russ Kuker, Frances Valdes-Albini, Giuseppe Del Priore, Aazim Arif, Kristin Schmiedehausen, Carmen Calfa. CD8+ Tumor Infiltrating Lymphocytes Turn a Cold Tumor Hot in Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-12.

A Pilot Study of the Combination of Entinostat with Capecitabine in Advanced Breast Cancer.

Breast cancer has an unacceptably high recurrence rate when any residual disease is found following neoadjuvant treatment of high-risk disease. Based on clinical data suggesting an adjuvant role for epigenetic modifying agents in breast cancer and preclinical data suggesting synergistic activity of entinostat combined with capecitabine, we conducted a phase I, open-label study of these agents in metastatic breast cancer (MBC). Both agents have published doses for use in combination therapy, but the agents had not previously been combined with each other in a human trial. A multisite phase I dose escalation study was performed at two academic centers. Patients with pretreated, HER2-negative MBC, and measurable disease were enrolled. Dual dose escalation was performed via a Bayesian partial order continual assessment method. Dose levels ranged from entinostat 3 mg to 5 mg and capecitabine 800 mg/m2 to 1000 mg/m2. Thirteen patients with MBC and a median of 4 lines of prior therapy were enrolled across four dose level combinations. The most common toxicities were neutropenia, thrombocytopenia, and palmar-plantar dysesthesia, which were expected toxicities. No new safety signals were observed. One dose-limiting toxicity was observed, which did not exceed a prespecified toxicity rate of 25%. The median treatment duration was 2.37 months. No partial nor complete responses were observed. The study was halted early prior to entering an expansion phase, due to drug supply limitations. The tested dosing combinations of entinostat and capecitabine are likely safe in heavily pretreated metastatic breast cancer. This study's clinical investigation of entinostat in breast cancer was halted, but drug development of this agent continues outside the US. There remains a need for postoperative adjuvant drug therapy for the subpopulation of breast cancer patients with high-risk residual cancer after curative therapy. This trial is registered with NCT03473639.

Utidelone-based therapy in advanced or metastatic solid tumors after failure of standard therapies: a prospective, multicenter, single-arm trial.

Treatment options are limited for tumors after failure of standard therapies. Utidelone (UTD1), a novel microtubule stabilizer, given via 5 days intermittent infusion, has demonstrated high activity in heavily pretreated metastatic breast cancer, while its efficacy in other cancers was unclear. Peripheral neuropathy is a common and severe adverse event (AE) of UTD1. We performed a prospective, multicenter, single-arm trial (ChiCTR2300074299) to evaluate the efficacy and safety of UTD1 with a changed administration mode in patients with advanced or metastatic solid tumors after failure of standard therapies. UTD1 (150 mg/m2, alone or in combination with other anticancer agents) was administrated via 120 h continuous intravenous infusion every 21 days until disease progression or intolerable toxicity. A total of 50 patients were enrolled and analyzed, including 20 breast cancer patients, 11 gynecological cancer patients, 8 gastrointestinal cancer patients, 6 lung cancer patients, and 5 patients with other solid tumors. The overall median progression-free survival (PFS) was 4 months, the overall objective response rate and disease control rate were 20% and 66%, respectively, and the median overall survival was not reached. Most of the AEs were grade 1 or 2 and were manageable and reversible, the rate of grade ≥3 AEs including peripheral neuropathy was 4%. This study demonstrated a promising anti-tumor activity of UTD1 in patients with advanced or metastatic solid tumors after failure of the standard therapies. Moreover, 120 h continuous intravenous infusion was a more tolerable administration mode than 5 days intermittent infusion, and worthy of further study.

Engineering nanoliposomes to enhance cancer immunotherapy by reversing immunosuppression and synergistically boosting tumour immunogenicity

The clinical success of immune checkpoint inhibitors (ICIs) has initiated a new era in the treatment of metastatic cancer. Unfortunately, the overall response rate of ICIs in pretreated metastatic breast cancer (BC) is generally less than 20% due to many challenges, including low immunogenicity and immunosuppressive tumour microenvironment (ITM). Herein, we synthesized nanoliposomes that codelivered diclofenac (DC) and Mn (5,10,15,20-tetrakis (4-chlorophenyl) porphyrin) Cl (PMnCl) (denoted MD@Lip) to overcome these challenges. DC could block lactate transporters (monocarboxylate transporters 1 and 4) on the cancer cell membrane, thus reducing the concentration of lactate, which acts as a critical regulator of the ITM. Meanwhile, PMnCl-induced sonodynamic therapy (SDT) could induce apoptotic and/or necrotic tumour cell death. Importantly, SDT could induce immunogenic cell death (ICD) during the tumour cell debris generation, which changed the state of tumour cells from nonimmunogenic to immunogenic. Thus, MD@Lip was verified to activate T cells, inactivate regulatory T cells and regulate the levels of immune cytokines, ultimately inhibiting primary and distant tumours by improving the antitumour effect of anti-PD1-based immunotherapy.

A review of treatment options in HER2-low breast cancer and proposed treatment sequencing algorithm.

The expansion of the spectrum of human epidermal growth factor receptor 2 (HER2)-status to HER2-low, defined as HER2 expression of 1+ by immunohistochemistry (IHC) or 2+ by IHC without gene amplification, has made a major impact in the field of oncology. The HER2-low expression has emerged as a targetable biomarker, and anti-HER2 antibody-drug conjugate trastuzumab deruxtecan has shown significant survival benefit in pretreated metastatic HER2-low breast cancer (BC). With these recent data, the treatment algorithm for hormone receptor-positive and triple-negative BC needs to be reconsidered, as approximately half of these BCs are HER2-low. Although there are different therapeutic agents for hormone receptor-positive and hormone receptor-negative HER2-low BCs, there is no consensus regarding the sequencing of these agents. In this article, the treatment options for HER2-low BC are enumerated and a treatment sequencing algorithm based on the current clinical evidence proposed.

Efficacy of apatinib 250 mg combined with chemotherapy in patients with pretreated advanced breast cancer in a real-world setting.

This study evaluated the efficacy and safety of apatinib (an oral small-molecule tyrosine kinase inhibitor targeting VEGFR-2) 250 mg combined with chemotherapy in patients with pretreated metastatic breast cancer in a real-world setting. A database of patients with advanced breast cancer who received apatinib between December 2016 and December 2019 in our institution was reviewed, and patients who received apatinib combined with chemotherapy were included. Progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), the disease control rate (DCR), and treatment-related toxicity were analyzed. In total, 52 evaluated patients with metastatic breast cancer previously exposed to anthracyclines or taxanes who received apatinib 250 mg combined with chemotherapy were enrolled in this study. Median PFS and OS were 4.8 (95% confidence interval [CI] = 3.2-6.4) and 15.4 months (95% CI = 9.2-21.6), respectively. The ORR and DCR were 25% and 86.5%, respectively. Median PFS for the previous line of treatment was 2.1 months (95% CI = 0.65-3.6), which was significantly shorter than that for the apatinib-chemotherapy combination (p < 0.001). No significant difference was identified in the ORR and PFS among the subgroups(subtypes, target lesion, combined regimens and treatment lines). The common toxicities related to apatinib were hypertension, hand-foot syndrome, proteinuria, and fatigue events. Apatinib 250 mg combined with chemotherapy provided favorable efficacy in patients with pretreated metastatic breast cancer regardless of molecular types and treatment lines. The toxicities of the regimen were well tolerated and manageable. This regimen could be a potential treatment option in patients with refractory pretreated metastatic breast cancers.

A pilot study of the combination of entinostat with capecitabine in high-risk breast cancer after neoadjuvant therapy.

e13107 Background: Breast cancer has an unacceptably high recurrence rate when residual disease is found following neo-adjuvant treatment of high-risk disease. Based on clinical data suggesting an adjuvant role for epigenetic modifying agents in breast cancer and preclinical data suggesting synergistic activity of entinostat combined with capecitabine, we conducted a phase I, open label study of these agents in metastatic breast cancer (MBC). Both agents have published doses for use in combination therapy, but the agents had not previously been combined with each other in a human trial. Methods: A multisite phase I dose escalation study was performed at two academic centers. Patients with pretreated, HER2 negative MBC, and measurable disease were enrolled. Dual dose escalation was performed via a Bayesian partial order continual assessment method. Dose levels ranged from entinostat 3mg to 5mg and capecitabine 800mg/m2 to 1000mg/m2. Results: Thirteen patients with MBC and a median of 4 lines of prior therapy were enrolled across four dose level combinations. The most common toxicities were neutropenia, thrombocytopenia, and palmar- plantar erythrodysesthesia, which were expected toxicities. No new safety signals were observed. One dose-limiting toxicity was observed, which did not exceed a pre-specified toxicity rate of 25%. The median treatment duration was 2.37 months. No partial nor complete responses were observed. The study was halted early prior to entering an expansion phase. Conclusions: The tested dosing combinations of entinostat and capecitabine are likely safe in heavily pretreated metastatic breast cancer patients. Entinostat clinical investigation in breast cancer was halted while this study was ongoing. Clinical trial information: NCT03473639 .

Anti-HER2 antibody inetetamab plus camrelizumab and utidelone for pretreated HER2-positive metastatic breast cancer: Final results from the phase 2 ICU trial.

1042 Background: We previously reported (Yan, ASCO 2022) promising efficacy and acceptable safety of anti-HER2 antibody inetetamab in combination with camrelizumab and utidelone regimen in preliminary 20 HER2-positive metastatic breast cancer (MBC) patients who progressed after at least two lines of HER2-directed therapies with trastuzumab and TKIs. Inetetamab is a novel anti-HER2 antibody. Camrelizumab is an anti-programmed death receptor 1 [PD-1] antibody. Utidelone, a genetically engineered epothilone analogue, has shown promising efficacy in heavily pretreated MBC. Here we report the final ICU study results. Methods: In the ICU study (NCT04681287), patients received intravenous camrelizumab (200 mg once every 3 weeks), inetetamab (initial dose of 8 mg/kg, then 6 mg/kg, once every 3 weeks), and utidelone (30 mg/m2, days 1-5, every 3 weeks) until disease progression or intolerable toxicity. The primary endpoint was 3-month progression-free survival (PFS) rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included objective response rate (ORR), PFS and safety. Simon’s two-stage design was adopted for this study. All AEs were graded according to the grading criteria in the Common Terminology Criteria for the Evaluation of Adverse Events, 5th edition. Results: From Apr 23 2021 to Sept 1 2022, a total of 46 HER2-positive MBC patients were enrolled with median age of 52 (range 43-57). As of Jan 18, 2023, the median follow-up was 11.37 months. There were 12 patients (26.09%) with ER+/PR+, 7 patients (15.22%) with ER+/PR-, one patient (2.17%) with ER-/PR+, 26 patients (56.52%) with ER-/PR-. The median number of previous systemic therapies for advanced disease was three. Previous HER2-targeted therapies included trastuzumab (46 [100%]), TKIs (46 [100%], of which pyrotinib 39 [84.78%] and lapatinib 12 [26.09%]), pertuzumab (13 [28.26%]), and margetuximab (3 [6.52%]), T-DM1 or other HER2-ADC (7 [15.22%]). The 3-month PFS rate in 46 patients was 71.84%. The confirmed ORR was 28% (13/46), include one (2.17%) patient achieved complete response. The median PFS was 5.59 months. The most common treatment-related adverse events (TRAEs) were peripheral neuropathy (40 [86.96%]), capillary proliferation (27 [58.7%]), and alopecia (17 [36.96%]). Grade ≥3 TRAEs included rash (3 [6.52%]), peripheral neuropathy (1 [2.17%]) and AST increase (1 [2.17%]). Moreover, there were no grade 4 or above TRAEs. No related treatment discontinuation or deaths occurred. Conclusions: Final efficacy and safety results were consistent with previous ICU study preliminary analyses. The ICU study showed a favorable benefit-risk profile and is an important option for Chinese patients with HER2-positive MBC after at least two lines of HER2-directed therapies with trastuzumab and TKIs. Clinical trial information: NCT04681287 .

Subtyping-based platform guides precision medicine for heavily pretreated metastatic triple-negative breast cancer: The FUTURE phase II umbrella clinical trial

Triple-negative breast cancer (TNBC) is a heterogeneous disease and lacks effective treatment. Our previous study classified TNBCs into four subtypes with putative therapeutic targets. Here, we report the final results of FUTURE, a phase II umbrella trial designed to explore whether the subtyping-based strategy may improve the outcomes in metastatic TNBC patients. A total of 141 patients with a median of three previous lines of therapies in the metastatic setting were enrolled in seven parallel arms. Confirmed objective responses were achieved in 42 patients (29.8%; 95% confidence interval [CI], 22.4–38.1). The median values of progression-free survival and overall survival were 3.4 (95% CI: 2.7–4.2) and 10.7 (95% CI: 9.1–12.3) months, respectively. Given Bayesian predictive probability, efficacy boundaries were achieved in four arms. Furthermore, integrated genomic and clinicopathological profiling illustrated associations of clinical and genomic parameters with treatment efficacy, and the efficacy of novel antibody–drug conjugates was explored in preclinical TNBC models of subtypes for which treatment was futile. In general, the FUTURE strategy recruits patients efficiently and provides promising efficacy with manageable toxicities, outlining a direction for further clinical exploration.

Abstract OT3-27-01: Subtyping-based platform guides precision medicine for heavily pretreated metastatic triple-negative breast cancer: a multicenter, phase 2, umbrella, FUTURE trial

Abstract Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease and lacks effective treatment. Our previous study classified TNBCs into four subtypes (luminal androgen receptor [LAR], immunomodulatory [IM], basal-like immune-suppressed [BLIS], mesenchymal-like [MES]) with distinct molecular features. We aimed to assess the efficacy and safety of molecular subtype-derived precision treatment in patients with heavily pretreated metastatic TNBC. Methods: This open-label, phase 2, umbrella trial included patients from four centers in China. Participants were women (aged ≥18 years) with histologically confirmed metastatic TNBC with disease progression after multiple lines of standard chemotherapy. Patients were enrolled into seven parallel arms according to their molecular subtypes: LAR with or without ERBB2 somatic mutation/amplification assigned to arm A (pyrotinib with capecitabine) and arm B (androgen inhibitor included therapy); IM assigned to arm C (anti-PD-1 antibody with nab-paclitaxel); BLIS with or without BRCA1/2 germline mutation assigned to arms D (PARP inhibitor included therapy) and E (anti-VEGFR included therapy); MES without or with PI3K-AKT mutation assigned to arms F (anti-VEGFR included therapy) and G (everolimus with nab-paclitaxel). Bayesian predictive probability was adopted to monitor each arm, which can be terminated independently according to a prespecified futility or efficacy boundary. This trial is registered with ClinicalTrials.gov, NCT03805399. Findings: Between October 18, 2018, and February 11, 2022, we enrolled 141 patients. All patients were heavily pretreated and resistant to six categories of the most common chemotherapeutic agents used in breast cancer treatment, with a median of 3 previous lines of therapies in the metastatic setting (Table 1 and 2). The median follow-up was 18.3 months (IQR 11.7-27.7). A confirmed objective response was achieved in 42 (29.8%, 95% CI 22.4-38.1) of the 141 patients. The median PFS was 3.4 months (95% CI 2.7-4.2), and the median OS was 10.7 months (95% CI 9.0-12.3) (Table 3). Arms A, C, E and G achieved efficacy boundaries, with 3 (75.0%) out of 4 patients in arm A, 20 (43.5%) out of 46 patients in arm C, 13 (28.3%) out of 46 patients in arm E, and 3 (33.3%) out of 9 patients in arm G achieving objective responses. Potential predictive biomarkers of efficacy in each arm were explored. Safety data were consistent with the known safety profiles of relevant drugs. Interpretation: We demonstrate the feasibility and clinical utility of a subtyping-based, genomic sequencing-guided strategy which allows the majority of heavily pretreated metastatic TNBCs to benefit from precision treatment. Most arms exhibit promising efficacy and manageable toxicities, providing subtyping schema to optimize personalized treatment. Table 1. The FUTURE trial schema. Patients are stratified into seven arms using the FUSCC 484-gene NGS panel testing and IHC subtyping. Abbreviations: mTNBC, metastatic triple-negative breast cancer; NGS, next-generation sequencing; IHC, immunohistochemistry; FUSCC, Fudan University Shanghai Cancer Center; LAR, luminal androgen receptor; IM, immunomodulatory; BLIS, basal-like immune-suppressed; MES, mesenchymal-like; n, number; AR, androgen receptor; PD-1, programmed cell death-1; PARPi, poly ADP-ribose polymerase inhibitor; VEGF, vascular endothelial growth factor; mTORi, mammalian target of rapamycin inhibitors. Table 2. Patient characteristics in the FUTURE trial. Table 3. Summary of treatment efficacy of TNBC in the FUTURE trial Citation Format: Zhi-Ming Shao, Zhong-Hua Wang, Yi-Zhou Jiang, Yin Liu, Xiu-Zhi Zhu, Yi Xiao, Song-Yang Wu, Wen-Jia Zuo, Qiang Yu, A-Yong Cao, Jun-Jie Li, Ke-Da Yu, Guang-Yu Liu, Jiong Wu, Tao Sun, Jiuwei Cui, Zheng Lv, Hui-Ping Li, Xiao-Yu Zhu. Subtyping-based platform guides precision medicine for heavily pretreated metastatic triple-negative breast cancer: a multicenter, phase 2, umbrella, FUTURE trial [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 OT3-27-01.

A nationwide observational study in heavily pretreated metastatic HER2-positive breast cancer patients

Background Current guidelines in HER2-positive metastatic breast cancer (mBC) recommend the combination of trastuzumab and a chemotherapeutic agent for 3rd line or later treatments. This study aims to describe the treatment of HER2-positive mBC in 3rd line or later after previous treatment with T-DM1 for mBC in a real-world setting. Material and methods This observational population-based study included all women diagnosed with HER2-positive mBC in Denmark, previously treated with T-DM1 in the metastatic setting. Patients were included on the date of progression leading to initiation of 3rd line treatment if the patient had received T-DM1 in 1st or 2nd line. If the patient received T-DM1 in 3rd line or later the inclusion was based on the date of progression on T-DM1. The primary end points were overall survival (OS) and progression-free survival (PFS). Results The study included 272 women with a mean age of 59 (27–86) and a median of 3 (2–11) treatment lines prior to inclusion. At index, all patients had received T-DM1 and 167 (62%) patients had received pertuzumab in the metastatic setting. During follow-up 183 patients received chemotherapy. Of these patients, 120 received chemotherapy combined with trastuzumab, 50 received chemotherapy combined with other HER2-targeted therapy, and 13 received chemotherapy as monotherapy. The remaining 89 patients received either HER2-targeted monotherapy (41), endocrine therapy (31), experimental treatment (10), or no treatment (7). Median PFS was 5.5 months (95% CI, 4.8–6.5) and median OS was 18.5 months (95% CI, 16.2–21.3). Conclusion In this real-world study, we found that patients were treated with a wide variety of anti-cancer agents with modest efficacy. However, patients in this study did not have access to newer therapies like tucatinib and T-DXd.

A propensity score–weighted study comparing a two- versus four-weekly pegylated liposomal doxorubicin regimen in metastatic breast cancer

A 4-weekly schedule of pegylated liposomal doxorubicin (PLD) has been approved for the treatment of metastatic breast cancer (MBC). Phase II trials have suggested interest in a 2-weekly regimen. This study aimed to compare the efficacy and safety of these two schedules. Data from MBC patients treated with PLD between 2011 and 2021 were retrospectively collected. The objective was to demonstrate the noninferiority of the 2-weekly versus the 4-weekly schedule in terms of 6-month progression-free survival (PFS). The prespecified noninferiority margin was calculated as 1.20. A propensity score to receive either schedule was estimated using a gradient boosting algorithm. Survival analyses using Cox regression models weighted by the propensity score were performed to compare the schedules. Among the 192 patients included, 96 (50%) underwent each schedule. The median number of previous systemic therapies was 4 (IQR, 3 to 6). Anthracyclines were previously given in early breast cancer in 63.9% of patients. The median follow-up was 10.0months (IQR, 5.0 to 20.1). A comparable distribution of adverse events was observed. The median PFS was 3.2months (95% CI, 2.9 to 3.9), and the median overall survival was 12.1months (95% CI, 10.8 to 14.9). The weighted hazard ratio for PFS was 1.12 (90% CI, 0.82 to 1.54), including the noninferiority boundaries. PLD appeared to be a well-tolerated drug in this heavily pretreated MBC population. The efficacy and safety of the 2-weekly schedule did not provide any advantage, suggesting no interest in changing the registered regimen.

Clinical outcomes of tucidinostat-based therapy after prior CDK4/6 inhibitor progression in hormone receptor-positive heavily pretreated metastatic breast cancer

BackgroundCDK4/6 inhibitors combined with endocrine therapy are standard first- or second-line treatment for patients with HR-positive and HER2-negative advanced breast cancer, however, there is currently no optimal recommendation for therapeutic strategies after progression on CDK4/6i. The aim of this study is to analyze the efficacy and safety of HDAC inhibitor Tucidinostat combined with endocrine therapy in patients after prior CDK4/6 inhibitor progression. MethodsThe pathological and clinical data of 44 HR-positive and HER2-negative breast cancer patients treated with tucidinostat after progression on CDK4/6i at the Breast Oncology Department of the Fifth Medical Center of the PLA General Hospital from July 2019 to October 2021 were retrospectively analyzed. Observation indexes included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR), objective response rate (ORR) and adverse events. At the same time, we attempted to identify potential genomic predictors using available next-generation sequencing (NGS). ResultsA total of 44 patients were enrolled in this study. Median follow-up was 10 months (1–26 months) by the data cutoff date (February 2022). The CBR was 6.8% (3/44), the median PFS was 2.0 months (95% CI 1.9–2.1), and the median OS was 14 months (95% CI 6.3–21.7). The mPFS was 4.1 months (95%CI: 0–8.2) in patients with 1 metastatic site, and the mPFS was 4.5 months (95%CI: 4.2–4.8) in patients who received sequential tucidinostat after CDK4/6i failure. Multivariate analysis showed that patients with 1 metastatic site or sequential tucidinostat treatment after failure of CDK4/6i were more likely to benefit from tucidinostat combined with endocrine therapy. Preliminary data showed PIK3CA mutation may be associated with resistance of tucidinostat therapy. No grade 4 adverse events and no treatment-related deaths were recorded in the study. Dose reductions because of adverse events occurred in 4 (9.1%) patients. ConclusionsThis study preliminarily shows that tucidinostat combined with endocrine therapy may be an optional sequential strategy for patients with HR+/HER2-advanced breast cancer that has progressed on CDK4/6 inhibitor, especially for these with lower tumor burden and fewer prior palliative treatment.

Antibody-drug conjugates targeting TROP-2: Clinical development in metastatic breast cancer

Antibody drug conjugates (ADCs) combine the potent cytotoxicity of chemotherapy with the antigen -specific targeted approach of antibodies into one single molecule. Trophoblast cell surface antigen 2 (TROP-2) is a transmembrane glycoprotein involved in calcium signal transduction and is expressed in multiple tumor types. TROP-2 expression is higher in HER2-negative breast tumors (HR+/HR-) and is associated with worse survival. Sacituzumab govitecan (SG) is a first-in-class TROP-2-directed ADC with an anti-TROP-2 antibody conjugated to SN-38, a topoisomerase inhibitor via a hydrolysable linker. This hydrolysable linker permits intracellular and extracellular release of the membrane permeable payload enabling the “bystander effect” contributing to the efficacy of this agent. There was significant improvement in progression free survival (PFS) and overall survival (OS) with SG versus chemotherapy in pretreated metastatic triple negative breast cancer (TNBC), resulting in regulatory approval. Common adverse events (AE) reported were neutropenia and diarrhea. SG also demonstrated clinical activity versus chemotherapy in a phase III trial of HR+/HER2-metastatic breast cancer (MBC) and is under evaluation in first-line metastatic and early stage TNBC as well. Datopotamab deruxtecan (Dato-DXd) is a TROP-2 ADC that differs from SG in that it has a cleavable tetrapeptide linker and a more potent topoisomerase inhibitor payload. This construct is highly stable in circulation with a longer half-life than SG, and undergoes cleavage in presence of intracellular lysosomal proteases. Dato-DXd demonstrated preliminary efficacy in unselected metastatic TNBC, with common AEs of low-grade nausea and stomatitis. Dato-DXd is being investigated in phase III studies in metastatic TNBC and HR+/HER2- MBC. These novel TROP-2 ADCs have the potential to deliver enhanced efficacy with reduced toxicity in MBC and possibly in early stage breast cancer (EBC).