Combination Of Eribulin Research Articles

Recombinant Methioninase Increases Eribulin Efficacy 16-fold in Highly Eribulin-resistant HT1080 Fibrosarcoma Cells, Demonstrating Potential to Overcome the Clinical Challenge of Drug-resistant Soft-tissue Sarcoma.

A major challenge in treating soft-tissue sarcoma is the development of drug resistance. Eribulin, an anti-tubulin agent, is used as a second-line chemotherapy for patients with unresectable or metastatic soft-tissue sarcoma. However, most patients with advanced soft-tissue sarcoma are resistant to eribulin and do not survive. Recombinant methioninase (rMETase) targets the fundamental and general hallmark of cancer, methionine addiction, termed the Hoffman Effect. The present study aimed to show how much rMETase could increase the efficacy of eribulin on eribulin-resistant fibrosarcoma cells in vitro. HT1080 human fibrosarcoma cells were exposed to step-wise increasing concentrations of eribulin from 0.15-0.4 nM to establish eribulin-resistant HT1080 (ER-HT1080). ER-HT1080 cells were cultured in vitro and divided into four groups: untreated control; eribulin treated (0.15 nM); rMETase treated (0.75 U/ml); and eribulin (0.15 nM) plus rMETase (0.75 U/ml) treated. The IC50 of eribulin on ER-HT1080 cells was 0.95 nM compared to the IC50 of 0.15 nM on HT1080 cells, a 6-fold increase. The IC50 of rMETase on ER-HT1080 and HT1080 was 0.87 U/ml and 0.75 U/ml, respectively. The combination of rMETase (0.75 U/ml) and eribulin (0.15 nM) was synergistic on ER-HT1080 cells resulting in an inhibition of 80.1% compared to eribulin alone (5.0%) or rMETase alone (47.1%) (p<0.05). rMETase thus increased the efficacy of eribulin 16-fold on eribulin-resistant fibrosarcoma cells. The present study showed that the combination of eribulin and rMETase can overcome high eribulin resistance of fibrosarcoma. The present results demonstrate that combining rMETase with first- or second-line therapy for soft-tissue sarcoma has the potential to overcome the intractable clinical problem of drug-resistant soft-tissue sarcoma.

Combination of eribulin and anlotinib exerts synergistic cytotoxicity in retroperitoneal liposarcoma by inducing endoplasmic reticulum stress

Primary retroperitoneal liposarcoma (RLPS) is a rare heterogeneous tumor occurring within retroperitoneal space, and its overall survival has not improved much in the past few decades. Based on a small-sample clinical practice at our center, patients with RLPS can greatly benefit from anlotinib and eribulin combination. In this study, we investigated the combinational effect of anlotinib and eribulin on RLPS. In vitro experiments revealed that a low dose of anlotinib significantly enhances the cytotoxic effects of eribulin, leading to a remarkable suppression of RLPS cell proliferation, viability, colony formation, migration, and cell-cycle progression compared to individual drug treatments. At the organoid level, the combination treatment causes the spheroids in Matrigel to disintegrate earlier than the single-drug group. In vivo, RLPS patient-derived xenograft (PDX) models demonstrated that the combination of these two drugs can obviously exert a safe and effective anti-tumor effect. Through transcriptome analysis, we uncovered and validated that the synergistic effect mainly is induced by the endoplasmic reticulum stress (ERS) pathway both in vitro and in vivo. Further analyses indicate that anlotinib plus eribulin treatment results in micro-vessel density and PD-L1 expression alterations, suggesting a potential impact on the tumor microenvironment. This study extensively explored the combination regimen at multiple levels and its underlying molecular mechanism in RLPS, thus providing a foundation for translational medicine research.

Genomic and transcriptomic profiles associated with response to eribulin and nivolumab combination in HER-2-negative metastatic breast cancer

BackgroundBiomarkers for predicting response to the immunotherapy and chemotherapy combination in breast cancer patients are not established. In this study, we report exploratory genomic and transcriptomic analyses of pretreatment tumor tissues from patients enrolled in phase II clinical trial of a combination of eribulin and nivolumab for HER-2-negative metastatic breast cancer (MBC) (KORNELIA trial, NCT04061863).MethodsWe analyzed associations between tumor molecular profiles based on genomic (n = 76) and transcriptomic data (n = 58) and therapeutic efficacy. Patients who achieved progression-free survival (PFS) ≥ 6 months were defined as PFS6-responders and PFS6-nonresponders otherwise.FindingsAnalyses on tumor mutation burden (TMB) showed a tendency toward a favorable effect on efficacy, while several analyses related to homologous recombination deficiency (HRD) indicated a potentially negative impact on efficacy. Patients harboring TP53 mutations showed significantly poor PFS6 rate and PFS, which correlated with the enrichment of cell cycle-related signatures in PFS6-nonresponders. High antigen presentation gene set enrichment scores (≥ median) were significantly associated with longer PFS. Naïve B-cell and plasma cell proportions were considerably higher in long responders (≥ 18 months).InterpretationGenomic features including TMB, HRD, and TP53 mutations and transcriptomic features related to immune cell profiles and cell cycle may distinguish responders. Our findings provide insights for further exploring the combination regimen and its biomarkers in these tumors.

The effects of the combination of temozolomide and Eribulin on T98G human glioblastoma cell line: an ultrastructural study

ABSTRACT Glioblastoma tumors are the most aggressive primary brain tumors that develop resistance to temozolomide (TMZ). Eribulin (ERB) exhibits a unique mechanism of action by inhibiting microtubule dynamics during the G2/M cell cycle phase. We utilized the T98G human glioma cell line to investigate the effects of ERB and TMZ, both individually and in combination. The experimental groups were established as follows: control, E5 (5 nM ERB), T0.75 (0.75 mM TMZ), T1 (1.0 mM TMZ), and combination groups (E5+T0.75 and E5+T1). All groups showed a significant decrease in cell proliferation. Apoptotic markers revealed a time-dependent increase in annexin-V expression, across all treatment groups at the 48-hour time point. Caspase-3, exhibited an increase in the combination treatment groups at the 48-hour mark. Transmission electron microscopy (TEM) revealed normal ultrastructural features in the glioma cells of the control group. However, treatments induced ultrastructural changes within the spheroid glioblastoma model, particularly in the combination groups. These changes included a dose-dependent increase in autophagic vacuoles and apoptotic morphology of the cells. In conclusion, the similarity in the mechanism of action between ERB and TMZ suggests the potential for synergistic effects when combined. Our results highlight that this combination induced severe damage and autophagy in glioma spheroids after 48 hours.

Safety and efficacy of eribulin plus anlotinib in patients with advanced soft tissue sarcoma (ERAS): A multi-center phase II study.

11561 Background: Both the microtubule-dynamics inhibitor eribulin and the multi-targeted tyrosine kinase inhibitor anlotinib exhibit single-agent anti-tumor activity in previously treated soft tissue sarcoma (STS). This study aimed to evaluate the efficacy and safety of the combination treatment of eribulin and anlotinib in patients with advanced STS. Methods: In this multi-center phase II study (ERAS), patients with advanced soft tissue sarcoma who relapsed/progressed after anthracycline chemotherapy or were not candidates for such treatment were included. Patients received eribulin (1.1 mg/m² intravenously on days 1 and 8) and anlotinib (12mg orally once daily on days 1-14) every 21 days for 6-8 cycles, followed by anlotinib maintenance. The primary endpoint was progression-free survival rate at 24 weeks (PFR24w). Secondary endpoints included median progression-free survival (mPFS), median overall survival (mOS), objective response rate (ORR), disease control rate (DCR) and safety. Results: Thirty-one patients were enrolled. Twenty-eight (90.3%) patients had received anthracycline chemotherapy, and the remaining 3 (9.7%) were chemotherapy-naïve. Pathological types included L-type sarcomas (10 leiomyosarcomas and 6 dedifferentiated liposarcomas) and non-L-type sarcomas (n =15, with 8 subtypes). As of the cut-off date of Jan 28, 2024, the median follow-up time was 30.4 weeks. Response evaluation was feasible in 29 patients. The ORR, DCR and predicted PFR24w were 20.7%, 82.8% and 65.5%, respectively. The mPFS was 30.1 weeks, with no significant difference observed between patients with L-type sarcomas and non-L-type sarcomas. The mOS was not reached. Nineteen (61.3%) patients experienced at least one grade 3/4 adverse event. The most common grade 3/4 adverse events included neutropenia (35.5%), leukopenia (25.8%), hypertension (16.1%), hypertriglyceridemia (16.1%) and increased gamma-glutamyl transpeptidase (16.1%). Conclusions: The combination of eribulin and anlotinib shows promising efficacy with an acceptable toxicity profile in patients with advanced STS, irrespective of pathological type. Clinical trial information: ChiCTR2300067650.

Efficacy and safety of eribulin plus gemcitabine in second-line or beyond for patients with HER2-negative metastatic breast cancer (MBC): A multicenter, open-label, single-arm, phase II study.

e13139 Background: The combination of eribulin and gemcitabine has demonstrated a similar progression-free survival (PFS) benefit as paclitaxel plus gemcitabine, with less neurotoxicity, for patients with MBC who have not received prior cytotoxic chemotherapy. However, the effect of eribulin plus gemcitabine on PFS in second line or beyond remains unclear. Methods: This open-label, single-arm, phase II study (NCT05263882) was conducted at 14 institutions in China. Eligible patients had histologically confirmed HER2-negative MBC and had received at least one prior taxane-containing chemotherapy regimen for advanced disease, and anthracycline-containing regimens in the adjuvant setting. Patients received intravenous infusions of eribulin (1.4 mg/m2) and gemcitabine (1.0 g/m2) on days 1 and 8 of a 21-day cycle. Efficacy outcomes, including PFS, objective response rate (ORR), and disease control rate (DCR), were assessed using RECIST v1.1. Adverse events (AEs) were graded according to NCI-CTC version 5.0. Results: A total of 70 patients were enrolled from November 2021 to October 2023; 47 (71.4%) had HR+HER2- and 18 (28.6%) had triple-negative MBC. The median patient age was 50 years (range: 31-68), and the sites of metastasis were the bone (68.6%), liver (52.9%), lymph nodes (48.6%), lung (44.3%) and brain (10.0%). Patients had received a median of 3 prior lines of systemic treatment, 2 lines of chemotherapy, and 1 line of endocrine treatment. Among all patients, the ORR was 48.6%, the DCR was 92.9% and the median PFS was 7.2 months. For the HR-positive subgroup, the median PFS was 8.4 months, while for the triple-negative subgroup, it was 6.3 months. Among HR+ patients who had received prior CDK4/6 inhibitor treatment, the median PFS was 7.2 months. In the subgroup of HR+ patients who had not received CDK4/6 inhibitor treatment, the median PFS had not been reached. For the HR+ HER2-low subgroup, the median PFS was 8.4 months. The most common grade 3-4 AEs were hematological, including neutropenia (38.6%), leukopenia (31.4%), anemia (24.3%), and thrombocytopenia (15.7%). Grade ≥3 perceived AEs were relatively low. Conclusions: Eribulin plus gemcitabine was effective in heavily pretreated patients with HER2- MBC, while maintaining a predictable and manageable safety profile. Clinical trial information: NCT05263882 . [Table: see text]

Phase II study of the combination of lenvatinib (L) and eribulin (E) in advanced solid tumors.

3158 Background: Tumor angiogenesis remains a focal point in cancer therapeutics, necessitating innovative strategies to counter resistance mechanisms. Lenvatinib, a multitargeted tyrosine kinase inhibitor, and eribulin, a microtubule inhibitor, exhibit promise in disrupting tumor vasculature. Understanding their efficacy and safety in combination therapy is crucial, especially in heavily pretreated patients with advanced solid tumors. Methods: A single-center phase II study (NCT02640508) enrolled patients with stage IV breast carcinoma, lung carcinoma, and sarcoma, evaluating the safety and efficacy of lenvatinib and eribulin combination therapy. Eribulin was given on day 1 and day 8 at 1.4 mg/m2 and lenvatinib at a dose of 20 mg starting on day 2 of a 21-day cycle. Immunohistochemistry assessed biomarkers CD31, e-cadherin, CA-9, and vimentin. Statistical analyses included multivariate modeling and Kaplan-Meier curves. The primary endpoint of the study was the overall response rate (ORR), defined per RECIST 1.1 as assessed by investigator imaging review. Secondary endpoints included safety, progression free survival (PFS) and overall survival (OS). Results: Among 29 patients enrolled, median age was 58 years, majority were female and had at least ≥3 prior lines of chemotherapy. Treatment with lenvatinib and eribulin resulted in an ORR of 24%, as seen in the table. Median PFS was 7.4 months and OS was 8.2 months. Toxicities were manageable with grade ≥3 neutropenia seen in 34.5%, febrile neutropenia in 17.2%, and hypertension in 13.8% of patients. Treatment-related adverse events leading to study-drug discontinuation occurred in 6.8% of patients. Vimentin-negative patients exhibited significantly increased OS (fold change 4.374, p&lt;0.001) and PFS (fold change 3.395, p&lt;0.001) after adjusting for age, CD31, and CA9. Conclusions: Lenvatinib combined with eribulin showcased promising anti-tumor activity in heavily pretreated patients with metastatic breast carcinoma, lung carcinoma, and sarcoma. Although manageable, neutropenia emerged as a notable adverse effect. These findings underscore the potential of this combination as a therapeutic strategy for advanced solid tumors, warranting further clinical investigation. The observed significant survival benefits in Vimentin-negative patients align with the biological role of Vimentin in tumor invasiveness and metastatic potential, supporting the plausibility of these results biologically. Acknowledgement: This clinical trial was supported by Eisai. Clinical trial information: NCT02640508 . [Table: see text]

Abstract PO5-06-02: Phase II Trial of Combination of Atezolizumab, Cobimetinib and Eribulin (ACE) or Atezolizumab and Eribulin (AE) in patients with metastatic inflammatory breast cancer (IBC): Clinical data of both cohorts

Abstract Background: Metastatic IBC is an unmet clinical need due to the aggressiveness of this breast cancer subtype. Gene expression analysis of IBC samples post-neoadjuvant chemotherapy has revealed that dysregulation of immune pathways is common in tumors that do not have a complete pathologic response (pCR) to chemotherapy. The immune checkpoint PD-L1 is expressed in a third of IBC cases, and the MEK inhibitor, cobimetinib, has been shown to enhance the expression of PD-L1, the target of atezolizumab. Taken together, dual targeted therapy with atezolizumab and cobimetinib is hypothesized to be synergistic. Eribulin is a standard of care chemotherapy used in patients who have progressed on anthracycline-taxane based regimens. Materials and Methods: Patients received triple or double combination therapy depending on the timing of their enrollment. Patients with metastatic IBC who had measurable disease after at least 1 standard regimen were eligible. Any receptor subtype was allowed, and PD-L1 positivity was not required. The study began with a single cohort (n=17 patients) receiving all 3 agents with a lead-in phase to determine the MTD of cobimetinib in this setting. The study was later amended to include only atezolizumab and eribulin (cohort 2). Ten patients were treated in cohort 2. The study closed early due to lack of efficacy in cohort 2 and the changing landscape of metastatic breast cancer therapies. In cohort 1, atezolizumab was given every 2 weeks (840 mg), cobimetinib was given at 60/40/20 mg once daily, and eribulin was given at 1.4mg/m2 on day 1 and day 8 of 21-day cycles. In cohort 2, atezolizumab was given every 3 weeks (1200 mg) during the PD window and cycles 1-4, and then every 4 weeks (1680 mg) during maintenance, and eribulin was given at 1.4mg/m2 on day 1 and day 8 of 21-day cycles. Results: The MTD of cobimetinib was 40mg. In cohort 1, 17 patients were treated, 14 had at least 1 restaging evaluation. Seven patients had a partial response (50%) and 3 stable disease. The cohort was predominantly triple receptor-negative (n=13/17), with a median age of 51 yrs. The median PFS for patients in cohort 1 was 6.2 months (0-54.1). There were 2 exceptional responders, both with triple negative subtype, one of whom remains on therapy for &amp;gt;4.5 years without evidence of disease. The median overall survival was 29.6 months (2.9-133). The AE profile was largely expected, with 3 irAEs (1 grade 5 colitis, and 2 grade 2 pneumonitis), and one other patient with cardiac dysfunction requiring discontinuation of cobimetinib and atezolizumab. The MTD of cobimetinib was 40 mg. Cobimetinib-related toxicities were mild and largely gastrointestinal tract related. In cohort 2, only 1 patient experienced PR, and the median PFS was 3 months (1.2-6.2) and overall survival 8.3 months (1.8-19.9). One patient experienced autoimmune related hepatitis requiring discontinuation of protocol therapy. Due to excesive myelosuppression, dose of erublin was reduced to 1.1 mg per meter squared on day 1 and 8 and pegfilgastrim was added on day 9&amp;lt; Conclusions: The response profile of the triple combination demonstrated promise, and suggests that MEK inhibition may warrant further investigation as a strategy in metastatic IBC in a larger sample size. However, there does not appear to be synergy between atezolizumab and eribulin without the addition of targeted therapy. Citation Format: Angela Alexander, Hope Murphy, James Reuben, H. T. Carisa Le-Petross, Deanna Lane, Monica Huang, Savitri Krishnamurthy, Yun Gong, Dan Gombos, Nimisha Patel, Richard Allen, Suyu Liu, Anisha Patel, Andrew Futreal, Ignacio Wistuba, Rachel Layman, Naoto Ueno, Debu Tripathy, Bora Lim, Vicente Valero. Phase II Trial of Combination of Atezolizumab, Cobimetinib and Eribulin (ACE) or Atezolizumab and Eribulin (AE) in patients with metastatic inflammatory breast cancer (IBC): Clinical data of both cohorts [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 PO5-06-02.

Abstract PO3-05-10: Efficacy and safety of eribulin plus gemcitabine in second-line or beyond for patients with HER2-negative metastatic breast cancer (MBC): A multi-center, open-label, single-arm, phase II study

Abstract Background: Eribulin is a halichondrin non-taxane inhibitor of microtubule dynamics approved in China for advanced breast cancer patients who have received at least two prior chemotherapy treatments. The combination of eribulin and gemcitabine has demonstrated a similar progression-free survival (PFS) benefit as paclitaxel plus gemcitabine, with less neurotoxicity, for patients with MBC who have not received prior cytotoxic chemotherapy. However, the effect of eribulin plus gemcitabine on PFS in second line or beyond remains unclear. Methods: This open-label, single-arm, phase II study (NCT05263882) was conducted at 13 institutions in China. Eligible patients had histologically confirmed HER2-negative MBC and had received at least one prior taxane-containing chemotherapy regimen for advanced disease, and anthracycline-containing regimens in the adjuvant setting. Patients received intravenous infusions of eribulin (1.4 mg/m2) and gemcitabine (1.0 g/m2) on days 1 and 8 of a 21-day cycle. Efficacy outcomes, including PFS, objective response rate (ORR), and disease control rate (DCR), were assessed using RECIST v1.1. Adverse events (AEs) were graded according to NCI-CTC version 5.0. Results: A total of 65 patients were enrolled from November 2021 to May 2023; 47 (72.3%) had HR+/HER2- and 18 (27.7%) had triple-negative MBC. The median patient age was 50 years (range: 31-68), and the sites of metastasis were the bone (70.8%), liver (58.5%), lymph nodes (50.8%), lung (43.1%) and brain (10.8%). Patients had received a median of 3 prior lines of systemic treatment, 2 lines of chemotherapy, and 1 line of endocrine treatment. Among all patients, the ORR was 52.3%, the DCR was 92.3% and the median PFS was 7.6 months (Table). For the HR-positive subgroup, the median PFS was 8.4 months, while for the triple-negative subgroup, it was 7.6 months. Among patients who had received prior CDK4/6 inhibitor treatment, the median PFS was 7.2 months. In the subgroup of patients who had not received CDK4/6 inhibitor treatment, the median PFS had not been reached. The most common grade 3-4 AEs were hematological, including neutropenia (41.6%), leukopenia (33.9%), anemia (23.1%), and thrombocytopenia (15.4%). No grade ≥3 perceived AEs were reported. Conclusion: Eribulin plus gemcitabine was effective in heavily pretreated patients with HER2- MBC, while maintaining a predictable and manageable safety profile. Table. Summary of efficacy outcomes Citation Format: PeiJian Peng, Xiao-Lu Xu, Jin-Cai Zhong, Jin-Hui Ye, Zhi-Hui Wang, Hong Wang, Hong Lin, Cai-Wen Du, Guorong Zou, Jie Ouyang, Ying-Ying Shi, Fei Xu, Geng-Sheng Yu, Yong-Kui Lu, Yong-Xia Wang, Shi-En Cui, Lu-Zhen Li. Efficacy and safety of eribulin plus gemcitabine in second-line or beyond for patients with HER2-negative metastatic breast cancer (MBC): A multi-center, open-label, single-arm, phase II study [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 PO3-05-10.

Abstract PO2-05-12: Retrospective analysis on therapeutic efficacy and predictive indicators of eribulin plus anti-angiogenic drugs for metastatic breast cancer

Abstract Background: Eribulin has been widely used for the treatment of metastatic breast cancer (MBC). It has been found that eribulin can work in synergy with Bevacizumab or Anlotinib to achieve anti-angiogenic effects and possible synergistic enhancement. To optimize the efficacy of eribulin usage in late-line MBC patients, it is essential to delve deeper into the effects of combined treatments and gather more real-world clinical outcomes. Therefore, we evaluated the efficacy and safety of eribulin plus the anti-angiogenic drugs in late-line MBC patients. Objective: This study aims to retrospectively analyze the therapeutic efficacy and safety of eribulin plus anti-angiogenic drugs in treating metastatic breast cancer and explore predictive indicators of the therapeutic efficacy of eribulin in treating MBC. Methods: A retrospective review study was performed. 40 Patients diagnosed with MBC and treated with eribulin in Xi’an international medical center hospital from May 2020 to May 2021 were enrolled in this study. Patients were evaluable for this study and divided into two groups based on whether they received eribulin monotherapy or combined therapy. 22 patients were treated with eribulin monotherapy, and 18 were treated with eribulin and anti-angiogenic drugs (Bevacizumab and Anlotinib). Patients’ treatment parameters and characteristics were recorded. The Kaplan-Meier method was used to calculate the median PFS and corresponding 95% confidence interval (CI), and the Cox regression model was used for multivariate analysis of predictive indicators. The Fisher exact probability test was used to compare the difference in adverse reactions between the two groups, with a level of significance set at p-value &amp;lt; 0.05. Results: All study patients have an average of 5 treatment lines and a median progression-free survival (mPFS) of 4.2 months. The eribulin plus anti-angiogenic drug treatment group had a significantly prolonged mPFS compared to the group without anti-angiogenic drug treatment (7.0 months vs 2.0 months, p &amp;lt; 0.001, log-rank). Multivariate analysis identified that the combination of anti-angiogenic therapy (HR = 0.043, p = 0.004) and the occurrence of grade 3-4 neutropenia after treatment were two predictive factors for longer PFS (HR = 0.322, p = 0.009). In contrast, prior resistance to taxanes was predictive of shorter PFS (HR = 4.583, p = 0.019). Other factors, including age, Eastern Cooperative Oncology Group (ECOG) performance status, hormone receptor (HR) type, expression status, human epidermal growth factor receptor-2 (HER-2) expression status, Ki-67 level, number of metastatic lesions, and number of prior lines of Eribulin therapy, were not significantly associated with PFS. The results of Fisher’s exact test show that there was no significant increase in treatment-related adverse events (all grades) after combination with anti-angiogenic drugs. Conclusion: A combination of eribulin and anti-angiogenic therapy has significantly prolonged mPFS in the treatment of MBC patients. Other factors such as prior non-taxane resistance, grade 3-4 neutropenia occurrence after treatment, and combined anti-angiogenic therapy can be used as biomarkers for predicting treatment efficacy. The adverse events are manageable and the safety of combined therapy can be guaranteed. Therefore, the eribulin plus anti-angiogenic combination may act as a potential therapy for late-line MBC patients with clinically beneficial therapeutic effects. Keywords: metastatic breast cancer, eribulin, anti-angiogenic therapy, retrospective analysis Citation Format: Junmei Zhang, Xuezheng Wang, Hongjuan Du, Yan Xue. Retrospective analysis on therapeutic efficacy and predictive indicators of eribulin plus anti-angiogenic drugs for 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 PO2-05-12.

Involvement of ferroptosis in eribulin-induced cytotoxicity in ovarian clear cell carcinoma

Ovarian clear cell carcinoma (OCCC) is a unique clinicopathological subtype of epithelial ovarian cancer that is resistant to standard chemotherapy. Eribulin, a microtubule dynamics inhibitor of halichondrin class, has unique effects in the cancer microenvironment such as induction of epithelization and reduction in metastatic potential in breast cancer cells; however, nothing is known about the effect of eribulin and the detailed mechanisms in OCCC. This study aimed to investigate the involvement of ferroptosis and its mechanism in the antitumor activity of eribulin in OCCC cells and a mouse xenograft model. We found that eribulin-induced cell death was reduced by ferroptosis inhibitors; deferoxamine, an iron chelator and ferrostatin-1, a lipid peroxidation inhibitor. Eribulin increased the levels of intracellular iron, reactive oxygen species (ROS), and lipid peroxides, and increased the mitochondrial membrane potential. Eribulin downregulated the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), and superoxide dismutase (SOD) activity. The combination of eribulin and ML210, a glutathione peroxidase 4-inhibiting ferroptosis inducer, had a synergistic effect on ferroptosis. Taken together, our findings show firstly that eribulin triggers ferroptosis in OCCC and this effect occurs via the suppression of the Nrf2–HO-1 signaling pathway, SOD activity and the promotion of lipid peroxidation. These findings suggest that eribulin-induced ferroptosis is associated with its anti-tumor effect and also could be a potential therapeutic target in OCCC.

Clinical activity of nivolumab in combination with eribulin in HER2-negative metastatic breast cancer: A phase IB/II study (KCSG BR18-16)

AimWe evaluated the efficacy and safety of nivolumab and eribulin combination therapy for metastatic breast cancer (BC) in Asian populations. MethodsIn this parallel phase II study, adult patients with histologically confirmed recurrent/metastatic hormone receptor-positive/HER2-negative (HR+HER2-) or triple-negative BC (TNBC) were prospectively enroled from 10 academic hospitals in Korea (ClinicalTrials.gov Identifier: NCT04061863). They received nivolumab (360 mg) on day 1 plus eribulin (1.4 mg/m2) on days 1 and 8 every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was the investigator-assessed 6-month progression-free survival (PFS) rate in each subtype. Secondary endpoints included investigator-assessed objective response rate (ORR) as per Response Evaluation Criteria in Advanced Solid Tumors version 1.1, disease control rate, overall survival, and treatment toxicity. The association between PD-L1 expression and efficacy was investigated. ResultsForty-five patients with HR+HER2- BC and 45 with TNBC were enroled. Their median age was 51 (range, 31–71) years, and 74 (82.2%) received one or two prior treatments before enrolment. Six-month PFS was 47.2% and 25.1% in the HR+HER2- and TNBC cohorts, respectively. Median PFS was 5.6 (95% confidence interval [CI]: 5.3–7.4) and 3.0 (95% CI: 2.1–5.2) months in the HR+HER2- and TNBC groups, respectively. ORRs were 53.3% (complete response [CR]: 0, partial response [PR]: 24) and 28.9% (CR: 1, PR: 12). Patients with PD-L1+ tumours (PD-L1 expression ≥1%) and PD-L1- tumours (ORR 50% versus 53.8% in HR+HER2-, 30.8% versus 29.0% in TNBC) had similar ORRs. Neutropenia was the most common grade 3/4 adverse event; the most common immune-related adverse events (AEs) were grades 1/2 hypothyroidism and pruritus. Five patients discontinued therapy because of immune-related AEs. ConclusionNivolumab plus eribulin showed promising efficacy and tolerable safety in previously treated HER2- metastatic BC. Trial registrationNCT04061863

Combined PI3K Inhibitor and Eribulin Enhances Anti-Tumor Activity in Preclinical Models of Paclitaxel-Resistant, PIK3CA-Mutated Endometrial Cancer.

Endometrial cancer stands as the predominant gynecological malignancy in developed nations. For advanced or recurrent disease, paclitaxel-based chemotherapy is the standard front-line therapy. However, paclitaxel resistance eternally develops. Based on the high prevalence of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation, reaching 50%, in endometrial cancer, we preclinically investigated the effectiveness of a combination of a phosphatidylinositol 3-kinase (PI3K) inhibitor with eribulin, a post-paclitaxel therapy for breast cancer, in treating paclitaxel-resistant, PIK3CA-mutated endometrial cancer. We generated paclitaxel-resistant cell lines from PIK3CA-mutated endometrial cancer cell lines by gradually increasing the concentration of paclitaxel in cell cultures. We observed that the PI3K/AKT and epithelial-mesenchymal transition (EMT) pathways in paclitaxel-resistant cells were significantly upregulated compared with those in parental cells. Then, we demonstrated that the combination of alpelisib (a PI3K inhibitor) and eribulin more effectively suppressed the cellular growth of paclitaxel-resistant cells in in vitro and in vivo xenograft models. Mechanistically, we demonstrated that the effect of the combination could be enhanced by inhibiting both the PI3K/AKT and EMT pathways. Therefore, we suggest that paclitaxel resistance is associated with the activation of the PIK3/AKT pathway in PIK3CA-mutated endometrial cancer, and the combination of a PI3K inhibitor and eribulin merits further clinical investigation.

P10.30.B COMBINATION TREATMENT WITH ERIBULIN AND TTFIELDS INDUCES APOPTOSIS AND G2/M CELL CYCLE ARREST IN HUMAN GLIOBLASTOMA CELLS

Abstract BACKGROUND TTFields has emerged to a first line treatment in newly diagnosed glioblastoma (GBM) patients. Several preclinical studies showed that the alternating electric fields inhibit proliferation and survival of human glioblastoma cells by disruption of the spindle apparatus and impairment of mitotic segregation. Eribulin is an antimitotic drug, that is currently used in the third line treatment of breast cancer. As it is also able to inhibit the pro-mitotic function of TERT, which is mutated in 80% of human glioblastoma, the drug was also shown to have a radiosensitizing and antiproliferative effect on human glioblastoma and ovarian cancer cell lines. This study aims to evaluate the effect of the combination of Eribulin and TTFields on the survival and cell cycle of glioblastoma cells. MATERIAL AND METHODS U87, A172 and four patient derived glioblastoma cell lines were cultured and plated to 80% confluence. Cells were then treated with TTFields at a frequency of 200kHz for 24 hours and/or received the ED50 and 0.5-fold ED50 of Eribulin. Controls remained untreated respectively. After 24 hours cells were harvested and counted by automatic cell count. Survival and cell cycle status were evaluated by FACS analysis. RESULTS The rate of early apoptotic cells was 82.28% in the group treated with TTFields and Eribulin. With TTFields treatment only 50.99% and with Eribulin alone 14.38% of cells were in an early apoptotic state. Untreated control cells had an apoptosis rate of 4.25%. The combination of TTFields and Eribulin was significantly more effective than the single treatment modalities (p&amp;gt;0.05). Treatment with TTFields increased the rate of cells an G2/M status. This effect was even stronger in the group with combination treatment. CONCLUSION Combination treatment of the antimitotic drug Eribulin with TTFields is able to improve the inhibitory effect of the drugs on cell survival. Furthermore the combination therapy effects the cell cycle of glioblastoma cells inducing G2/M arrest. Future preclinical studies should focus on the antimitotic effect and the influence of the treatment on genome integrity for a more detailed insight into the mechanisms of action.

Results of a Phase Ib Study Investigating Durvalumab in Combination with Eribulin in Patients with HER2-Negative Metastatic Breast Cancer and Recurrent Ovarian Cancer

Introduction: The release of tumor-associated antigens with cytotoxic chemotherapy treatment may enhance the response to immune checkpoint blockade. Eribulin is a microtubule inhibitor with proven overall survival (OS) benefit in metastatic breast cancer (MBC), which may also enhance intratumoral vascular remodeling. Durvalumab, a humanized monoclonal antibody, targets the programmed cell death ligand-1 (PD-L1) receptor. This study sought to determine the maximum tolerated dose and recommended phase II dose (RP2D) of eribulin in combination with durvalumab, as well as the safety and preliminary antitumor activity of the combination in patients with previously treated HER2-negative (HER2−) MBC and recurrent ovarian cancer (ROC). Methods: Cohorts of 3–6 patients with HER2− MBC and ROC were treated in a modified 3+3 design. Eligible patients received escalating doses of eribulin (1.1 mg/m2 or 1.4 mg/m2 IV on day 1 and day 8) with durvalumab (1.12 g IV on day 1) in 21-day cycles until dose-limiting toxicity (DLT), intolerable adverse events (AEs), disease progression, or other reasons for withdrawal. Primary endpoint: the rate of DLTs during cycles 1 and 2 of therapy. Secondary endpoints: AE rate, objective response rate (ORR), progression-free survival (PFS), and OS. Results: Nine patients with a median of 4 prior therapies for advanced disease were treated: 5 patients with HER2− MBC (1 with triple-negative disease and 4 with hormone-positive disease) and 4 patients with ROC. The RP2D of eribulin was 1.4 mg/m2 in combination with durvalumab. There were no DLTs experienced during the first two cycles of therapy. The most common treatment-related AEs (>50%) were fatigue, neutropenia, decreased white blood cell count, anemia, AST and alkaline phosphatase elevation, hyperglycemia, and nausea; most were grade 1 or 2. There was one immune-related AE of grade 3 (hepatitis) after 5 cycles of treatment, for which patient came off study. Two other patients discontinued study drug related to toxicity (neutropenia [n = 1], hepatic toxicity [n = 1]). ORR was 55%, and 4 additional patients experienced stable disease. All MBC patients exhibited a response to therapy. Median PFS was 6.2 months. Median OS was 15.0 months. Conclusion: The combination of eribulin at a dose of 1.4 mg/m2 with standard dose durvalumab had a favorable AE profile in patients with previously treated HER2− MBC and ROC. The early antitumor activity observed in all MBC patients enrolled in the study suggests that further investigation of this combination is warranted.

Combination of eribulin with trastuzumab and pertuzumab for HER2 positive advanced or recurrent breast cancer: JBCRGM03.

e13031 Background: Pertuzumab (P) was an effective first-line treatment for HER2 positive metastatic breast cancer (MBC) in the CLEOPATRA study, improving both overall and progression-free survival (PFS). However, it is challenging to provide intravenous docetaxel to MBC patients over long term at a dosage of 75 mg/m2 every three weeks. Eribulin (E) is a well tolerated cytotoxic agent. In a multicenter, open-label phase II research (UMIN000012232), we have shown the effectiveness and safety of E combined with trastuzumab (T) with P as first- and second-line treatment for metastatic or advanced BC. Methods: The study included HER2 positive MBC patients with no or one previous treatment, including advanced or recurrent chemotherapy. All patients were administered with T and taxane as perioperative or first-line chemotherapy. E (1.4 mg/m2) along with T (8 mg/kg loading dosage &gt; 6 mg/kg), and P (840 mg loading dose &gt; 420 mg) was administered intravenously on days 1 and 8 of a 21-day cycle, once every three weeks. The primary end point was PFS and the secondary endpoints were the response rate (RR) based on RECIST ver1.1. Overall patient survival effectiveness following P administration, E compliance, and success of follow-up therapies were observed. Results: A total of 50 patients were enrolled, with 49 of them qualifying for the safety analysis. However, the full analysis set (FAS) consisted of 46 individuals. The average patient age was 56 years old (range 23–70), and 9 (18%) and 40 (82%) patients received care in first- and second-line settings, respectively. The median PFS for patients who received main therapy was 20.5 months, whereas the median PFS for patients who received subsequent treatment was 8.6 months. Thirty-five patients (76.1%) were able to receive concomitant E until the end of protocol treatment. The overall RR was 56.5% among the 46 patients in the FAS. Nine patients (19.5%) responded completely, whereas 17 patients (37.0%) responded partially. There were 13 cases of stable disease (28.2%), six cases of progressing disease (13.0%), and one case was not evaluable (1.2%). The median survival of the primary treatment population was not reached; however, the median survival of the secondary treatment population was 42.4 months. Twenty three patients received T-DM1 as a follow-up treatment, 13 patients received TP plus chemotherapy, and five patients received additional therapies. The average duration of treatment with T-DM1 as a consequent therapy was approximately four months, whereas the average duration of treatment with HP plus chemotherapy was 11 months. Conclusions: For HER2positive MBC, E in combination with T plus P was well tolerated and may be an alternative to docetaxel-based combination therapy. Results from the JBCRG M06 trial research, which compares taxanes combination with T plus P with E combined with T plus P in first-line therapy, are still pending. Clinical trial information: UMIN000012232 .

Phase 2 small cell lung cancer (SCLC) cohort of a phase 1b/2 trial of a liposomal formulation of eribulin in combination with nivolumab.

8593 Background: E7389-LF is a liposomal formulation of the microtubule dynamics inhibitor eribulin. Combining E7389-LF with an immune checkpoint inhibitor (ICI; eg, nivolumab) may improve antitumor response via vascular remodeling. The phase 1b part of the open-label Study 120 evaluated the dosing and safety of E7389-LF in combination with nivolumab in patients (pts) with solid tumors. The phase 2 part assessed efficacy and safety in disease cohorts; herein, we report results from the SCLC cohort. Methods: Pts with unresectable and measurable SCLC who had progression during or after 1st-line (1L) platinum-based chemotherapy with/without an ICI were enrolled to the SCLC cohort of the phase 2 part of Study 120. Pts received E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg IV Q3W. The primary objective of the phase 2 part was to assess the objective response rate (ORR). Secondary objectives included assessments of safety and progression-free survival (PFS); exploratory objectives included the disease control rate (DCR), overall survival (OS), and biomarker analysis. Tumor response was assessed by investigators per RECIST v1.1 Q6W. All adverse events (AEs) were monitored and recorded. Results: In the SCLC cohort, 34 pts were enrolled; the median age was 66.0 years (range 46–81). At data cutoff (May 31, 2022), 5 pts (14.7%) were undergoing treatment. Discontinuations occurred in 29 pts (85.3%)—26 (76.5%) primarily due to disease progression, 3 (8.8%) due to an AE. Efficacy analyses included 33 pts, as 1 pt had their diagnosis of SCLC changed to a different cancer type after being enrolled. Of the 33 evaluable pts, 27 (81.8%) had an ICI as part of their prior 1L therapy. The ORR of E7389-LF in combination with nivolumab was 24.2% (95% CI 11.1–42.3) in the evaluable population; the DCR was 75.8% (95% CI 57.7–88.9). Median PFS was 3.98 mos (95% CI 2.63–4.40); the 6-mo PFS rate was 27.7% (95% CI 13.0–44.6). At a median follow-up period of 10.6 mos, median OS was not reached (95% CI not estimable); the 6-mo OS rate was 90.9% (95% CI 74.4–97.0). Treatment-related, treatment-emergent (TE)AEs of any grade and of grade ≥3 severity occurred in 97.1% (n = 33) and 82.4% (n = 28) of the 34 enrolled pts, respectively; the most common treatment-related TEAE was neutropenia (any grade: 58.8% [n = 20]; grade ≥3: 52.9% [n = 18]). The neutrophil count nadir occurred around cycle 1 day 8. TEAEs led to dose reduction of E7389-LF in 19 pts (55.9%). Withdrawal of E7389-LF or nivolumab occurred in 5 pts (14.7%): acute kidney injury, cough, myocarditis, pneumonitis, and radiation pneumonitis (n = 1 each). Changes in vascular and immune-related plasma markers were observed. Conclusions: E7389-LF in combination with nivolumab showed notable antitumor activity as 2L therapy in pts with SCLC, as evidenced by the notable ORR of 24.2%. No new safety signals were observed for this combination. Clinical trial information: NCT04078295 .

Clinical outcomes of patients with metastatic breast cancer treated with eribulin: A real-world evidence study from China.

e13126 Background: Eribulin is a novel synthetic analog of halichondrin B that acts as a microtubule inhibitor and inhibits the G2-M growth phase. Eribulin was approved for metastatic breast cancer (MBC) based on the landmark phase 3 EMBRACE trial (Cortes et al, Lancet 2011; NCT00388726); however, only a small number of Asian patients were included in that trial. Therefore, in this real-world study, we retrospectively assessed the clinical outcomes of Chinese patients with MBC who received eribulin. Methods: Adult patients with MBC who received eribulin as several lines of therapy were retrospectively analyzed. Socio-demographic, clinical, pathology, imaging, and therapy records were reviewed. Progression-free survival (PFS) and tumor response were evaluated. Results: A total of 85 patients were included. The median age was 45 years (range, 21–63). Eribulin was used as a first, second, third, and fourth or more chemotherapy agent in 13 (15.3%), 16 (18.8%), 11 (12.9%) and 45 (52.9%) of patients with MBC, respectively. Eribulin was monotherapy in 32.9% of patients; eribulin plus anti-HER2 targeted therapy was used in 9.4% of patients; eribulin plus immunotherapy was used in 5.9% of patients; eribulin plus other chemotherapy was used in 36.5% of patients, and eribulin plus antiangiogenic therapy was used in 9.4% of patients. The objective response rate (ORR) was 28.2% overall. By number of lines of therapy, the first-line ORR was 38.5% and the second-line ORR was 37.5%. On subgroup analysis, ORR of patients with liver metastasis and lung metastasis was 43.9% and 38.6 %, respectively. By molecular classification, the ORR of patients with HR+/HER2− disease was 66.7%; among patients with HER2+ disease, 32.6%; and among patients with triple-negative BC, 13.3%. The 6-month PFS rate was 33.6% overall. By number of lines of therapy, the 6-month PFS rate among patients who received eribulin as first-line treatment was 67.7% and among patients who received eribulin as second-line treatment, 38.3%. Among patients who received eribulin monotherapy, the 6-month PFS rate was 21.4% and among patients who received eribulin combination therapy, 41.2%. No adverse reactions related to neutrophils were reported. Conclusions: This real-world retrospective study suggests that eribulin was effective in Chinese patients with MBC with a range of prior lines of chemotherapy, supporting the use of eribulin in the treatment of Chinese patients with MBC.

429 Eribulin Synergizes with STING Agonists by Enhancing Type 1 Interferon Expression and Improves Antitumor Efficacy as Combination Treatment

OBJECTIVES/GOALS: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks effective targeted treatment options. TNBC's greater degree of immunogenicity than other breast tumors makes immunotherapy a viable strategy. Strategies to improve the immunotherapy response includes targeting the cGAS-STING innate immune pathway with STING agonists. METHODS/STUDY POPULATION: We have previously shown in vitro that eribulin, a microtubule destabilizer currently used in the treatment of TNBC, functions as an indirect STING agonist because it promotes the release of mitochondrial DNA into the cytoplasm. Separately, eribulin also significantly enhances type I interferon expression induced by STING agonists measured by qRT-PCR through a second TBK1-dependent mechanism downstream of STING activation through detecting higher amounts of phosphorylated IRF-3 by western blot protein analysis. Mechanisms of eribulin-mediated interferon expression occur in immune and TNBC cells and are shared with other microtubule destabilizers but not with the microtubule stabilizing agent paclitaxel. RESULTS/ANTICIPATED RESULTS: We determine that the enhancement of type I interferon expression by eribulin is pharmacologically synergistic with multiple STING agonists. The significant enhancement by eribulin led us to evaluate the antitumor efficacy of eribulin in combination the STING agonist ADU-S100 in a challenging spontaneous mammary tumor model MMTV-PyVT. We show that the combination treatment significantly decreased tumor growth which allowed for longer survival compared to other groups. This is particularly interesting because of our previous studies showing that eribulin alone, but not paclitaxel, promotes the activation of CD4+ T-cells in the spleen and draining lymph nodes of BALB/c mice with 4T1 tumors through flow cytometric analysis. DISCUSSION/SIGNIFICANCE: These data contribute to accumulating evidence that there are important mechanistic differences between the microtubule targeted chemotherapeutics currently used in the treatment of TNBC and suggest that eribulin can act as an immune adjuvant in addition to its anti-mitotic effect.

Abstract P3-02-03: A phase Ib trial of bintrafusp alfa and eribulin in patients with metastatic triple negative breast cancer (TNBC)

Abstract Background: Metastatic TNBC is an aggressive breast cancer subtype with poor prognosis and limited systemic therapy options. While pembrolizumab in combination with chemotherapy is approved for PD-L1 positive TNBC, limited immunotherapy options exist for patients with progressive and/or PD-L1 negative disease. TGFβ released by cancer cells and stromal fibroblasts attenuates the intrinsic antitumor potential of immune cells within the tumor microenvironment mediating resistance to immunotherapy. Consequently, inhibition of TGFβ signaling could potentially enhance antitumor responses to anti-PD-L1/PD-1 therapies. Bintrafusp alfa is a bifunctional fusion protein composed of the extracellular domain of TGF-β receptor II (a TGF-β “trap”) fused to a human IgG1 monoclonal antibody blocking programmed cell death ligand 1. Preclinical studies have shown that eribulin downregulates TGFβ by phosphorylation of Smad proteins. Therefore, combining eribulin with bintrafusp alfa may have a synergistic effect. This study evaluated the combination of bintrafusp alfa with eribulin in patients with metastatic TNBC. Methods: This is a phase 1b, open label, single center study evaluating bintrafusp alfa in combination with eribulin in patients with metastatic TNBC who had relapsed/progressed on prior therapies. Patients with ER/PR ≤10% with measurable disease were enrolled. Patients who received prior anti-PD-1/PD-L1 therapies in the metastatic setting were excluded. Patients received bintrafusp alfa 1200 mg intravenously every 2 weeks in combination with eribulin (1.4 mg/m2 (dose level 1), 1.1 mg/m2, or 0.7 mg/m2) on days 1, 8, 22, 29 on every 6-week cycle. Primary objectives were to determine the recommended phase II dose (RP2D) as well as to evaluate the safety and tolerability of eribulin in combination with the fixed dose of bintrafusp alfa. Secondary objective was to determine the overall response rate (ORR) according to RECIST 1.1. Bayesian optimal interval (BOIN) design was employed to identify the RP2D. Toxicities assessed using CTCAE v4.03. Tumor assessments were performed every 6 weeks. Results: A total of 25 patients were enrolled on the study. Twenty-one patients were evaluable (3 screen failures, 1 received only one dose of study treatment). Median age 59 (range 27-85). Median number of prior therapies 2 (range 0-8). The most common reason for protocol discontinuation was disease progression (n = 15, 71%). Four patients experienced dose limiting toxicities (DLTs); 3 with decreased neutrophil count and 1 with increased aspartate aminotransferase. Five patients (24%) experienced grade 4 toxicities (increased aspartate aminotransferase, hypokalemia, hypophosphatemia, neutropenia). Nine patients (43%) experienced grade 3 toxicities. Three patients (14%) discontinued study due to toxicity. Total of 2 deaths were observed, none related to treatment. Most common toxicities (any grade) include anemia (n = 13 patients), elevated aspartate aminotransferase (11), neutropenia (n = 10), elevated aminotransferase (9), headache (n = 9), hypokalemia (n = 8), hyperglycemia (n = 8), leukopenia (n = 8), and fatigue (n = 8). RP2D was eribulin 1.1 mg/m2 with bintrafusp alfa 1200 mg. Six patients had PR (28.6%), 2 had SD (9.5%) and 12 had PD (57.1%) as the best response. One patient withdrew before response evaluation. Median PFS was 1.7 months (95% CI: (1.2, 5.9) and median OS was 11.1 months (95%CI: (5.2, 15.7). Conclusions: The combination of bintrafusp alfa with eribulin has manageable safety profile with meaningful clinical activity in patients with TNBC. Further studies evaluating TGF inhibitors in breast cancer are warranted. Citation Format: Senthil Damodaran, Diane Liu, Jill Schwartz, Vicente Valero, David Ramirez, Sadia Saleem, Naoto T. Ueno, Nuhad K. Ibrahim, Meghan S. Karuturi, Rashmi K. Murthy, Stacy Moulder, Jennifer K. Litton. A phase Ib trial of bintrafusp alfa and eribulin in patients with metastatic triple negative breast cancer (TNBC) [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 P3-02-03.