Treatment Of Metastatic Breast Cancer Research Articles

Abstract PO1-11-02: Reporting of Post-protocol Therapies in Metastatic Breast Cancer Registration Clinical Trials: A Systematic Review

Abstract BACKGROUND As the treatment for metastatic breast cancer (MBC) often includes sequential lines of therapy, data on post-protocol treatment in clinical trials are valuable in the assessment of long-term outcome. The objective of this study was to assess the reported data on post-protocol therapy in clinical trials supporting US Food and Drug Administration (FDA) approval of drugs for MBC. METHODS We identified all initial and subsequent published trials supporting FDA approved indications for MBC between 1/2000-2/2023. Collected data included study design, patient characteristics and whether reporting on post-protocol therapy was available. Differences in study design and population between studies with and without data on post-protocol therapy were evaluated. FINDINGS A total of 41 indications for MBC were identified. Supporting studies comprised 20,152 patients. Data were evaluated from 241 publications or abstracts. Reporting of post progression therapy was available for 21 (51%) indications. Of these, post-progression therapy data were often partial and the appropriateness of the therapy could not be evaluated. At the time of FDA approval, data on overall survival (OS) were reported only in 17 (41%) studies. Of these, in 8 studies OS was significantly improved, in 7 studies OS was not improved and 2 studies were single arm. Differences between studies with and without data on post progression therapy are presented in the Table. Studies with OS as their primary endpoints were associated with significantly higher reporting of post-protocol therapy, while studies with both OS and progression free survival (PFS) as their primary endpoint had low reporting rate. There were no other statistically significant differences. Reporting post-protocol therapy has not changed over time with reported data in 50% and 52% studies between 2000-2010 and 2011-2023, respectively. CONCLUSIONS Data on post progression therapy in trials supporting FDA approval of drugs for MBC are available in fewer than half of indications. Reported data are often partial and may not include sequential therapies consistent with standard of care. As subsequent lines of therapy may have a crucial role in patients' outcome, post protocol reporting should be included in the regulatory submission and be made available publicly. Differences between studies with and without data on post progression therapy Citation Format: Shlomit Shachar, Yasmin Korzets, Daniel Shepshelovich, Noa Zlotchover, Eitan Amir, Ariadna Tibau, Hadar Goldvaser. Reporting of Post-protocol Therapies in Metastatic Breast Cancer Registration Clinical Trials: A Systematic Review [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 PO1-11-02.

Abstract PO2-27-06: ANXA9 facilitates the exocrine secretion of S100A4 and promotes pleural metastasis in breast cancer

Abstract Metastasis to distant organs stands as the primary contributor to mortality in cases of breast cancer. While localized breast cancer boasts a 5-year survival rate of roughly 99%, this figure drastically declines to approximately 26% for patients afflicted with distant metastasis. Regrettably, the current therapeutic landscape lacks efficacious and targeted interventions for the treatment of metastatic breast cancer. Our investigation has revealed a significant upregulation of S100A4 in metastatic breast cancer tissues, with notably high expression observed in the malignant pleural effusion of patients in advanced stages of the disease. Upon acceptance of the effective treatment, the expression of S100A4 in malignant pleural effusion decreased, along with a decrease in several cytokines, including IL-6, IL-8, CCL2, and CCL5. The breast cancer cellular models demonstrated that ANXA9 has the ability to regulate the excretion of S100A4 from cells into the surrounding medium. Similarly, the mice model of pleural metastasis indicated that the downregulation of ANXA9 (sh-ANXA9) resulted in decreased levels of S100A4 and cytokines IL-6, IL-8, CCL2, and CCL5 in the mice's hydrothorax. Additionally, our findings suggest that ANXA9 regulates the excretion of S100A4 through phosphorylation of ANXA9. The cellular membrane harbored phosphorylated ANXA9, which exhibited two phosphorylation sites. Upon mutation of these sites, the level of ANXA9 phosphorylation decreased, leading to a reduction in the exocrine release of ANXA9 from cells into the medium. Our research further revealed the significant involvement of ANXA9 in facilitating the progression of breast cancer, thereby suggesting that therapeutic interventions targeting ANXA9 could prove efficacious in treating metastatic breast cancer. This work was supported by Shanghai Sailing Program to Dengfeng Li (No. 20YF1437800), grant from the National Natural Science Foundation of China to Dengfeng li (No. 82103454) and grant from the National Natural Science Foundation of China to Lin Fang (No. 82073204). Citation Format: Xiqian Zhou, Dengfeng Li, Lin Fang, Junyong Zhao. ANXA9 facilitates the exocrine secretion of S100A4 and promotes pleural metastasis in 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 PO2-27-06.

Abstract PO3-12-05: Patient (pt)-provider communication challenges about side effects/toxicities from metastatic breast cancer (mBC) treatments

Abstract Introduction: Treatment decisions for ER+/HER2- mBC may be influenced by pt knowledge about treatment side effects, which is shaped by pt-provider communication. We conducted a survey of pts with ER+/HER2- mBC to better understand pt expectations and experiences of treatment toxicities, the extent they were discussed by the pts’ medical team (MT), and the sources/types of side effect information pts prefer. Methods: The 55-question, online ESR1 QUAlity of Life Survey 3 (EQUALS 3) survey was emailed to US pts from the Cure Media Group and authors’ contacts, and posted to private BC Facebook and Twitter pt groups for 2 weeks in June 2023. Eligible pts had ER+/HER2- mBC and reported changing treatments due to progression. Pts received a $10 gift card at survey completion. Survey answers were descriptively summarized. Results: 213 pts completed the survey; they were < 60 yrs of age (77%), White (44%) or Hispanic/Latino (48%), peri-/postmenopausal (54%), and urban-area residents (51%); and had college education (71%) and household income >$50K (66%). Most pts were on 2nd (36%) or 3rd+ (51%) therapy lines. Current mBC treatments were endocrine therapy ± targeted agent (70%), antibody-drug conjugate (8%), chemotherapy (11%), and others (10%). Most pts’ oncologists were female (65%), BC specialists (51%), and from an academic hospital (61%). Only half (49%) of surveyed pts felt extremely/very comfortable discussing side effects with their MT. Although 86% felt well informed about treatment toxicities, MTs did not proactively ask about pts’ greatest concerns on side effects for 15% of pts, nor about what side effects pts would find tolerable or intolerable for 25%. Oncologist/MT inquired about acceptability of side effects most often with treatment change (25%) or when brought up by the pt (20%), and at every single visit for only 19% of pts. Most pts felt extremely prepared for treatment toxicities (78%) and well prepared to manage them (86%), but 19% of pts still felt that their MT did not provide optimal guidance on managing potential side effects. Pt-centered conversations were most often missing: what rare but serious side effects to expect (44%), how to deal with potential side effects (39%), and what common side effects to expect (32%). Pts also reported that the likelihood of experiencing side effects (40%), what rare but serious side effects to expect (39%), and how to deal with potential side effects (28%) were not well presented. To facilitate treatment decisions, pts would like more time discussing treatment options (48%) or side effects (39%); additional written or visual resources on side effects (29%, 23%, respectively) or efficacy (39%, 8%); and the ability to ask questions and receive meaningful answers (39%), talk to other pts (20%), or listen to videos of their stories (11%). Pt testimonials (45%), toxicity descriptions/examples (42%), and toxicity management strategies (36%) were the most common additional forms of information that pts would like to have had on side effects. Conclusion: In this survey of pts with ER+/HER2- mBC, not all pts were comfortable discussing treatment toxicities with their MT, but MTs are mostly addressing side effects. However, there is still room for communication improvement and additional forms of toxicity information are needed for optimal decision-making. Despite generally feeling well prepared for toxicities, a significant proportion of pts report that the range and specifics of side effects and how to manage them were missing or not well presented in MT discussions. This survey highlights the need to improve both provider and pt education with the goal of effectively communicating toxicity specifics of mBC therapies, as well as the need for standardized pt education tools detailing risks and benefits of mBC therapies to assist pts in shared decision-making conversations. Citation Format: Sarah Sammons, Jane Meisel, Timothy Pluard, Kelly Shanahan, Fumiko Chino, Dario Trapani, Dominic Carroll, Monica Kozlowski, Elizabeth Attias, Nicole Kuderer. Patient (pt)-provider communication challenges about side effects/toxicities from metastatic breast cancer (mBC) treatments [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 PO3-12-05.

Abstract PO2-10-08: Contemporary HER2-Positive MBC Treatment Recommendations Among Community Healthcare Professionals: Analysis of an Online Interactive Decision Support Tool

Abstract Background: The management of HER2-positive (HER2+) metastatic breast cancer (MBC) has continued to evolve, with multiple FDA approvals of novel HER2-targeted agents since late 2019. Considering the growing HER2+ MBC treatment armamentarium, we sought to identify current practice patterns among community healthcare professionals (HCPs) for HER2+ MBC by comparing HCP and key opinion leader (KOL) treatment recommendations using an online decision support tool. Methods: An online decision support tool was developed with input from 5 KOLs to provide therapy recommendations for 630 HER2+ MBC patient case scenarios based on conventional considerations including distribution of metastatic disease, treatment history, duration of response, and specific comorbidities. HCP tool users entered specific patient criteria to define a case along with their intended management for each case. The tool then showed 5 KOL recommendations for the user-entered patient case, and the users were asked to indicate if the expert recommendations confirmed or changed their intended approach. An analysis of expert recommendations and user-selected therapy was performed. Results: Between November 2022 and July 2023, 313 patient cases were entered by 242 participating HCPs. HCP and KOL treatment recommendations were frequently discordant (Table). For patients with de novo HER2+ MBC (n = 55), there was strong concordance (63%; P = .0001) between HCP and KOL recommendations. However, weak treatment selection concordance (53%; P < .0001) was observed for patients with disease progression after standard neoadjuvant/adjuvant therapy with chemotherapy plus HER2-targeted agents (n = 57). In the second-line setting, 43% concordance was observed for patients with non‒central nervous system (CNS) disease progression without CNS progression after first-line therapy with THP (n = 67; P < .0001), whereas 61% concordance was observed for patients with non-CNS and CNS disease progression after first-line therapy with THP (n = 61; P < .0001). In the third-line setting, 31% concordance was observed for patients with non-CNS disease progression without CNS progression (n = 32; P < .0001), and 47% concordance was observed for patients with non-CNS and CNS disease progression (n = 19; P = .0009). For HCPs whose treatment plan did not match KOL recommendations in these scenarios, 62% indicated that KOL recommendations confirmed or changed their intended therapy, but 19% indicated that there were barriers to implementing those recommendations. Conclusions: These data suggest ongoing challenges to optimally incorporate novel HER2-targeted therapies in the care of patients with HER2+ MBC, particularly in the second line and beyond, but an online tool providing KOL advice on specific patient scenarios confirmed or changed the clinical approach for a majority of HCPs. Thus, continued development of resources for HCPs, including online decision support tools, may be increasingly important given the rapidly evolving treatment landscape. Table. Summary of Treatment Choices by KOLs or HCPs for Select Patient Scenarios Citation Format: Kristen Rosenthal, Sara Hurvitz, Komal Jhaveri, Heather McArthur, Sara Tolaney, Timothy Quill. Contemporary HER2-Positive MBC Treatment Recommendations Among Community Healthcare Professionals: Analysis of an Online Interactive Decision Support Tool [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 PO2-10-08.

Abstract PO1-10-06: Understanding clinical meaningfulness in metastatic breast cancer treatment decision-making: experiences and perspectives of patients, caregivers, and clinicians

Abstract Background: While many clinical and non-clinical factors inform metastatic breast cancer (mBC) treatment recommendations; patient preferences, values, and care goals also influence how treatment options are weighed, deliberated, and decided upon. Additionally, in the mBC care setting, clinical meaningfulness and clinically meaningful outcomes (e.g., survival, quality-of-life) are important factors to consider along the care continuum. However, the extent to which patients and their oncology care team align on the interpretation and use of these concepts during treatment decision-making has not been well elucidated. This study examined perspectives on the concepts of (i) clinical meaningfulness and (ii) clinically meaningful outcomes associated with mBC treatment among five key stakeholder groups: patients, caregivers, oncologists, advanced practice providers (APPs), and oncology nurses. Methods: Qualitative semi-structured in-person and web-based focus groups were conducted between March and June 2023 among: (i) people living with mBC; (ii) unpaid or informal caregivers to people with mBC; and providers involved in the care of patients with mBC, including (iii) oncologists, (iv) APPs (i.e., physician assistants and nurse practitioners), and (v) oncology nurses. Discussion guides were developed to elicit stakeholder perspectives on clinical meaningfulness and clinically meaningful outcomes to help identify areas of convergence and divergence between and within stakeholder groups. All discussions were audio recorded and transcribed. The constant comparative approach was used to identify key themes. Results: Twenty-two focus groups were conducted with 50 patients, 24 caregivers, 8 oncologists, 13 APPs, and 17 oncology nurses. Overall, patients and caregivers were unfamiliar with the concepts of clinical meaningfulness and clinically meaningful outcomes, underscoring the critical need for using accessible and patient-friendly terminology in treatment decision-making discussions. While some providers were familiar with these concepts, they reported not using these terms when discussing treatment recommendations with patients. Although some provider participants thought clinical meaningfulness described quantitative endpoints (e.g., additional months of survival), participants across all stakeholder groups described patients’ abilities to achieve life goals (e.g., participation in milestone events and social activities, ability to travel) as paramount. Recommendations for improving treatment decision-making discussions included taking a patient-centered approach, with inclusive, dynamic patient-provider discussions and continuous evaluation of patient priorities across the care continuum, not just at diagnosis. Meaningful outcomes beyond overall survival need to be considered, including quality of life, progression-free survival, minimal or manageable side effects, and improvement in symptom burden and functioning. Across all stakeholders, participants stressed that outcomes considered meaningful are highly individualized and dynamic, evolving over time as patients move through the treatment journey and life stages. Conclusions: Clinical meaningfulness is poorly understood and not often considered in the clinical setting when making mBC treatment decisions, highlighting a need for accessible and patient-friendly terminology in mBC treatment decision-making conversations. While participants valued overall survival, the importance of meaningful outcomes that support patients’ quality of life was emphasized. Study findings can be used to inform both practice and clinical research to better capture meaningful outcomes for patients. Citation Format: Stephanie Graff, Emily Freeman, Meaghan Roach, Rozanne Wilson, Ricki Fairley, Mary Gullatte, Jeanne Stemland, Becky Chan, Paulina Wochal, Julie Katz, Suepattra May-Slater. Understanding clinical meaningfulness in metastatic breast cancer treatment decision-making: experiences and perspectives of patients, caregivers, and clinicians [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 PO1-10-06.

Abstract PO3-06-09: A phase II study of nivolumab plus ipilimumab and androgen receptor antagonist bicalutamide to stimulate thymic T cell generation in HER2-negative metastatic breast cancer

Abstract Background: Systemic chemotherapy is used commonly in breast cancer and is associated with lymphopenia, potentially limiting efficacy of immune checkpoint blockade. The androgen receptor (AR) serves as a negative regulator of thymic function. AR antagonists, such as bicalutamide, may stimulate thymic production of naïve T-cells, which may help to restore lymphocyte diversity and augment immunotherapy response. The AR is expressed in 50% of hormone receptor negative (HR-) metastatic breast cancer (MBC) and >75% of HR+ MBC, and bicalutamide is clinically active with stable disease as best response. We hypothesize that bicalutamide could be combined with dual immune checkpoint blockade (anti-programmed death 1, nivolumab; plus anti-cytotoxic T-lymphocyte antigen 4, ipilimumab), stimulating T-cell production and resulting in durable clinical response. Methods: This is a phase II Simon 2-stage trial of nivolumab (240 mg IV q2w), ipilimumab (1 mg/kg IV q6w), and bicalutamide (150mg oral daily) for first- or second-line treatment of HER2-negative MBC (NCT03650894). The primary endpoint is iRECIST 24-week clinical benefit rate (CBR), evaluated separately for HR+ MBC (n=15) and AR+/HR- MBC (n=15). An optimum Simon 2-stage design (80% power, 5% one-sided alpha) is employed to evaluate an alternative hypothesis of >50% CBR compared to historical control of < 30% CBR for conventional chemotherapy, with expansion of each cohort planned if ≥6/15 responses are observed. Secondary outcomes include best overall objective response rate (ORR), progression-free and overall survival (PFS,OS), and safety. Exploratory endpoints include assessment of peripheral T-cell counts and T cell receptor excision circles (TREC PCR, Mayo Laboratories, a surrogate of thymic T-cell production) over time. Results: Durable responses were observed, with an ongoing complete response at 41+ months in a patient who discontinued due to toxicity (AR+/HR- cohort, PD-L1 CPS score 3%). Therapy was tolerated with a toxicity profile consistent with prior studies of ipilimumab & nivolumab, with five subjects (19%) requiring treatment discontinuation related to toxicity. Outcomes by cohort and PDL1 are summarized in Table 1. Using mixed effects linear models, therapy was associated with a significant expansion of CD8+ T cells (23/mcL/month, p< .01) but not CD3+ T cells (7/mcL/month, p=.59) or CD4+ T cells (4/mcL/month, p=.65). Baseline TREC counts were higher in younger participants (mean: < 50y 2156/mcL; 50-65y 961/mcL; >65y 311/mcL). TRECs did not increase globally, however TREC expansions were observed in several younger participants. Conclusions: The regimen of ipilimumab, nivolumab, plus bicalutamide is safe and clinically active in 1st/2nd-line HER2-negative MBC. Neither cohort crossed the Simon futility barrier for cohort expansion, however durable responses were observed including in PD-L1-negative patients, highlighting the unmet need for biomarkers to identify candidates for chemotherapy-sparing checkpoint blockade. Further research is indicated to evaluate the impact of AR antagonists on T-cell function and thymic stimulation in MBC. Acknowledgements: Drug and study support was provided by Bristol-Myers Squibb and The BMS International Immuno-Oncology Network (II-ON). Clinical outcomes XX XX HR: hormone receptor; AR: androgen receptor; CPS: PD-L1 combined positive score Citation Format: David Page, Alexander Hall, Krystle Collins, Nicole Moxon, Staci Mellinger, Tracy Kelly, Aysha Kelley, Nicole Fredrich, Amanda Seino, Gabriella Liberatore, Alison Conlin, Zheng Topp, Kelly Perlewitz, Sasha Stanton, Walter Urba, Yaping Wu, Maritza Martel, Zhaoyu Sun, Yoshinobu Kogushi, William Redmond, Tiffany Traina, Ayca Guculp. A phase II study of nivolumab plus ipilimumab and androgen receptor antagonist bicalutamide to stimulate thymic T cell generation in HER2-negative 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 PO3-06-09.

Abstract PO5-05-07: Efficacy and safety of first line CDK4/6i plus endocrine therapy for patients with HR+/HER2- metastatic breast cancer:initial real-world experience at Ho Chi Minh city oncology hospital, Viet Nam

Abstract Background The cyclin-dependent kinases (CDK)4/6 inhibitors (CDK4/6i) palbociclib and ribociclib have been available in Viet Nam since 2021 for the treatment of hormone receptor-positive metastatic breast cancer (MBC). Data regarding CDK4/6i benefit in Vietnamese MBC are sparse. This study evaluated the impact of CDK4/6i in first-line HR+/HER2− MBC using real-world experience at Ho Chi Minh City Oncology Hospital. Methods A single-institution study analyzed retrospective data from 108 patients treated with palbiciclib or ribociclib with endocrine therapy in first-line in HR+/HER2– MBC patients at Ho Chi Minh city oncology hospital. Patient characteristics, PFS, treatment response, and toxicity profiles were analyzed. Results Baseline patients’ characteristics are detailed in Table 1.The median follow-up was 12.5 months (95% CI: 10.9-13.3). Best responses by the line of therapy are in Table 2. The median PFS has still not been reached. The PFS rates at 6, 12 and 18 months were 94.4%, 93.5% and 91.5%, respectively. Patients with bone-only metastasis have a better PFS than visceral metastasis (p = 0.059). Patients with recurrent disease had shorter PFS (p = 0.083) than those presenting with de novo metastasis. The most common reasons for toxicity were neutropenia (92.6%), anemia (35.2%), thrombopenia (22.2%) and the incidence of diarrhea was only 2,8%. None were related to QTc-prolongation Conclusion The real-world effectiveness and safety with CDK4/6 inhibitors in our institution HR+/HER2– MBC patients mimics that observed in the clinical trials. This finding supports the use of CDK4/6i in combination with endocrine therapy as standard of care for HR+/HER2- MBC in Viet Nam. The study also suggests the need for more study of under-represented minority populations. Further studies are ongoing to validate these findings incorporating additional cancer centers. Keywords: advanced/metastatic breast cancer, Asia, CDK4/6 inhibitors, real world Table 1. Patient Demographics and Baseline Disease Characteristics (N=108) Characteristics N (%) Age, y: Median 52 Stage Recurrent from earlier stage, stages 0–III 67 (62) De novo, newly diagnosed stage IV at enrolment 41 (38) DFI < 12 months 5 (4.6) 12-24 months 12 (11.1) > 24 months 51 (47.2) No. of metastatic sites 1 49 (45.4) 2 37 (34.3) ≥ 3 22 (20.4) Metastasis pattern Bone only 30 (27.8) Other 78 (72.2) CDK4/6i Palbociclib 35 (32.4) Ribociclib 73 (67.6) Partner ET AIs 94 (87) Fulvestrant 14 (13) Table 2. Best responses of therapy (N=108) Best responses (N,%) CR 2 (1.9) PR 29 (26.9) SD 67 (62.1) PD 10 (9.3) Total 108 (100) ORR 31 (28.8) CBR 76 (70.3) Table. Citation Format: Hoang-Quy Nguyen, Hong-Duc Phan-Thi, Thi-Hong-Van Le. Efficacy and safety of first line CDK4/6i plus endocrine therapy for patients with HR+/HER2- metastatic breast cancer:initial real-world experience at Ho Chi Minh city oncology hospital, Viet Nam [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 PO5-05-07.

Abstract PO5-21-09: Clinical outcomes by age subgroups in the phase 3 TROPiCS-02 study of sacituzumab govitecan vs treatment of physician’s choice in HR+/HER2‒ metastatic breast cancer

Abstract Background Sacituzumab govitecan (SG) is a Trop-2directed antibody-drug conjugate approved for second-line or later (2L+) treatment of metastatic triple-negative breast cancer in multiple countries and for 2L+ treatment of HR+/HER2‒ (IHC 0, 1+, or 2+/ISH) metastatic breast cancer (mBC) in the US. SG significantly improved progression-free survival (PFS) and overall survival (OS) vs treatment of physician’s choice (TPC) in patients (pts) with pretreated, endocrine-resistant HR+/HER2‒ mBC in the TROPiCS-02 study. The incidence of HR+/HER2‒ mBC increases with age, especially after 65, and older pts often have poorer prognosis due to comorbidities, increased toxicity, and reduced efficacy of chemotherapy. In TROPiCS-02, pts aged ≥ 65 years (yr) derived consistent PFS benefit and clinically meaningful improved OS with SG vs TPC. In this analysis, we present additional efficacy and safety outcomes by age subgroup. Methods Pts with HR+/HER2‒ mBC who had received at least 1 endocrine therapy, taxane, and CDK4/6 inhibitor, and 2 to 4 prior lines of chemotherapy for mBC, were randomized to either SG (10 mg/kg IV days 1 and 8, Q3W) or TPC. The primary end point was PFS, and secondary end points included OS, objective response rate (ORR), and safety. A post hoc analysis was conducted by age subgroups (< 65 vs ≥ 65, < 75 vs ≥ 75). Results In total, 543 pts were randomized to the SG (n = 272; 73 [27%] ≥ 65, 16 [6%] ≥ 75) and TPC (n = 271; 67 [25%] ≥ 65, 8 [3%] ≥ 75) groups. Baseline characteristics were generally similar across treatment arms in each age subgroup, but a higher proportion of pts had performance status 1 vs 0 in the ≥ 65 vs < 65 and ≥ 75 vs < 75 subgroups, respectively. The data cutoff date was July 1, 2022. SG demonstrated longer median PFS and OS vs TPC across age subgroups. Hazard ratios (HR) for PFS with SG vs TPC were 0.69, 0.59, 0.70, and 0.30 for the < 65, ≥ 65, < 75, and ≥ 75 subgroups, respectively (Table). The HR for OS were 0.81, 0.80, 0.82, and 0.56 in these subgroups, respectively (Table). Median duration of response (DoR) was also longer with SG vs TPC across age subgroups, although median DoR was not estimable in the ≥ 75 subgroup (Table). ORR was higher with SG vs TPC, except in the ≥ 75 subgroup (Table). Safety was generally similar with SG vs TPC across subgroups with the following differences. Grade ≥ 3 treatment-emergent adverse events were more common in the ≥ 75 subgroup than the other subgroups (SG, 81% in ≥ 75 vs 68%-73% for all others; TPC, 71% in ≥ 75 vs 60%-61% for all others). TEAEs leading to dose reduction were also more common in pts treated with SG in the ≥ 75 subgroup, but were consistent across other subgroups (Table). However, sample sizes in the ≥ 75 subgroup were small, which limits interpretation (Table). TEAEs leading to treatment discontinuation were more common in older pts, irrespective of treatment group (Table). Conclusions SG showed benefit in PFS and OS vs TPC in pts with HR+/HER2‒ mBC across age subgroups, consistent with the intent to treat population. SG was associated with a slight increase in toxicity for elderly pts, as expected. SG demonstrated a favorable benefit/risk profile, with efficacy benefit and acceptable toxicity, for elderly pts. Table. Citation Format: Aditya Bardia, Peter Schmid, Sara Tolaney, Frederik Marmé, Javier Cortés, Theresa Valdez, Hao Wang, Wendy Verret, Hope Rugo. Clinical outcomes by age subgroups in the phase 3 TROPiCS-02 study of sacituzumab govitecan vs treatment of physician’s choice in HR+/HER2‒ 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 PO5-21-09.

Abstract PO3-06-10: Real World Outcomes with Sacituzumab Govitecan in Metastatic Triple Negative Breast Cancer Patients: A Multi-Institution Study

Abstract Background Sacituzumab govitecan (SG) is approved for treatment of metastatic triple negative breast cancer (mTNBC) in the second line and beyond. Little is known about the real-world outcomes of SG. We aim to evaluate the real-world effectiveness and toxicity outcomes of SG in heterogenous heavily pretreated mTNBC patients (pts) to investigate the consistency of the outcomes in comparison to the clinical trial population. Methods A multi-center retrospective study of pts with mTNBC treated with SG in the US from January 2021 until May 2023 was conducted. Demographics and clinicopathological variables including site of metastases, prior lines of therapy, relative dose intensity (RDI), adverse events (AEs), HER2 immunohistochemistry (IHC) score at time of metastasis, clinical response, clinical benefit rate (CBR) defined as (complete response, partial response (PR) or stable disease (SD) > 6 months) and last follow-up were collected. For continuous variables, Mann-U Whitney and Kruskal Wallis tests were used to compare mean, median, standard deviation, and range. For categorical variables, Fisher's exact tests and Pearson Chi-square tests were used. Univariate and multivariate cox regression models examined RDI and survival outcomes. SAS v9.4 was used to perform statistical analysis at a significance level of 0.05. Results A total of 111 pts were analyzed. The median age was 58 years (range 29-84). The majority of pts were heavily pretreated: 59.1% received >3 prior lines of treatment (Tx) in the metastatic setting, 54.1% received prior immune checkpoint inhibitor (ICI), 8.1% received prior olaparib. 55% of pts had significant disease burden defined by >=3 organs involved by metastatic disease, with 22.5% having brain metastasis at the time of initiation of SG. Of note, 51% had primary refractory disease defined as relapse within 12 months of completion of adjuvant chemotherapy. 98.1% experienced any grade AEs, with the most common being anemia 63.1%. Grade 3 AEs occurred in 51.4% pts with neutropenia being the highest 32.4% followed by anemia 14.4%, diarrhea 7.2% and fatigue 7.2%. Tx interruptions and dose reductions due to AEs occurred in 52.3% of patients and Tx discontinuation rate due to AEs was 11.8%. Elderly pts (defined as >65 years) did not have higher rates of dose reductions due to AEs compared to young pts (< = 65 years) (37.8% vs 59.7 %), p=0.043). The median RDI is 92% (interquartile range (IQR) 33%-100%). The median RDI in elderly pts was 94% (IQR 50%-100%). Among pts in which response was assessed, objective response rate (ORR) was 26.6% (25 pts had PR), and 38.3% had SD. Interestingly, the rate of alopecia was higher in pts who had PR as the best response (28%), compared to 5.6% in pts who had SD, and 3% in progressive disease (PD) p=0.004. The median prior line of therapy in pts who had PR and SD as best response was 2 (IQR 1, 5) (IQR1, 12), respectively, compared to a median of 3 (IQR 1, 7) in pts with PD, p< 0.001. The CBR was 49% (46/94). The median duration of clinical benefit was 7 months IQR (2, 16) with median overall survival of 13 months IQR (2.5, 39) compared to 5.7 months IQR (0.03, 27) in pts without clinical benefit (p< 0.001). 56.9% (62/109) of pts had HER2 low disease and the clinical benefit rate in this subgroup was 14.3% (23/62). Conclusion: In a heavily pretreated cohort, SG retains clinical activity and tolerability in mTNBC. This is reassuring given pts on clinical trials tend to be healthier compared to real-world clinical practice. Citation Format: Sabah Alaklabi, Arya Mariam Roy, Paola Zagami, Nicole Held, Saba Shaikh, Lubna Chaudhary, Yara Abdou, Shipra Gandhi. Real World Outcomes with Sacituzumab Govitecan in Metastatic Triple Negative Breast Cancer Patients: A Multi-Institution 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 PO3-06-10.

Abstract PS15-06: Results of the window-of-opportunity PIONEER trial evaluating addition of the progesterone receptor (PR) agonist megestrol to letrozole for early stage estrogen receptor (ER) positive breast cancer: exploiting ER-PR interaction

Abstract Background: Pre-clinical data suggest that combining anti-estrogen treatment with a progesterone receptor agonist leads to greater inhibition of tumor proliferation, due to molecular interactions between ER and PR [1]. A high dose of the PR agonist megestrol (160mg daily) is approved as monotherapy for the treatment of ER positive metastatic breast cancer. A lower dose of megestrol (20-40mg daily) can be an effective treatment for severe hot flashes associated with endocrine therapy [2] but whether this dose has anti-tumor activity is unknown. The PIONEER trial evaluated the potential anti-proliferative effect of low and high dose megestrol in combination with letrozole, relative to letrozole alone, using a short-term preoperative ‘window’ trial design assessing the direct effects of the trial treatment on tumor tissue before and after treatment. Methods: Eligible patients were post-menopausal women with histologically confirmed ER+ (Allred ≥ 3) HER2 negative breast cancer at least 10mm in size, with an ECOG performance status ≤ 2, planned for primary surgery or endocrine therapy. Enrolled patients were randomised 2:3:3 to Arm A: letrozole alone, Arm B: letrozole + lower-dose megestrol (40mg) or Arm C: letrozole + higher-dose megestrol (160mg). Treatment was given for 15 (13-19) days prior to surgery or end of treatment (EOT) core biopsy. The primary endpoint was change in tumor proliferation between baseline and EOT in Arm A vs (Arms B+C combined), measured by Ki67 immunohistochemistry (IHC). Secondary endpoints were comparison of Ki67 change in high versus low dose megestrol arms, absolute Ki67 at EOT, and change in tumor apoptosis (cleaved caspase 3 IHC), proliferation (Aurora Kinase A IHC), PR and androgen receptor expression. Exploratory analysis of ER chromatin binding (ChIP-Seq) was conducted on paired fresh-frozen samples from a subset of patients. Results: A total of 243 patients were randomised from July 2017 to October 2022 with recruitment paused for 3 months at onset of the COVID pandemic. 198 patients completed treatment and had evaluable tissue samples at baseline and EOT (Arm A: n = 51, Arm B: n = 74, Arm C: n = 73). Baseline mean Ki67 values were well balanced. Therapy was well tolerated and adverse events ≥ grade 3 were similarly rare across arms (A: 3.3%, B+C: 3.5%). The mean % reduction in Ki67 for each arm was: Arm A (letrozole): 71%, Arm B (letrozole + 40mg megestrol): 79%, Arm C (letrozole + 160mg megestrol): 80%. There was a statistically significantly greater reduction in Ki67 with megestrol combinations (B+C) versus letrozole alone (A) (P = 0.013). Analyses of secondary IHC endpoints and ER ChIP-Seq are ongoing and will be presented. Conclusion: Addition of the PR agonist megestrol enhanced the anti-proliferative effect of letrozole in this window-of opportunity trial. Megestrol combinations were well tolerated, and the anti-proliferative effect was observed in both low and high dose arms. These data support the potential use of low-dose megestrol as an inexpensive and well-tolerated means of improving aromatase inhibitor efficacy. Low dose megestrol can also ameliorate hot flashes and therefore might be a strategy to improve both treatment adherence and clinical outcomes for patients taking adjuvant endocrine therapy.

Abstract PO3-06-11: Undated analyses from a Phase Ib open-label study of Pucotenlimab (HX008) in combination with gemcitabine and cisplatin as first-line treatment of metastatic triple-negative breast cancer

Abstract Background: Gemcitabine plus cisplatin (GP) therapy war preferred in China as the first-line therapy for metastatic triple-negative breast cancer (mTNBC), with a median progression-free survival (PFS) of 7.73 months, and a median overall survival (OS) of 19.37 months [1]. Pucotenlimab (HX008) is a novel humanized IgG4 anti-PD-1 monoclonal antibody with an engineered Fc domain. Preliminary results from the phase 1b trial [2] have shown that HX008 combined with GP has a manageable safety profile and demonstrates promising antitumor activity in patients (pts) with mTNBC. Here, we present the updated results from the long-term survival analysis. Methods: Eligible subjects were those who were treatment-naïve mTNBC patients and had measurable lesion. Participants received HX008 at a dose of 3 mg/kg every 3 weeks in combination with chemotherapy (gemcitabine + cisplatin) for 6 cycles and maintained with HX008 until disease progression or unacceptable toxicity occurred. The primary endpoints included overall response rate (ORR) and safety, and the secondary endpoints included duration of response (DoR), PFS, and OS. Results: Between July 2019 and March 2020, a total of 31 pts were enrolled in this study. The median age of patients was 50 years (range 29–69). By the cut-off date (April 24th, 2023), the median follow-up period was 20.7 m (IQR: 12.2, 25.6). The confirmed ORR was consistent with the previously reported data and remains at 74.2% (95% CI: 55.4%, 88.1%). The median PFS was 9.0 months (95% CI, 7.3, 9.3). The median DoR was 7.3 months (95% CI, 5.0, 9.8). The OS was immature, with the result of 23.1 months (95% CI, 13.4, NE), while the 12-m, 24-m and 36-m OS rate was 77.4% (95%CI: 64.0%, 93.6%), 42.7% (95%CI: 28.0%, 65.3%), and 24.4% (95%CI: 11.3%, 52.7%), respectively. The most common grade 3 or 4 treatment-related adverse events included neutropenia (71.0%), leukopenia (45.2%), anemia (38.7%), and thrombocytopenia (32.3%). There was no treatment-related death and no new safety signals were identified. Conclusion: The combination therapy of HX008 plus GP demonstrates favorable clinical efficacy with a manageable safety profile in pts with mTNBC. The combination therapy led to a longer PFS and OS than GP therapy reported previously, regardless of PD-L1 status. The safety profile was consistent with the known toxic effects of each agent. In this updated analysis, no new safety signals were identified. Clinical trial information: NCT04750382

Abstract PO2-11-10: Can chemotherapy-induced peripheral neuropathy be predicted? Implications for future prevention and treatment of this side-effect

Abstract Background: The pain and sensory abnormalities associated with chemotherapy-induced peripheral neuropathy (CIPN) may persist for months or even years after chemotherapy. CIPN has a negative impact on routine activities, functions, and behaviors in the domestic, work, and social lives of cancer patients, adversely affecting the quality of their survivorship. CIPN is a major adverse effect of taxanes and other agents, possibly requiring dose-reduction or early termination of treatment. Taxane-based regimens are first-line treatment in both early-stage and metastatic breast cancer and therefore place numerous women at risk for developing CIPN. Regrettably, taxane-induced neurotoxicity can be arduous to predict, and there are no preventive or curative treatments currently available. Our work aims to assess a predictive tool for identification of patients at high risk of developing neuropathy and the progression of symptoms towards chronic CIPN. We hypothesized that oxidative stress might be a triggering event for the development of CIPN and that changes in glutathione recycling can identify patients at high risk for developing prolonged and severe CIPN. This hypothesis is based on reports in the literature proposing that CIPN is triggered by damage to the myelin sheath, which protects nerves from damage, by drug-induced free radicals in and around the nerves. Damage to myelin, a lipid- and protein rich sheath, by lipid peroxidation can result in loss of signal transmission, false signaling, or signal overload. Prolonged exposure to elevated levels of free radicals might result in structural changes to the nerves. Methods: Cancer patients seeking treatment at the Lankenau Medical Center Cancer center were asked to participate in our Institutional Review Board approved study of adverse effects. In this on-going study, the cohort (Ntotal =352) includes 104 breast cancer patients that are predominantly Caucasian with 14.9% African American. The median age is 56 (range 26 – 82) and 60.9% were treated with a taxane-based regimen. Nearly half the breast cancer group were diagnosed with Stage I disease. All consented patients donated a tube of blood prior to each treatment and filled out the Rotterdam Symptom Checklist (RSCL). Blood samples were analyzed for glutathione recycling using the ChemoTox assay (MNT™ Test, MYNARI Biomedical) and lipid peroxidation using a thiobarbituric acid reactive substances (TBARS) test (Cayman Chemical). All samples were analyzed in duplicate, and results analyzed using GraphPad Prism 8.4.3. Results: Preliminary results from the first 83 breast cancer patients showed African American patients reported a higher rate of NCCN grade 2 and 3 CIPN while Caucasians reported a higher rate of severe, long-lasting CIPN. Our results showed that patients who reported CIPN at later cycles had diminished glutathione recycling capacity already after the first treatment. Drop in recycling capacity had an inverse relationship with lipid peroxidation and grade of CIPN. Both decreased recycling capacity and increase in lipid oxidation were apparent already after the first treatment in patients that reported CIPN after cycle 6-8 or after completion of treatment Discussion: There are many proposed mechanisms for the development of CIPN. One mechanism that is shared by both most agents is damage induced by free radicals released following chemotherapy. We show that patients with reduced ability to neutralize free radicals have elevated and prolonged lipid peroxidation. Both processes precede the development of CIPN by several treatment cycles. Therefore, this test could identify patients that might benefit from other regimens rather than a taxane-based therapy. The test could also aid in the identification of patients for preventive therapy once such agents become available. Citation Format: Alisha Maity, Nolan Metz, Kathryn Fleck, Zonera Ali, Aarthi Shevade, Arezoo Ghaneie, Margaretha Wallon. Can chemotherapy-induced peripheral neuropathy be predicted? Implications for future prevention and treatment of this side-effect [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 PO2-11-10.

Abstract PO4-04-06: Exploring the use of tyrosine kinase inhibitors (TKIs) in the management of HER2-positive metastatic breast cancer post trastuzumab emtansine (T-DM1) therapy failure: Insights from a real-world study

Abstract Background Trastuzumab emtansine (T-DM1) is the established standard second-line treatment for HER2-positive metastatic breast cancer (MBC) patients who have previously received trastuzumab. However, there is ongoing debate regarding the subsequent therapeutic options following T-DM1 failure. This study aimed to evaluate the efficacy and safety of tyrosine kinase inhibitors (TKIs)-based therapy in HER2-positive MBC patients with resistance to T-DM1. Methods During the period from September 2018 to October 2021, a multicenter real-world study was conducted, enrolling a total of 53 patients diagnosed with HER2-positive metastatic breast cancer (MBC). These patients underwent TKIs-based therapy following the failure of T-DM1 treatment. The primary focus of the study was on evaluating progression-free survival (PFS) as the main endpoint. Secondary endpoints encompassed objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), and safety assessments. Results A total of 53 patients received TKIs-based therapy as a second-line or later treatment. The median progression-free survival (PFS) for TKIs-based therapy was 11.9 months (95% CI 7.9-15.9). The objective response rate (ORR) and clinical benefit rate (CBR) were found to be 19.6% and 72.5%, respectively. Among patients with brain metastasis (n=12), a median PFS of 10.5 months (95% CI 7.5-13.5) and an intracranial ORR of 33.3% were observed. Patients treated with pyrotinib (n=21) showed improved PFS compared to those treated with lapatinib (n=30), as well as patients who had derived favorable benefit from T-DM1 (PFS ≥ 6 months). Hormone receptor status (HR) and response to T-DM1 were identified as independent factors affecting the effectiveness of TKIs-based therapy. The most frequently reported adverse events included thrombocytopenia (23.6%), diarrhea (15.7%), leucopenia (15.7%), and hand-foot syndrome (15.7%). Conclusion TKIs-based therapy demonstrated favorable effectiveness and safety in HER2-positive metastatic breast cancer (MBC) patients who had previously received T-DM1 but experienced treatment failure. This includes patients with brain metastases. Notably, individuals who derived favorable benefits from prior T-DM1 treatment displayed significantly prolonged progression-free survival (PFS) when undergoing subsequent TKIs-based therapy. Citation Format: Yongmei Yin, Chunxiao Sun, Yijia Hua, Nan Jin, Wei Li, Xiang Huang. Exploring the use of tyrosine kinase inhibitors (TKIs) in the management of HER2-positive metastatic breast cancer post trastuzumab emtansine (T-DM1) therapy failure: Insights from a real-world 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 PO4-04-06.

Abstract PS12-08: MORPHEUS Hormone Receptor-Positive Breast Cancer: interim analysis of a Phase Ib/II, study of fulvestrant ± atezolizumab and abemaciclib triplet treatment in patients metastatic disease

Abstract BACKGROUND Endocrine therapy (ET) is the mainstay of treatment for metastatic hormone receptor-positive breast cancer (HR+ BC). ET resistance and disease progression are expected, thus novel therapies, like cancer immunotherapy, are needed. Prior data suggest that abemaciclib (abema), a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has immunomodulatory activity. In the MORPHEUS HR+ BC study (NCT03280563), atezolizumab (atezo; anti–programmed death-ligand 1 [PD-L1]) was tested in combination with fulvestrant (FUL), with and without abema, in patients (pts) with HR+ metastatic BC. We present 24-week interim analyses. METHODS Pts with measurable disease progression during first- or second-line therapy for metastatic or inoperable locally advanced HR+ BC and prior treatment with a CDK4/6 inhibitor were randomized to receive FUL (control) or FUL + atezo (1200 mg intravenous every 3 weeks) or FUL + atezo + abema (150 mg twice a day); prior FUL was not permitted. Pts were treated until loss of clinical benefit or unacceptable toxicity. Primary endpoints were objective response rate (ORR) per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 and safety. Progression-free survival (PFS) was a secondary endpoint. Baseline tumor samples were analyzed for PD-L1 expression (SP263), CD8 T cell infiltration, and gene expression by RNAseq. RESULTS As of Dec 2022, 40, 31, and 25 pts (38, 30, and 20 evaluable pts) were randomized to atezo + abema + FUL, atezo + FUL, and FUL, respectively. Pts were followed for ≥ 24 weeks. Demographics were similar among the groups, with most pts receiving prior palbociclib (palbo) as part of their only prior metastatic therapy. Details and best confirmed ORRs are shown in the table. Median PFS was 6.34 months (95% confidence interval [CI] 5.52, 16.03) in the atezo + abema + FUL arm, 3.15 months (95% CI 1.51, 7.79) in the atezo + FUL arm, and 1.95 months (95% CI 1.45, 4.93) in the FUL arm. The hazard ratio of atezo + abema + FUL vs FUL was 0.43 (95% CI 0.24, 0.78). Safety data are shown in the table. Mild/moderate (grade 1/2) interstitial lung disease (ILD)/pneumonitis (7.7%) was observed in the atezo + abema + FUL arm. At baseline, tumors exhibited low prevalence of PD-L1 (median immune cells: 0.5%, tumor cells: 0%) and CD8 infiltration (12% inflamed phenotype), which did not associate with response in any arm. RNAseq analysis indicated that response to atezo + abema + FUL was strongly associated with low baseline expression levels of proliferation and metabolism signatures and trended with high expression of some immune signatures. CONCLUSIONS The triplet therapy of atezo + abema + FUL showed improved ORR and PFS compared with FUL monotherapy in the second- or third-line setting post-CDK4/6 inhibitor. This combination of atezo + abema + FUL was tolerable, with no unexpected safety signals, including no high-grade ILD/pneumonitis. Efficacy and safety Data are number of patients (%), unless otherwise specified. * Patient was treated in the second line and incorrectly included in this group. Abema, abemaciclib; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; atezo, atezolizumab; CDK4/6, cyclin-dependent kinase 4/6; CI, confidence interval; ful, fulvestrant; irAE, immune-related adverse event; L, line; ORR, objective response rate; PFS, progression-free survival; TRAE, treatment-related adverse event. Citation Format: Kyung Hae Jung, Seock-Ah Im, Denise Yardley, Sara Hurvitz, Keun Seok Lee, Amir Sonnenblick, Shlomit Shachar, Antoinette Tan, Elizabeth Comen, Einav Gal-Yam, Adam Brufsky, Hope Rugo, Jing Zhu, Kelly DuPree, Vanessa Breton, Fiona Young, Richard Schwab, Edward Cha, Melinda Telli. MORPHEUS Hormone Receptor-Positive Breast Cancer: interim analysis of a Phase Ib/II, study of fulvestrant ± atezolizumab and abemaciclib triplet treatment in patients metastatic disease [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 PS12-08.

Abstract PO2-20-07: A case report of a severe cutaneous adverse event in triple negative breast cancer treated with chemoimmunotherapy

Abstract Introduction Cutaneous adverse events related to immune checkpoint inhibitors (ICI) are common and most are mild. However, numerous case reports have documented severe ICI-related skin-toxicities such as Stevens-Johnsons Syndrome (SJS) most commonly among patients with melanoma and lung cancer as immunotherapy has now become a mainstay of treatment in these tumors. The use of ICIs in breast cancer treatment has only recently become standard of care for treatment of metastatic and high risk early-stage triple negative breast cancer with the publication of two landmark clinical trials, KEYNOTE-355 and KEYNOTE-522, respectively. While these trials report low rates of severe skin reactions, little is known about ICI-related severe skin toxicities in patients with breast cancer. Case description A 58-year-old female with clinical stage IIB (cT2N0M0) triple negative breast cancer was undergoing neoadjuvant treatment with pembrolizumab, an anti-programmed death (PD-1) monoclonal antibody, coupled with a chemotherapy back-bone of 12 weekly treatments of carboplatin and paclitaxel followed by 4 cycles of doxorubicin and cyclophosphamide. She developed an erythematous and itchy rash on the right breast and axilla approximately 61 days into her treatment course after having received her fourth dose of pembrolizumab. Over the next 10 days, she developed progression of the rash with painful red papules coalescing into reticulated plaques and dusky blistering of the skin involving the right arm, axilla, abdomen, inguinal folds, thigh, and back, totaling < 10% total body surface area. Notably, the rash did not have mucosal involvement. She was hospitalized for close monitoring and treatment. A punch biopsy of the rash revealed interface dermatitis with areas of full thickness skin necrosis consistent with erythema multiforme, SJS, toxic epidermal necrolysis (TEN), or a fixed drug eruption. Her skin continued to slough in the distribution of rash and a diagnosis of SJS was made. The patient had no response to initial treatment with high dose steroids. Cyclosporine was added, resulting in rapid improvement of her rash. The patient’s neoadjuvant treatment was stopped given the grade 3 SJS she experienced. Despite this truncated neoadjuvant treatment, she had excellent clinical response as her tumor was no longer palpable. She proceeded with a partial mastectomy and sentinel lymph node biopsy. Pathology revealed a pathological complete response. She did not receive any further systemic therapy in the adjuvant setting. Three months later, she was evaluated in clinic without evidence of SJS on physical exam. She was rapidly tapered off cyclosporine over one week without recurrence of her rash. Discussion Severe cutaneous adverse events related to ICIs remains an emerging area of study. In SJS, drug-specific CD8+ T lymphocytes utilize granulysin to mediate keratinocyte apoptosis. It is hypothesized that the blocking of the PD-1/PD-L1 interaction by ICIs results in the disruption of T-cell homeostasis leading to self-directed cytotoxic and inflammatory reactions and ultimately epidermal detachment. In contrast, Molina et al 2020 postulate that such ICI-related skin reactions may represent a separate clinical entity from SJS. In their case report of seven patients, they propose the term “progressive immunotherapy-related mucocutaneous eruption” (PIRME), which the authors suggest is characterized by delayed symptom onset, mild initial presentation, rare ocular involvement, benign clinical course, and favorable treatment response. Further characterization of ICI-related cutaneous adverse events is needed to understand the disease course, optimal treatment, and importantly, implications for re-challenging patients with immunotherapy. Clinicians taking care of breast cancer patients treated with ICIs need to be educated to recognize the associated skin toxicities as patients can rapidly worsen without appropriate treatment. Citation Format: Annie Zhang, Mara Beveridge, Bahar Moftakhar. A case report of a severe cutaneous adverse event in triple negative breast cancer treated with chemoimmunotherapy [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 PO2-20-07.

Abstract PO4-19-09: Comparison of clinical efficacy between letrozole + ribociclib vs. Fulvestrant + letrozole + ribociclib in Hormone receptor positive, HER2 negative metastatic breast cancer – a randomized, phase 2 study (KCSG BR22-20)

Abstract Background The current standard first-line treatment in advanced or metastatic hormone receptor (HR) positive breast cancer is combination of aromatase inhibitor (AI) and cyclin D kinase-4/6 (CDK4/6) inhibitor. Emergence of ESR1 mutation is a key mechanism of resistance during first-line AI + CDK4/6 inhibitor treatment. Selective estrogen receptor downregulator (SERD) such as elacestrant or fulvestrant is suggested as second-line treatment, but the progression-free survival (PFS) outcome of second-line treatment is reported up to 3.78 months in patients who harbour ESR1 mutation. Recently, early switch of AI + CDK4/6 inhibitor to fulvestrant + CDK4/6 inhibitor at the point of rising ESR1 mutation showed prolongation of PFS up to 6 months, suggesting there may be a new strategy to overcome ESR1 mutation by modifying endocrine treatment. SWOG S0226 suggested that upfront fulvestrant + AI is feasible and associated with prolongation of PFS compared to AI alone. After CDK4/6 inhibitor has been introduced to standard treatment, there were no trials evaluating the role of AI + fulvestrant with CDK4/6 inhibitor. In this trial, we investigated triplet combination of AI + fulvestrant + CDK4/6 inhibitor as a treatment to overcome resistant mechanism such as development of ESR1 mutation when compared to current standard treatment of AI + CDK4/6 inhibitor as the first line treatment in HR positive advanced or metastatic breast cancer. Methods This study is a randomized, multicenter, open-label phase II trial comparing AI plus ribociclib versus AI, fulvestrant plus ribociclib in HR-positive advanced or metastatic breast cancer. De novo patients or patients with treatment-free interval (TFI) over 12 months after completion of adjuvant AI can be enrolled. If patients received adjuvant tamoxifen, patients with TFI less than 12 months can be also enrolled for the study. Prior endocrine treatment or cytotoxic chemotherapy at metastatic setting was not allowed. In cases of premenopausal women, gonadotropin releasing hormone agonist (GnRHa) is administered every 4 weeks with treatment. A total of 202 patients will be enrolled for 30 months, and 30 months of follow-up is planned after last-patient enrolment. Patients are randomized to 1:1, stratified based on the presence of visceral metastasis and previous administration of adjuvant AI. Study treatment of the control arm consists of letrozole 2.5mg daily with ribociclib 600mg (Day 1-Day 21 daily by month, 1 week off) until progression. In the experimental arm fulvestrant 500mg intramuscular injection is added (Day 1, Day 15, Day 29 and every 4 weeks thereafter) until progression. For exploratory analysis of ESR1 mutations, circulating tumor DNA (ctDNA) is collected at baseline, and then every 3 months thereafter. Primary endpoint is to evaluate the difference of 24-months PFS rate. Secondary endpoint included PFS, overall survival (OS), emergence and frequency of ESR1 mutation, overall response rate (ORR) and clinical benefit rate (CBR). The analysis is planned after completion of 30 months of follow-up, which provides approximately 90% power to detect superiority 24 months-PFS rate assumed by Kaplan-Meier curve of letrozole + fulvestrant + ribociclib versus letrozole + ribociclib using a log-rank test, assuming a hazard ratio of 0.64 at a two-sided alpha of 0.2. Citation Format: Jieun Lee, Su-Jin Koh, Jung Hye Kwon, Gun Min Kim, Jee Hung Kim, Ho Young Kim, Hee-Jun Kim, Keon-Uk Park, Kyong Hwa Park, Yeon Hee Park, Mi Sun Ahn, Hee Kyung Ahn, Gyeong-Won Lee, Kyoung Eun Lee, Kyung-Hun Lee, Moon Hee Lee, Sung Sook Lee, Jung Lim Lee, Kyung Hae Jung, Joo Young Jung, In Hae Park. Comparison of clinical efficacy between letrozole + ribociclib vs. Fulvestrant + letrozole + ribociclib in Hormone receptor positive, HER2 negative metastatic breast cancer – a randomized, phase 2 study (KCSG BR22-20) [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 PO4-19-09.

Abstract PS12-06: A phase 2 study of abemaciclib monotherapy for patients with retinoblastoma-positive (Rb+), triple-negative metastatic breast cancer

Abstract Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors can significantly extend survival when given in combination with endocrine therapy as treatment for hormone receptor-positive metastatic breast cancer. Preclinical studies suggest CDK4/6 inhibitor monotherapy might also be effective in a subset of triple-negative breast cancers (TNBCs), including those that express a functional retinoblastoma (RB) protein and/or those of the Luminal Androgen Receptor (LAR) subtype. Currently, the clinical activity of CDK4/6 inhibitor therapy in TNBC has not been reported. Methods: We conducted a single-arm phase II study of abemaciclib monotherapy in patients with locally advanced or metastatic TNBC. Key eligibility criteria included: (i) Measurable disease by RECIST 1.1; (ii) Between 1-3 prior lines of systemic therapy for advanced TNBC; (iii) RB-positive tumor (defined as ≥ 50% of tumor cells staining positive for RB by immunohistochemistry [archival or fresh sample] on central testing); (iv) ECOG PS 0/1. Patients were treated with abemaciclib 200 mg orally (28-day cycles) twice daily until disease progression, unacceptable toxicity, withdrawal of consent, or death. Tumor biopsies were mandatory at baseline and C2D1 if tumor tissue was safely accessible. The primary outcome was objective response rate (ORR). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR: CR + PR + SD ≥ 24 weeks), and safety and tolerability. The study had a two-stage design. Thirteen patients were enrolled in the first stage, with the plan to enrol a further 25 patients if at least one objective response was observed. Results: One unconfirmed partial response was observed in stage 1, and a total of 27 patients were enrolled before the trial was closed early due to slow accrual. The median age was 61 years and patients had received a median of 2 prior lines of systemic therapy for metastatic disease. Twelve patients had received prior immunotherapy. After a median follow-up of 28.5 months, the confirmed ORR was 0% and the CBR was 15%, with 4 of 27 patients experiencing stable disease for ≥ 24 weeks. The median PFS was 1.94 months (95% CI: 1.8 – 11.5 months), and the median OS was 8.44 months (95% CI: 4.6 – 15.6 months). There was no significant difference in PFS or OS between patients with PD-L1-positive versus PD-L1-negative disease, or Androgen Receptor (AR) positive versus negative tumors by immunohistochemistry. The most common adverse events of grade 2 or higher were diarrhea (41%), neutropenia (41%), anemia (30%), and nausea (30%). RNA-sequencing of baseline biopsies has been performed to identify biomarkers associated with clinical benefit, and results will be presented at the meeting. Conclusions: Abemaciclib monotherapy did not show clinical activity in patients with Rb+ metastatic TNBC. This finding suggests that future trials of CDK4/6 inhibition as monotherapy in TNBC are not warranted. Citation Format: Shom Goel, Bojana Jovanović, Xiangying Chu, Melissa Hughes, Ayesha Mohammed-Abreu, Julie Kasparian, Timothy Erick, Molly DiLullo, Eileen Wrabel, Rinath Jeselsohn, Nabihah Tayob, Stuart Schnitt, Nancy Lin, Sara Tolaney. A phase 2 study of abemaciclib monotherapy for patients with retinoblastoma-positive (Rb+), triple-negative 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 PS12-06.

Abstract PO3-05-14: Practice patterns for sequential use of antibody-drug conjugate after antibody-drug conjugate in metastatic breast cancer: results from a physician survey

Abstract Introduction: Antibody-drug conjugates (ADCs) have become a key part of metastatic breast cancer (MBC) treatment. Trastuzumab deruxtecan (T-DXd), and Sacituzumab Govitecan (SG) are approved ADCs available for the treatment of MBC. Completed trials that led to the approval of these ADCs did not include patients who had received the other ADC as prior therapy. Little is known about the optimal sequencing of these agents and how clinicians are incorporating ADC sequencing decisions at bedside. Methods: An online survey regarding the use of sequential ADCs was distributed electronically from April 2023 to July 2023 among US clinicians who treat patients with breast cancer. The survey included eight questions assessing clinician practice settings and the use of ADC sequencing and five case-based scenarios (table 1). Descriptive statistics were used to assess survey responses. Results: 107 survey responses were received, out of which 72% were female responders and 93% were medical oncologists. The majority of responders practiced in an academic setting (83%) and reported being involved in clinical research (82%). 58% of responders have been in practice for >10 years and 68% treat >20 breast cancer patients per week. 87% had prescribed an ADC post-ADC for MBC. 46% of responders thought that the degree of benefit for an ADC post-ADC would be similar to the benefit noted in the pivotal ADC trials, and 54% thought that the degree of benefit with sequencing would be lower than in the pivotal trials. Regarding the case-based questions for patients with triple-negative breast cancer and HER2 low disease who had disease progression on first-line metastatic therapy, 64-71% of clinicians opted to give SG as the first ADC followed by T-DXd as the second ADC in sequence, regardless of age, PDL1 status and prior metastatic therapies. For a patient with hormone-positive (HR+), HER2 low MBC, who had received capecitabine as the first metastatic chemotherapy, 50% opted to give T-DXd as the first ADC followed by SG as the second ADC, and 40% opted to give weekly paclitaxel followed by SG as the first ADC. For a patient with HR+, HER2 low MBC who had received two prior chemotherapies for metastatic disease, 77% opted for T-DXd as the first ADC, followed by SG as the second sequential ADC. When grade 1 pneumonitis was added as a comorbidity to the case, only 16% opted to give T-DXd as the first ADC choice. Conclusion: Almost 90% of clinicians report prescribing sequential ADCs for MBC, yet there is little uniformity in how these ADCs are sequenced. More than 50% felt that the benefit of the second ADC in the sequence will be lower than the registration trials that led to the approval of the ADC in a setting of no prior ADC treatment. The optimal sequencing of ADCs remains an area of unmet need and further studies are needed to guide optimal medical decisions regarding sequential ADC-based treatment algorithms for patients with MBC. Table 1. Case-based scenarios for ADC sequencing Citation Format: Yara Abdou, Prarthna Bhardwaj, Rachel Abelman, Laura Spring, Aditya Bardia, Lisa Carey, Priyanka Sharma. Practice patterns for sequential use of antibody-drug conjugate after antibody-drug conjugate in metastatic breast cancer: results from a physician survey [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 PO3-05-14.

Abstract PO2-23-12: Innovative Metastatic Breast Cancer Therapy, CBT300, Reverses Drug and Immune Resistance

Abstract For many patients with metastatic breast cancer (MBC), their disease is treatable but incurable. Although the rate of death from MBC has significantly decreased over the last 10 years due to early detection and new treatment options, MBC still accounts for over 40,000 deaths each year in the US that has been consistent for the past 30 years. Recently, it is estimated that 90% of those deaths were due to drug resistant recurrent disease. Nearly 45% of MBC deaths can be attributed to a subpopulation of patients with metastatic triple negative breast cancer (mTNBC). Despite MBC’s initial sensitivity to chemotherapy, it often recurs at greater than 40% in stage I-III patients and greater than 80% in stage IV patients which have a dismal 5-year survival of 12%. African American women have a 40% greater incidence of death from MBC despite a 4% lower risk of diagnosis. Unfortunately, current therapies do little to reduce drug resistance and death for recurrent drug resistant MBC. Currently, the only therapies approved by the FDA for recurrent TNBC patients are Keytruda plus chemotherapy and an Antibody Drug Conjugate (ADC) called Sacituzumab Govitecan. Keytruda (anti-PD-L1) is an immune checkpoint inhibitor(ICI) given with chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin). The second recently approved therapy, Sacituzumab Govitecan (SG), is composed of an antibody to human trophoblast cell-surface antigen 2 (Trpo-2) coupled to SN-38 (topoisomerase I inhibitor). Although these results are very encouraging, the 80% of TNBC patients that either do not have high positive PD-L1 tumors, or don’t respond to these therapies and become drug resistant suggests that most patients with TNBC will have recurrent disease with little or no hope for survival. For contrast, our novel MBC therapy, CBT300, targets cell surface GRP78 that has been found in over 95% of MBC and in 93% of TNBC tumors. We can now show that inhibition of cell surface GRP78 can a) induce apoptosis of drug resistant TNBC cells in vitro and in vivo, b) eliminate drug resistance showing synergistic effects with chemotherapy in vitro and in vivo, c) decrease amount of chemotherapy in combination with CBT300 and d) reduce immune suppression. Recent publications show that GRP78 is found on many types of tumor cell surfaces but not on normal cell surfaces. In fact, tumor cell surface GRP78 (csGRP78) is important for many aspects of MBC development, including cell survival, proliferation, chemoresistance, angiogenesis, metastasis formation, immune suppression, and stem cell formation. Recently, it has been shown that increased cell surface GRP78 expression in TNBC patients was significantly associated with later stage, increased distant metastasis, increased aggressiveness, shorter disease-free survival, and decreased overall survival. In studies to help understand how cell surface GRP78 causes MBC progression and drug resistance, we discovered a novel GRP78 binding transmembrane protein on TNBC cells called Receptor Tyrosine Kinase Orphan Receptor-1 (ROR1). Using the GRP78 binding domain from ROR1 and a human Fc IgG1 domain, we created a biologic fusion protein that is a potent and cell surface specific GRP78 inhibitor, CBT300. We now show that CBT300’s elimination of cell surface GRP78 destabilizes and removes oncofetal proteins ROR1, Cripto-1, and checkpoint protein PD-L1 from tumor cell surfaces resulting in reversal of chemoresistance, reduction in immune suppression, inhibition of stem cell phenotype and increased tumor cell apoptosis. Since ROR1, Cripto-1 and PD-L1 are three of the major redundant pathways for tumor drug resistance, immune suppression and stem cell formation, the ability to inhibit all these pathways with CBT300, a single safe and very efficacious therapy, is very innovative and could be a significant advance for the treatment of MBC. Citation Format: Elizabeth Stolarik, Jorryn Zelek, Mariah Thigpen, Anita Davidson, Donald Davidson. Innovative Metastatic Breast Cancer Therapy, CBT300, Reverses Drug and Immune Resistance [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 PO2-23-12.

Abstract PO4-04-14: Change of first-line treatment pattern in metastatic luminal breast cancer: Results from the Austrian AGMT_MBC-Registry

Abstract Background: For patients with HR+/HER2- (luminal) metastatic breast cancer (MBC), international guidelines recommend endocrine-based first-line therapy [ET] in combination with a CDK4/6 inhibitor for most patients. Only for patients with imminent organ failure, first-line chemotherapy should be considered. To clarify changing patterns of first-line treatments over time in an Austrian population of luminal MBC patients, we analyzed the data from the MBC registry of the Austrian Study Group for Medical Tumor Therapy (AGMT-MBC-Registry). Methods: The AGMT-MBC-Registry is an ongoing multicenter registry for MBC patients in Austria. Only patients with luminal MBC and sufficient outcome data were included in this analysis. Patients were assigned to one of the following groups according to the year of start of first-line treatment for MBC: 2001-2010, 2011-2013 (no CDK4/6i available for first-line in both periods), 2014-2016 (CDK4/6i available in early access programs and clinical trials for first-line only), 2017-2019, and 2020-2022 (CDK4/6i available in both periods). Time to first chemotherapy (TTC) defined as start of first-line treatment until first application of a cytotoxic agent, and overall survival (OS) defined as start of first-line treatment until death were calculated by the Kaplan-Meier method and compared using the log-rank test. OS analysis was adjusted for disease free survival (DFS) category (de novo, DFS < 24 month, DFS ≥ 24 month), menopausal status (pre-, postmenopausal, unknown), age at diagnosis of metastatic disease (continuous), number of metastatic sites at diagnosis (1, 2-3, > 3), visceral disease (no, yes), and Charlson comorbidity index at diagnosis (continuous). Results: As of May 16th 2023, 1,330 patients with HR+/HER2- disease receiving at least one treatment-line for MBC were evaluable. First-line treatments significantly changed over time (P < 0.001). In patients diagnosed between 2001 and 2010, 61.4% were treated with first-line chemotherapy compared to 10.0% in patients diagnosed between 2020 and 2022 (Table 1). Additionally, TTC also significantly increased over time (P < 0.001; Table 2). In contrast, the proportion of patients treated with a first-line CDK4/6i plus endocrine therapy combination increased over time from 4.4% in 2014-2016 up to 75.5% in the period of 2020-2022. Additionally, adjusted median overall survival estimates significantly increased over time (P < 0.001; Table 2). Conclusion: In our registry, the proportion of patients with luminal MBC treated with first-line chemotherapy significantly decreased over time, whereas the proportion or patients treated with first-line CDK4-6 inhibitors significantly increased. This is in line with the change of guideline recommendation as well as the availability of CDK4-6 inhibitors over the last 2 decades. The availability of new treatment options has significantly increased median overall survival over time. Table 1: First-line treatment pattern over time Period N ET ET plus CDK4/6i Chemotherapy Others* 2001-2010 220 84 (38.2%) 0 (0.0%) 135 (61.4%) 1 (0.5%) 2011-2013 238 116 (48.7%) 0 (0.0%) 110 (46.2%) 12 (5.0%) 2014-2016 318 174 (54.7%) 14 (4.4%) 99 (31.1%) 31 (9.7%) 2017-2019 293 60 (20.5%) 190 (64.8%) 36 (12.3%) 7 (2.4%) 2020-2022 249 22 (8.8%) 188 (75.5%) 25 (10.0%) 14 (5.6%) Overall 1,318 456 (34.6%) 392 (29.7%) 405 (30.7%) 65 (4.9%) Legend: N - number of patients, ET - endocrine therapy (tamoxifen, aromatase inhibitor and/or fulvestrant), CDK4/6i - CDK4/6 inhibitor; * e.g. endocrine treatment plus everolimus or investigational study treatment Table 2: Time to first chemotherapy (TCC) and overall survial (OS) over time Period Median TTC [months] Adjusted median OS [months] 2001-2010 0.0 (0.0 - 0.0) 49.4 (41.2 - 56.6) 2011-2013 4.3 (0.0 - 13.8) 48.2 (38.3 – 69.7) 2014-2016 20.0 (14.0 - 26.4) 60.3 (50.2 - 77.5) 2017-2019 40.1 (33.3 - 59.8) 60.8 (52.8 - NR) 2020-now 30.4 (27.6 - NR) NR (NR - NR) Legend: N - number of patients, NR - not reached Citation Format: Gabriel Rinnerthaler, Simon Gampenrieder, Angelika Pichler, Walter Herz, Andreas Petzer, Renate Pusch, Marija Balic, Christoph Suppan, Sonja Heibl, Lukas Scagnetti, Margit Sandholzer, Clemens Schmitt, August Zabernigg, Daniel Egle, Petra Pichler, Christopher Hager, Florian Roitner, Johannes Andel, Kathrin Strasser-Weippl, Rupert Bartsch, Michael Hubalek, Michael Knauer, Christian F. Singer, Richard Greil. Change of first-line treatment pattern in metastatic luminal breast cancer: Results from the Austrian AGMT_MBC-Registry [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 PO4-04-14.