Hormone receptor-positive (HR+), HER2-negative breast cancer represents the most common subtype of breast cancer and is characterized by a risk of late recurrence. Neoadjuvant endocrine therapy with aromatase inhibitors (AIs) is a well-tolerated option in postmenopausal women; however, strategies to enhance its efficacy are needed. Combination of AI with immunotherapy is a promising approach. We evaluated the efficacy and safety of combining an AI with the anti-program death ligand 1 antibody durvalumab in the neoadjuvant setting. This single-arm, phase II study used a Simon two-stage design. Postmenopausal patients with early-stage HR+/HER2-negative breast cancer received durvalumab every 4 weeks plus daily AI for 6 months prior to surgery. The primary endpoint was the achievement of a modified Preoperative Endocrine Prognostic Index (mPEPI) score of 0. Seventeen patients were enrolled and received durvalumab plus daily AI for six months before surgery. Treatment was well tolerated, with most adverse events being grade 1–2. A clinical complete response was seen in 58.8

BACKGROUND:Immunotherapy is a growing treatment option for challenging breast cancer (BC) subtypes. Systemic administration can have significant adverse events (AEs), prompting interest in intratumoral injection. We evaluated the safety and feasibility of intratumoral injections at our institution. METHODS:This is an IRB-approved retrospective review of neoadjuvant patients who received intratumoral talimogene laherparepvec (TVEC) (NCT02779855) for triple negative breast cancer (TNBC), dendritic cells (DC1) for HER2+ (NCT05325632), HER2 + /ER- (NCT03387553), or TNBC (NCT05504707), or Voyager V1 virus (VV1) (NCT01042379) for high-risk lesions on ISPY2. This study outlines the safety and feasibility of intratumoral injections assessed by AEs, adherence to therapy, and ultrasound guidance. RESULTS:The study included 111 female patients (mean age 51; range 26-80). Forty-seven (42.3%) received TVEC, 62 (55.9%) received DC1, and 2 (1.8%) received VV1. Three patients missed one injection; 110 patients had ultrasound-guided injections. Mean neoadjuvant therapy length was 172 days (range 127-244). Local AEs included pain (20.7%), injection site reaction (27.9%), and hematoma (5.4%). Systemic AEs were reported more frequently, most commonly chills (52.3%), headache (39.6%), and fever (36.8%). DISCUSSION:Intratumoral IT injection is a viable treatment option that may minimize systemic exposure while maintaining therapeutic efficacy. Breast surgeons can play a role in intratumoral IT in BC.

TPS1140 Background: Patients with triple negative breast cancer (TNBC) are at a high risk to develop brain metastases. The prognosis and quality of life for triple negative brain-metastatic breast cancer remains very poor. Treatment options are limited and improvement in efficacy is needed. Sacituzumab govitecan (SG) has shown blood brain barrier (BBB) penetration in preclinical and clinical settings with anti-tumor activity in the phase III ASCENT Trial (NCT02574455). Radiotherapy can open the BBB and has been shown to be safe in combination with anti-PD-1 therapy in our previous trial (NCT03807765). Therefore, combining radiation with the anti-PD-1 monoclonal antibody, zimberelimab, and SG may provide a synergistic anti-tumor approach. We hypothesize the use of SG and zimberelimab with stereotactic radiosurgery (SRS) among patients with metastatic TNBC with brain metastases will be safe and improve progression free survival compared to treatment with SG alone. Methods: The study is designed as a single-arm, nonrandomized, open-label, phase I/II trial of SG and zimberelimab with SRS among patients with metastatic TNBC with brain metastases. The primary endpoint will be neurologic toxicity defined by CTCAE v5 criteria (phase I) and 12 month PFS (phase II). TNBC patients ≥ 18 years old with ≤ 15 brain metastases with at least one measurable lesion ≥ 0.5 cm per RANO-BM criteria will be enrolled. Treatment will be initiated with SRS followed 1 week later by SG on days 1 and 8 (10 mg/kg) with zimberelimab on day 1 (360 mg IV) repeated every 3 weeks. Follow-up imaging response assessments will be conducted at q9 week intervals. An interim analysis will be performed after 21 patients are enrolled. An additional 10 patients will be enrolled if interim futility criteria are not met. Clinical trial information: NCT06238921 .

Background: Patients (pts) with breast cancer (BC) harboring low expression of hormone receptors (HR) and human epidermal growth factor receptor-2 (HER2) have poorer outcomes compored to other subsets of BC. Results from the KEYNOTE-522 trial showed that activation of the immune system using a PD1/PD-L1 approach leads clinically meaningful improvement in the outcomes of patients with these high-risk tumors. Dendritic cells (DCs) are antigen presenting cells which are pivotal for robust cytotoxic responses via broader activation of the adaptive immune system. Methods: DecipHER is a dose-escalation, dose-expansion phase 1 trial designed to assess the safety and preliminary effiacy of autologous HER2- and HER3-primed DCs in combination with KEYNOTE-522 regimen in a maximum of 30 pts. Pts with clinical stage cT1-cN1/2 or cT2-4cN0/2, HR < 20, HER2-negative BCs are eligible. Pts with inflammatory BC and uncontrolled immune-mediated diseases are excluded. After collection through apheresis, autologous DCs are primed against 6 HER2 and 8 HER3 immunogenic peptides. Pts receive alternating US-guided intratumoral HER2 and HER3 DCs injections administered twice a week for 8 doses starting 2 weeks prior to neoadjuvant KEYNOTE-522 regimen. The dose-escalation phase of the study had a classic 3+3 design ( ie DL1-3 [10-20, 30-50, 80-100 million], maximum n=18). Additionally, 12 pts will be treated at the maximum tolerated dose (MTD) in the dose-expansion cohort. Dose-limiting toxicities (DLT) were defined as grade 3 or higher non-hematologic or hematologic adserve events (AEs) thought to be at least possibly related to DCs; any grade 4 nausea, vomiting or diarrhea [or grade 3 if duration > 3 days]) during the 5 weeks following treatment initiation. Secondary endpoints include absolute risk of AEs, pathological complete response (PCR) and recurrence-free survival. Tumor tissue, blood and stool samples are being collected for correlative analyses. Results: A total of 12 pts (6 on DL3) were enrolled between 08/2022 and 01/2024. The median age was 51.5 (35-71) and 25% of pts were black; 91% had grade 3, 41.7% had T3 and 75% had N1 BCs. One patient received only 2 HER2- and 4 HER3-primed DCs due to low cell yeild. Grade 1 and 2 AEs that were at least possibiliy related to DCs (>10%) were headache (66.7%) chills (50%), fatigue (33.3%), flue-like symptoms (33.5%), fever (25%), nausea (16.7%) and pain (16.7%). No DC-associated grade 3 or higher AEs were observed. None of the toxicities met the definition of DLT. For DL1, 2 out of 3 pts had an SAE ( i. cholelithiasis complicated by sepsis and ii. pneumonitis and syncope; 5 and 14 weeks after last DC injection; respectively). No SAEs were observed on dose levels 2 or 3. Immune-related AEs were pneumonitis (1pt), hypothyrodism and adrenal insuficiency (1 pt), hyperthyroidism (1pt). pCR was observed in 5 out of 10 evaluation pts. Base on thees findings, DL3 (80-100 million) was selected for the dose-expansion cohort. Conclusion: Intratumoral DCs in combination with standard neoadjuvant chemotherapy and pembrolizumab were well tolerated in pts with high-risk HR <20, HER2-negative BCs. The dose-expansion cohort portion of this trial is ongoing; correlative analyses will follow. The study is open at H. Lee Moffitt Cancer Center. Clinical trial information NCT05504707. Funding: Shulas' foundation. Citation Format: Ricardo Costa, Aixa E. Soyano, Avan Armaghani, Jennifer Childress, Loretta Loftus, Edith Abraham, Junmin Whiting, Qianxing Mo, Zena Jameel, Tracey O'Connor, Kimberley Lee, Susan Hoover, John Kiluk, Catherine Lee, Christine Laronga, Nazanin Khakpour, Hyo S. Han, Hatem H Soliman, Brian J. Czerniecki. Results of the Dose-Escalation Cohort of a Phase 1 Trial of Intratumoral HER2- and HER3-Primed Dendritic Cells Injections for the Treatment of Early-Stage TNBC and HR Low Positive Breast Cancer. DecipHER trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-08-28.

BACKGROUND:Screening of asymptomatic stage IV breast cancer with brain MRIs is currently not recommended by National Comprehensive Cancer Network Guidelines. The incidence of asymptomatic brain metastasis is not well documented. METHODS:The study is designed as a single-arm, phase II trial, with the goal of investigating surveillance brain MRIs in neurologically asymptomatic patients with metastatic breast cancer. Breast cancer patients were classified into triple-negative (TN), HER2+, and hormone receptor (HR)+/HER2-. Patients underwent a surveillance brain MRI and a second brain MRI at 6 months if the baseline MRI was negative. Asymptomatic, stage IV breast cancer patients, ECOG ≤ 2, and life expectancy ≥ 6 months were eligible. The primary objective was to determine the frequency of asymptomatic brain metastasis in metastatic breast cancer. Clinical trial information: NCT05115474. RESULTS:A total of 101 patients completed the surveillance brain MRI including 40 HR+/HER2-, 33 HER2+, and 28 TN patients. The overall frequency of brain metastasis on initial surveillance brain MRI was 14% (n = 14) with rates of 18%, 15%, and 10% in TN, HER2+, and HR+/HER2- patients, respectively. Following the 6-month MRI, the cumulative rates of brain metastasis increased to 25% in TN, 24% in HER2+, and 23% in HR+/HER2- patients. CONCLUSIONS:The highest frequency of brain metastases at baseline was in TN and HER2+ breast cancer. Following the 6-month MRI, the cumulative frequency was approximately a quarter across all subtypes. These results warrant confirmatory trials to refine brain MRI surveillance recommendations for neurologically asymptomatic stage IV breast cancer.

e13082 Background: Immunotherapy has been used in hormone receptor positive (HR+) HER2 negative metastatic breast cancer (MBC) and has shown modest clinical response and improved clinical benefit rate (CBR). Capecitabine has shown immunomodulatory activity by increasing interferon-gamma from activated tumor infiltrating immune cells, thus inducing PD-L1 expression. Therefore, patients may derive clinical benefit from the combination of capecitabine with cemiplimab. In our published preclinical studies, immunotherapy with activated lymphocytes administered a few days before chemotherapy to pre-sensitize the tumor and its microenvironment demonstrated substantial tumor cell death and response compared with a single agent alone. We hypothesize that timing and sequencing are important for a successful combination strategy. Methods: This is a phase I, single-arm, prospective trial for patients with HR+/HER2- MBC without prior chemotherapy or immunotherapy. The study was conducted at Moffitt Cancer Center between October 2021 and October 2023. Patients received a fixed dose of cemipilimab IV 350 mg on day 1 in combination with Capecitabine orally twice daily for 14 days on and 7 days off starting on day 3 of a 21-day cycle. Patients were started at capecitabine 800 mg/m2 and if well tolerated then increased to 1000 mg/m2. The primary endpoint was an analysis of adverse events and dose-limiting toxicity (DLT). Secondary endpoints included objective response rate (ORR), CBR, and progression free survival (PFS). Results: Thirteen eligible patients with HR+/HER2- MBC were enrolled. The median age was 57 years (46-70 years), 11 were Caucasian, 1 was Black/African American and 1 was Asian/Pacific Islander. All patients had progression on prior endocrine treatment (1 to 6 lines of treatment, mean 2.6) and 92.3% had received prior treatment with CDK4/6 inhibitor. The most common adverse events were hand and foot syndrome (30.8%, n = 4) followed by cough, decreased absolute neutrophil count, thromboembolic event, and dyspnea which occurred each in 15.4% (n = 2) patients. Only 1 immune related event of dry mouth (sicca) was seen (7.7%). A partial response (PR) was seen in 2 patients (15.4%), stable disease (SD) in 6 patients (46.2%) and progressive disease (PD) in 5 patients (38.5%). Median PFS is 4.1 months (95% CI 2.8 – NR). The ORR was 15.4% (95% CI: 4.3% - 42.3%), and the CBR was 61.5% (95% CI: 35.5% - 82.3%). 2 patients (15.4%) derived long term responses who continued treatment beyond 2 years. Conclusions: Our study found that the sequence of cemiplimab in combination with capecitabine had an acceptable safety profile. No unexpected adverse events or DLT were seen. Patients derived a reasonable clinical benefit from the combination treatment. 2 patients derived long term responses beyond 2 years. Further studies and biomarker analysis are warranted to explore this combination and improve patient selection. Clinical trial information: NCT05064085 .

Background: For over 20 years, patients (pts) with human epidermal growth factor receptor-2-positive (HER2+) advanced breast cancer (BC) have been routinely treated with HER2-targeted therapies. In December 2019, the FDA approved the use of a noval antibody drug conjugate ( trastuzumab deruxtecan [T-dxd]) for the treatment of pts with HER2+ progressive advanced BCs based on the impressive results of a phase 2 trial (DESTINY-B01). A subsequent phase 3 trial (DESTINY-B03) comfirmed its clinical efficacy with improvements in both progression-free and overall survivals compared to trastuzumab emtansize (T-DM1) ( HR 0.33 and HR0.64; respectively). Notwithstanding, T-dxd was associated wtih increased absolute risk (AR) of clinically relevant adverse events (AEs) such as intersticial lung disease (ILD), ie all-grade AR of 15%. There is pressing need for improved knowledge on the effictiveness and tolerability of this novel agent in a real-world population. Methods: After IRB approval, we conducted a retrospective single-institution cohort study of pts with HER2+( per ASCO/CAP guidelines) metastatic or unresectable locally advanced BC treated wtih T-dxd. We assessed the safety, tolerability, and effectiveness of T-dxd in this real-world population. Deidentified patient-, tumor- and outcome-related data including the AR of AEs of interest, and treating-physician assessments of tumor response, progressive-free and overall survivals were collected and summarized. Kaplan-Meier methods were applied to survival analyses and stratified analyses of interest were conducted. A two-sided P value < .05 was considered statistically significant. Results: A total of 84 women and 1 man with HER2+ advanced BC treated with T-dxd between 01/2020 and 06/2024 were included. Most women were post-menopausal (75.3%), had hormone receptor + BC ( 58.8%) and visceral metastasis (94.1%). At the time of initiation of T-dxd, 17.6% had ECOG PS of 3-4 and 28% were smokers; median age in years was 57 (28-76). In addition, 69.4% of the pts had 1-2 prior lines of therapy for metastatic BC, 12.9% had 4 or more prior lines of therapy. Up to 44.7% of the pts had prior treatment T-DM1 and 69.4% of the pts started T-dxd at full dose regimen ( 5.4mg/kg every 3 wks). The estimated median progression-free survival wa 12.7 months (95% CI, 9.7-19.5) and no significant diferrences were appriciated in stratified analyses according to tumor HR expression, presence of visceral disease or prior diagnosis of CNS disease metastatic disease or prior treatment wtih T-DM1. The medial overall survival for this cohort was estimated at 28.5 months ( 95% CI, 17.3-NE). As many as 40% of the pts required dose reductions and fatigue was the most common reaso for dose reduction (9.4%), only 16.5% of the pts permanently discontinued T-dxd due to AEs. Common all-grade AEs were ILD (7.1%), alopecia (14.1%), diarrhea (42.4%), vomiting (49.4%) and nausea (80%), fatigue (95.3%). Grade 3 or higher AEs were observed as follows: ILD (1.2%), peripheral neuropathy (1.2%), LVEF decrease (1.2%), increased AST (2.4%), increased alkaline phosphatase (2.4%), nausea (3.5%), leukopenia (8.3%), neutropenia (10.6%), anemia (13%), and fatigue (16.5%). No grade 5 AEs were observed. Conclusion: T-dxd showed effectiveness to treat pts with HER2+ metastatic or advanced BC in this real-world cohort of patients with pre-treated high-risk pts. Pts treated wtih T-dxd are at risk of clincally relavant but manageable AEs and require close monitoring. Citation Format: Ameer Basta, Kyle Lien, Weihong Sun, Aixa E. Soyano, Avan Armaghani, Loretta Loftus, Junmin Whiting, Tracey O'Connor, Brian J. Czerniecki, Ricardo L. B. Costa. A Cohort Study of the effectiveness and tolerability of Trastuzumab Deruxtecan For The Treatment of Metastatic or Locally Advanced HER2-positive Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-08-04.

598 Background: TVEC is an engineered herpes simplex oncolytic virus (HSV OV) approved for the treatment of melanoma. We published a phase 1/2 trial combining TVEC with NACT in early stage TNBC demonstrating increased pathologic complete response (pCR) compared to expected rates with NACT. We are presenting updated long term follow up data on this cohort of both phase 1 and 2 evaluable patients. Methods: Stage II-III TNBC pts were enrolled into a single arm, optimal phase 1/2 trial with TVEC (10^6 PFU 1 st dose then 10^8 PFU x 4 doses) weeks 1,4,6,8,10 + weekly paclitaxel (80mg/m2) IV x 12, followed by dose dense AC (doxorubicin/cyclophosphamide 60/600 mg/m2) IV q2weeks x 4 alone (wT-AC) given preoperatively. Primary endpoint was pCR rate. Secondary endpoints included 5 year disease free survival/overall survival rates (DFSR/OSR), safety, immune correlates. Results: Forty six patients were enrolled at Moffitt (5/2018 – 4/2020) and evaluable for response and outcomes. Study demographics: median age 49 (27-66), 69.5% White, 13% Black, 13% Hispanic, clinical stage II 80% and III 20%, node + 45%. The pCR rate for the phase 1/2 cohort was 45.6% (95% CI 30.9-60.9). Additionally, 10 patients had residual cancer burden (RCB) 1 responses (associated w/ favorable outcomes) 21.7% (95% CI 10.9-36.3%). At median follow up of 70 months (range 17-98), six patients have had a breast cancer recurrence DFSR=86.9% (95% CI 73.7-95.0) and four patients died OSR=91.3% (95% CI 79.2-97.6). DFSR in pCR group = 95.2% (95% CI 76.1 – 99.9) and non-pCR group = 80% (95% CI 59.3 – 93.1%). All but one of the recurrences occurred in patients with non-PCR responses (RCB 2-3) to TVEC+NACT. Clinical stages at presentation for patients with recurrences were 5 stage II and 1 stage III. No patients had any HSV reactivation or autoimmunity events during the post study surveillance period. Greater immune enrichment of B and T cell subsets in pCR vs. non-pCR tumors was observed during TVEC treatment. Conclusions: To our knowledge, this is the first report on longer term outcomes for early TNBC treated with OV. TVEC plus wT-AC demonstrates promising long term outcomes when compared to the more intensive KEYNOTE 522 checkpoint regimen. Additional investigation of oncolytic viruses administered during NACT for TNBC is warranted to confirm this benefit. Clinical trial information: NCT02779855 .

Introduction: Two antibody-drug conjugates (ADCs), trastuzumab deruxtecan (T-Dxd) and sacituzumab govitecan (SG), were approved by the FDA for HER2 low and HER2 negative metastatic breast cancer (MBC) respectively and the current data of the optimal sequencing of ADCs is limited. This study evaluated the efficacy of the second ADC (ADC2) following the first ADC (ADC1) in HER2-low MBC patients (pts) who have received both ADCs of T-Dxd and SG. Methods: This study represents an IRB approved retrospective cohort study of adult pts (age ≥ 18 years) at Moffitt Cancer Center between December 1, 2019, to January 31, 2024 with HER2-low MBC treated with both ADCs. Data was obtained via abstraction of the electronic medical record. The primary objective was to evaluate progression free survival (PFS) after ADC 1 (PFS1) and after ADC2 (PFS2). PFS is defined as the time from first dose of ADC to time of imaging showing progression or death. The Kruskal-Wallis test was applied to assess the association between continuous and categorical variables, while the Chi-square test or Fisher's exact test was used to evaluate the association between two categorical variables. All statistical tests were two-sided, with a significance level set at p < 0.05. Results: Overall, 34 pts met inclusion criteria. Seventeen pts received T-Dxd as ADC1 and 17 patients received SG as ADC1. The cohort included one male patient, 41.2% (14/34) were hormone receptor (HR) positive, and 58.8% (20/34) were triple negative breast cancer (TNBC) from metastatic biopsy. Two of the patients with TNBC MBC had ER or PR positive ≤ 10%. Two of the 34 patients were still receiving ongoing therapy with ADC2 at the time of the data cutoff. All of the HR positive subgroup received T-Dxd first followed by SG, and most TNBC patients (85%) received SG first followed by T-Dxd. Overall median PFS1 (mPFS1) with ADC1 in all comers was 5.8mo, and median PFS2 (mPFS2) with ADC2 was 2.4mo. PFS1 and PFS2 by drug sequence can be seen in table 1. Eight patients had significantly longer PFS2, defined as having received at least 8 cycles of therapy, and six of these patients received T-Dxd as ADC2. Five of the eight pts with this longer PFS2 were TNBC at the initial diagnosis and remained TNBC at time of ADC treatment. The other three pts were TNBC at initial diagnosis and changed to HR positive disease at time of ADC treatment. 67.6% (n=23) of pts received ADC therapies back-to-back with no lines of therapy in between, while 20.6% (n=35) of pts received one line of therapy in between ADCs. mPFS1 for those who received back-to-back therapy was 5.8mo while those with one line of therapy in between had a mPFS1 of 4.3mo. Of the 7 pts with brain metastases at start of ADC1, mPFS1 was 8.5mo. Of the 10 pts with brain metastases at the start of ADC2, mPFS2 was 2.9mo. Ten (29.4%) pts experienced any grade 2 or above adverse events (AEs) with ADC1, while 12 (35.3%) pts experienced any grade 2 AEs with ADC2. Further description of AEs will be discussed at the presentation. Conclusion: Our data demonstrates that mPFS is shorter following ADC2 which is consistent with limited available data to date. Interestingly, there were 8 pts with prolonged PFS2 of over 6 months, having received 8 or more cycles of therapy prior to progression. Overall, our study is limited by its retrospective nature and small sample size. Citation Format: Utsav Joshi, Junmin Whiting, Mo Qianxiang, Melissa Armitage, Jorge Avila, Kimberley T. Lee, Avan Armaghani, Tracey O'Conner, Ricardo Costa, Aixa Soyano Muller, Loretta Loftus, Hatem Soliman, Hyo S. Han. Single-center experience in antibody drug conjugate sequencing in HER2-low metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-12-08.

TPS1132 Background: Hormone receptor positive (HR+) HER2 negative metastatic breast cancer (MBC) remains a difficult clinical problem. Endocrine therapies have remained the mainstay of therapy for decades and despite combination with targeted agents and development of novel targeted therapies, the 5-year survival rate of MBC remains low. Resistance to ET can occur due to the development of point mutations in the estrogen receptor alpha type I (ESR1), which constitutively activates the receptor, making it resistant to anti-estrogen. We produced a peptide library of the entire wild type (WT) ESR1 and identified four promiscuous peptide epitopes that routinely drive a CD4 Th1 response in healthy donors and breast cancer patients. Additionally, we created overlapping peptides around each known ESR1 mutation site and pulsed them on type I polarized dendritic cells (DC1) also resulting in an increased CD4 Th1 response. We hypothesize that ER alpha receptor can serve as a target for the immune response and ESR1 mutations that develop in HR+ breast cancer patients can be utilized as a neoantigen that will drive CD4 Th1 responses and antibodies that can be developed as an immune based therapy for patients with HR+ MBC. Combining DC1 vaccination with novel endocrine therapies such as Elacestrant, we expect an increase in ESR1 degradation and enhanced antigen presentation leading to an expanded immune and clinical response. Methods: In this open pilot study, up to 18 patients with HR+ HER2 negative, ESR1 mutated MBC with measurable or evaluable disease will be enrolled to determine the feasibility and safety of the combination of DC1 vaccines and Elacestrant. Prior use of elacestrant is exclusionary. Eligible patients will undergo apheresis of peripheral blood to collect and create DC1 vaccines. DC1 will be pulsed with ESR1 WT and mutated peptides. Patients will be injected in their groin nodes (or accessible tumor if available) weekly with these pulsed DC1 (20-50 million) for eight consecutive weeks. They will alternate between WT ESR1 DC1s and mutated ESR1 DC1s. Patients will receive combination of DC1 vaccinations and Elacestrant at 345 mg orally daily concurrently during vaccination and continued after. After the initial vaccination series, patients will undergo radiological assessment of their disease, and if no evidence of progression they will receive booster DC1s every four weeks x 3 doses. The primary objective of this pilot study is safety and feasibility. Secondary objectives include preliminary efficacy, biomarkers assessment, safety and patient reported outcomes. Tumor tissue and blood samples will be collected for correlative analyses including ctDNA and changes in variant allele frequency of ESR1 during treatment. The study is open at H. Lee Moffitt Cancer Center. Clinical trial information: NCT06691035 .

Importance:Current chemotherapy regimens for patients with ERBB2 (formerly HER2)-positive breast cancer are associated with considerable morbidity. These patients may benefit from more effective and less toxic therapies. Objective:To evaluate the safety, immunogenicity, and preliminary efficacy of intratumoral (IT) delivery of conventional type 1 dendritic cells (cDC1) in combination with ERBB2-targeted therapies. Design, Setting, and Participants:This phase 1 (lead-in phase of a single-center phase 2 trial) nonrandomized clinical trial was conducted at Moffitt Cancer Center (Tampa, Florida). Patients were enrolled from October 2021 to October 2022. Data were analyzed in 2023 Patients with early-stage ERBB2-positive breast cancer with tumors 1 cm or larger were eligible. Interventions:Treatment included IT delivery of cDC1, 6 times weekly, followed by paclitaxel, 80 mg/m2, intravenously, 12 times weekly. Trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and pertuzumab (840 mg loading dose, then 420 mg) were administered intravenously every 3 weeks for 6 cycles starting from day 1 of cDC1 injections. Two dose levels (DLs) of IT cDC1 (DL1 = 50 million and DL2 = 100 million cells) were evaluated, including 6 patients in each DL. Main Outcomes and Measures:The primary outcomes were the safety and immune response, and the secondary outcomes were the antitumor efficacy as measured by breast magnetic resonance imaging and residual cancer burden at surgery following neoadjuvant therapy. Results:Twelve ERBB2-positive patients were enrolled and received treatment (DL1 = 6 and DL2 = 6). Nine patients had hormone receptor-positive disease and 3 had hormone receptor-negative disease, with clinical stage I (n = 5), II (n = 4), and III (n = 3). The most frequently observed adverse events with cDC1 were grade 1 to 2 chills (50%), fatigue (41.7%), headache (33%), and injection site reactions (33%). DL2 was associated with a diminished anti-ERBB2 CD4 T-helper 1 blood response with a concomitant increase in innate and adaptive responses within the tumor. Preimmunotherapy and postimmunotherapy breast magnetic resonance imaging results showed 9 objective responses, 6 partial responses, 3 complete responses, and 3 stable diseases. Following surgery, 7 patients had a pathologic complete response. Conclusions and Relevance:In this nonrandomized clinical trial, the addition of IT cDC1 and trastuzumab/pertuzumab before neoadjuvant chemotherapy was well tolerated with manageable adverse effects. Based on safety and immunogenicity, DL2 was selected for the phase 2 dose. Trial Registration:ClinicalTrials.gov Identifier: NCT05325632.

Type 1 dendritic cell vaccines targeting HER2 (HER2-DC1) reinvigorates antitumor immunity which correlates with neoadjuvant therapy response. A pilot trial (clinicaltrials.gov,NCT03387553,1/2/2018) using HER2-DC1 pre-neoadjuvant therapy evaluated feasibility/safety and pathologic response rates/immunogenicity. Stage II-III ER-HER2+ breast cancer patients prescribed neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) were enrolled. HER2-DC1 (2×107 cells/vaccine) was given for 3 weeks prior to chemotherapy intranodal (IN) 1x/week (Arm A), IN 2x/week (Arm B), and 2x/week alternating intratumoral (IT) and IN (Arm C). HER2 ELISPOT counts (EHC) and immunofluorescence analysis of biopsies were performed. Six patients enrolled in Arms A and B, 18 patients in Arm C. Neoadjuvant HER2-DC1 demonstrated no unexpected safety signals. Pathologic complete response rates (pCR) across arms A, B, C were 42.8%, 66.6%, and 72.7%. Intranodal HER2-DC1 increased EHC, but IT + IN HER2-DC1 reduced EHC, possibly due to increased T cell tumor trafficking. Immunofluorescence showed increased T cell infiltration following IT + IN injections. Additional IT HER2-DC1 investigation is warranted.

e13101 Background: Capivasertib and alpelisib have shown efficacy in clinical trials of HR+/HER2- MBC when used in patients (pts) with PI3K pathway alterations after progression on endocrine therapy. However, gaps remain in understanding their real-world efficacy and safety, particularly for capivasertib in pts whose clinical characteristics differ from trial populations and those previously treated with alpelisib. Methods: We conducted a retrospective analysis of 34 HR+/HER2- MBC pts treated with capivasertib at Moffitt Cancer Center after its approval in 11/2023. The primary endpoint was progression-free survival (PFS), defined as the time from capivasertib initiation to radiographic progression, last follow-up, or death. Secondary endpoints included PFS without (PFS1) and with prior alpelisib treatment (PFS2) and the adverse effects (AE) of capivasertib. Results: Median age of pts at capivasertib initiation was 61 years (range: 31–74). Most were Caucasian (88.2%), had ECOG performance status 0–1 (93.9%), and presented with HR+/HER2-low disease (73.5%). At capivasertib initiation, 85.3% had bone metastases, 76.5% had visceral disease, and 17.6% had brain metastases. Median number of prior therapies in the metastatic setting was 2 (range: 1-9). All pts were treated with CDK4/6 inhibitors, 44.1% received prior T-DXd, and 44.1% received other chemotherapy. Thirteen pts (38.2%) had been treated with alpelisib, including two who transitioned to capivasertib without intervening therapies. Thirteen pts remain on treatment with capivasertib as of data cut off on 1/24/2025. Most common mutations in PI3K pathway included- PIK3CA (85.3%), AKT (23.5%), and PTEN (17.6%). Additionally, 26.5% had co-mutations in ESR1. Four pts had partial response and 6 had stable disease (3 had durable response > 24 weeks) as best overall response. With a median follow-up of 6 months (range: 0.9–13 months), the median PFS was 3.5 months (95% CI 2.4-7.6) for the entire group. Median PFS1 (6.3 months, 95% CI 2.3-NR) and median PFS2 (3.4 months, 95% CI 2.4-NR) were comparable (HR 0.75, 95% CI 0.31–1.82, p = 0.53). The most common AE of any grade attributed to capivasertib included diarrhea (52.9%), nausea (35.3%), loss of appetite (35.3%), fatigue (29.4%), and hyperglycemia (14.7%). Grade ≥3 AE were limited to diarrhea and hyperglycemia, each occurring in one pt. Dose interruptions and reductions due to AE were required in 9.4% and 6.3% of pts, respectively. Conclusions: Our findings suggest that capivasertib could be an option for pts previously treated with alpelisib, with a manageable toxicity. The shorter PFS observed in our study compared to the CAPItello-291 trial is likely due to relatively short follow-up period, with 13 pts still on treatment at last follow-up, and the inclusion of a heavily pretreated population, many of whom had received multiple lines of chemotherapy, including T-DXd.

Introduction: Alpelisib is approved in combination with endocrine therapy (ET) to treat patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) progressive metastatic breast cancer (MBC). The SOLAR-1 trial demonstrated the efficacy of this oral agent and showed that, while alpelisib improves outcomes compared to placebo, it is also associated with clinically relevant adverse events (AEs). There is a pressing need for improved knowledge on the effectiveness and tolerability of this agent in real-world patient populations. Methods: We conducted a retrospective cohort study of patients with HR+, HER2- MBC treated with alpelisib and ET. We assessed the safety, tolerability, and effectiveness of alpelisib in a real-world population. Deidentified patient-, tumor-, and outcome-related data, including AEs, were collected and summarized. Kaplan-Meier methods were applied for survival analyses, and stratified analyses of interest were conducted. A p value <0.05 was considered statistically significant. Results: A total of 76 women treated with alpelisib + ET were included in our cohort. Most had been previously treated with cyclin-dependent kinase (CDK) 4/6 inhibitors and chemotherapy for MBC. The estimated median progression-free survival was 5.2 months (95% CI, 4.1-8.0). The median overall survival was longer among patients without prior everolimus therapy (hazard ratio, 4.28 [95% CI, 1.64-11.16]; p = 0.0012), and no significant outcome differences were observed between patients treated with different starting doses of alpelisib. Approximately 31.6% of patients permanently discontinued alpelisib due to AEs, and 32.9% had at least one dose reduction. The most common grade 3/4 AEs were hyperglycemia (21%), fatigue (13.2%), and diarrhea (10.5%). Conclusions: For progressive HR+, HER2- MBC, alpelisib + ET showed effectiveness in a real-world patient population that was comparable to published clinical trial data, regardless of starting dose. However, the effectiveness of alpelisib following previous everolimus exposure may be limited and, hence, should be a consideration to decide sequencing of therapy in these patients. Patients treated with alpelisib are at risk for clinically relevant AEs and require close monitoring.