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Background: In early-stage triple-negative breast cancer (TNBC), there is accumulating evidence of a correlation between tumor-infiltrating lymphocytes in tumor tissue and favorable clinical outcomes, with a high CD8+/regulatory T-cell (Treg) ratio after neoadjuvant chemotherapy being predictive of overall survival and associated with pathologic complete response (Ladoire S, et al. Br J Cancer. 2011; Park YH, et al. Nat Commun. 2020). Trilaciclib is a transient inhibitor of cyclin-dependent kinase 4/6 that is administered intravenously prior to chemotherapy. In preclinical studies, trilaciclib has been shown to have immune-enhancing effects by differentially arresting CD8+ T-cell and Treg subsets, which is followed by the faster recovery of CD8+ T cells than Tregs in the tumor microenvironment. Methods: This phase 2, single-arm, open-label study aims to evaluate neoadjuvant, single-dose trilaciclib followed by trilaciclib plus dose-dense anthracycline/cyclophosphamide and taxane in patients with early-stage TNBC (NCT05112536). Patients with previously untreated, non-metastatic, confirmed TNBC and a primary tumor ≥ 1.5 cm of any nodal status receive a single dose of trilaciclib 240 mg/m2 during the lead-in phase, followed by 4 cycles of doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2, and 12 weekly cycles of paclitaxel 80 mg/m2. Trilaciclib 240 mg/m2 is administered prior to the first chemotherapy dose of each cycle. Pembrolizumab 400 mg every 6 weeks starting on day 1, cycle 1, and/or carboplatin AUC 1.5 every week starting on day 1, cycle 5, is allowed per investigator discretion. Tumor biopsies and peripheral blood samples are collected prior to any treatment, 7 days ± 1 day post administration of trilaciclib, and during surgery, with an additional blood sample collection on day 1, cycle 2. The primary objective is to evaluate the immune-based mechanism of action of trilaciclib after a single dose of trilaciclib, as measured by changes in the CD8+/Treg ratio in tumor tissue. Pathologic complete response, safety and tolerability, and additional exploratory immune biomarker endpoints will also be assessed. Results: As of June 3, 2022, 9 patients with early-stage TNBC had been enrolled and 8 patients had received the trilaciclib lead-in dose and initiated doxorubicin/cyclophosphamide. Patients had a median age of 53.0 years, and all had stage II tumors at diagnosis, with 7 having ductal carcinoma. The median number of chemotherapy cycles received was 3 (range 1–6), and all 8 patients received pembrolizumab. Seven patients continue study treatment; 1 patient discontinued due to disease progression. Five patients had an adverse event (AE) related to any study treatment, including 4 patients with ≥ 1 trilaciclib-related AE. There were no grade ≥ 3 treatment-related AEs or serious AEs. On-treatment, post-trilaciclib monotherapy biopsies were available for 4 patients. Following neoadjuvant trilaciclib treatment, the median density of stromal CD8+ T cells increased from 103.1/mm2 at baseline to 229.8/mm2 at day 7. The median CD8+/Treg ratio increased in 2 patients from 1.85 at baseline to 1.90 at day 7. Conclusions: Preliminary analysis of on-treatment tumor biopsies from 4 patients suggests that a single dose of trilaciclib may modulate the immune cell composition in the tumor microenvironment to support antitumor immune responses. The increase in CD8+ T cells following 7-day neoadjuvant treatment with trilaciclib supports previous data suggesting a role in T-cell infiltration. The complete dataset from all patients (estimated enrollment: N ≈ 24) and additional biomarker analyses will be presented. Citation Format: Michael Danso, Joyce O’Shaughnessy, Lisa S. Wang, Kailash Mosalpuria, Sara Hurvitz, Shom Goel, Sarah Ahn, Subing Cao, John S. Yi, Taofik Oyekunle, Amanda Jacobson, Andrew Beelen, Jeremy Force. Trilaciclib induces immune changes within the tumor microenvironment in early-stage triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-06-03.

Abemaciclib has activity in xenograft models of triple negative breast cancer with intact Rb-signaling

Whole exome sequencing analysis of a panel of 44 breast cancer cell lines, enriched for somatic alterations with functional consequence in cancer

The cyclinD:CDK4/6:Rb axis is dysregulated in a variety of human cancers. Targeting this pathway has proven to be a successful therapeutic approach in ER+ breast cancer. In this study, in vitro and in vivo preclinical breast cancer models were used to investigate the expanded use of the CDK4/6 inhibitor, abemaciclib. Using a panel of 44 breast cancer cell lines, differential sensitivity to abemaciclib was observed and was seen predominately in the luminal ER+/HER2− and ER+/HER2+ subtypes. However, a subset of triple-negative breast cancer (TNBC) cell lines with intact Rb signaling were also found to be responsive. Equivalent levels of tumor growth inhibition were observed in ER+/HER2−, ER+/HER2+ as well as biomarker selected TNBC xenografts in response to abemaciclib. In addition, abemaciclib combined with hormonal blockade and/or HER2-targeted therapy induced significantly improved antitumor activity. CDK4/6 inhibition with abemaciclib combined with antimitotic agents, both in vitro and in vivo, did not antagonize the effect of either agent. Finally, we identified a set of Rb/E2F-regulated genes that consistently track with growth inhibitory response and constitute potential pharmacodynamic biomarkers of response to abemaciclib. Taken together, these data represent a comprehensive analysis of the preclinical activity of abemaciclib, used alone or in combination, in human breast cancer models. The subtypes most likely to respond to abemaciclib-based therapies can be identified by measurement of a specific set of biomarkers associated with increased dependency on cyclinD:CDK4/6:Rb signaling. These data support the clinical development of abemaciclib as monotherapy or as a combination partner in selected ER+/HER2−, HER2+/ER+, and TNBCs. Mol Cancer Ther; 17(5); 897–907. ©2018 AACR.

File containing three supplemental tables listing the mean tumor volumes and responses in the ER+/HER2-, HER2+/ER+ and TNBC xenografts

Supplementary Figure from Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2− Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial

Purpose: This study examined the feasibility, efficacy (abscopal effect), and immune effects of TGFβ blockade during radiotherapy in metastatic breast cancer patients.Experimental Design: Prospective randomized trial comparing two doses of TGFβ blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 weeks for five cycles, with focal radiotherapy to a metastatic site at week 1 (three doses of 7.5 Gy), that could be repeated to a second lesion at week 7. Research bloods were drawn at baseline, week 2, 5, and 15 to isolate PBMCs, plasma, and serum.Results: Twenty-three patients were randomized, median age 57 (range 35–77). Seven grade 3/4 adverse events occurred in 5 of 11 patients in the 1 mg/kg arm and in 2 of 12 patients in the 10 mg/kg arm, respectively. Response was limited to three stable disease. At a median follow up of 12 months, 20 of 23 patients are deceased. Patients receiving the 10 mg/kg had a significantly higher median overall survival than those receiving 1 mg/kg fresolimumab dose [hazard ratio: 2.73 with 95% confidence interval (CI), 1.02–7.30; P = 0.039]. The higher dose correlated with improved peripheral blood mononuclear cell counts and a striking boost in the CD8 central memory pool.Conclusions: TGFβ blockade during radiotherapy was feasible and well tolerated. Patients receiving the higher fresolimumab dose had a favorable systemic immune response and experienced longer median overall survival than the lower dose group. Clin Cancer Res; 24(11); 2493–504. ©2018 AACR.

Purpose:Ribociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase III MONALEESA-7 trial of pre-/perimenopausal patients with hormone receptor (HR)-positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months).Patients and Methods:Patients were randomized to receive ET [goserelin plus nonsteroidal aromatase inhibitor (NSAI) or tamoxifen] with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan–Meier methods.Results:The intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo [hazard ratio = 0.76; 95% confidence interval (CI), 0.61–0.96]. Kaplan–Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged less than 40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of cyclin-dependent kinase 4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug–drug interactions were observed between ribociclib and either NSAI.Conclusions:Ribociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged less than 40 years, with HR+/HER2− ABC with 53.5 months of median follow-up (ClinicalTrials.gov, NCT02278120).

Contains supplementary tables and methods

Supplementary Table S1. Antibodies and dextramers used for flow cytometric analysis Supplementary Table S2. Patients with one or more treatment positively-related (maximum grade possible, probable, definite) AEs by treatment arm Supplementary Table S3. Levels of circulating tumor-specific CD8+ T cells with reactivity for JARID1B, Muc1 or Her2 in breast cancer patients with HLA-A*0201 status Supplementary Table S4. Humoral immune responses were not significantly affected following TGFβ blockade and radiation Supplementary Figure S1: Study schema Supplementary Figure S2. Gating strategy in panel 1. Supplementary Figure S3. Gating strategy in panel 2. Supplementary Figure S4. Changes in PBMC, survivin- and JARID1B-reactive CD8 T cells in response to TGFβ blockade and radiation. Supplementary Figure S5. Diametrically opposing dynamics in the myeloid suppressor compartment versus the suppressor T cell pool in response to TGFβ blockade and radiation. Supplementary Figure S6. Changes in plasma levels of tryptophan and kynurenine in response to TGFβ blockade and radiation.

Purpose:Addition of alpelisib to fulvestrant significantly extended progression-free survival in PIK3CA-mutant, hormone receptor–positive (HR+) advanced/metastatic breast cancer in the phase III SOLAR-1 study. The combination of alpelisib and letrozole also had promising activity in phase I studies of HR+ advanced/metastatic breast cancer. NEO-ORB aimed to determine whether addition of alpelisib to letrozole could increase response rates in the neoadjuvant setting.Patients and Methods: Postmenopausal women with HR+, human epidermal growth factor receptor 2-negative, T1c-T3 breast cancer were assigned to the PIK3CA-wild-type or PIK3CA-mutant cohort according to their tumor PIK3CA status, and randomized (1:1) to 2.5 mg/day letrozole with 300 mg/day alpelisib or placebo for 24 weeks. Primary endpoints were objective response rate (ORR) and pathologic complete response (pCR) rate for both PIK3CA cohorts.Results:In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade ≥3 adverse events (≥5% of patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculo-papular rash (8%). The primary objective was not met; ORR in the alpelisib versus placebo arm was 43% versus 45% and 63% versus 61% in the PIK3CA-mutant and wild-type cohorts, respectively. pCR rates were low in all groups. Decreases in Ki-67 were similar across treatment arms and cohorts. In PIK3CA-mutant tumors, alpelisib plus letrozole treatment induced a greater decrease in phosphorylated AKT versus placebo plus letrozole.Conclusions:In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HR+ early breast cancer.

Supplementary Table from Updated Overall Survival of Ribociclib plus Endocrine Therapy versus Endocrine Therapy Alone in Pre- and Perimenopausal Patients with HR+/HER2− Advanced Breast Cancer in MONALEESA-7: A Phase III Randomized Clinical Trial

Background: Resistance to current endocrine therapies remains a clinical challenge. Fulvestrant has established estrogen receptor (ER) degradation as a critical therapeutic strategy characterized by approximately 50% ER degradation, a clinical benefit rate (CBR) of < 20% in the post CDK 4/6 setting, and a suboptimal intramuscular route of administration. ARV-471 is a selective, orally bioavailable PROteolysis-TArgeting Chimera (PROTAC®) small molecule that induces degradation of wildtype and mutant ER. ARV-471 demonstrates superior ER degradation and antitumor activity compared to fulvestrant in endocrine sensitive and resistant xenograft models. Methods: This is a multi-center, first-in-human, open label study to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of ARV-471 administered orally in patients with ER+/HER2- advanced/metastatic breast cancer. The phase 1 monotherapy dose escalation used a 3+3 design with backfill to assess ARV-471 in pre-/post-menopausal women. Premenopausal women had to be on ovarian suppression. Patients were required to have received at least one prior CDK 4/6 inhibitor and at least 2 prior endocrine therapies. Up to 3 prior lines of chemotherapy were allowed. Results: As of June 6th, 2021, 50 patients were treated in the monotherapy escalation at total daily doses of 30mg (n=3), 60mg (n=3), 120mg (n=7), 180/200mg (n=11), 360mg (n=15), 500mg (n=8), and maximum administered dose of 700mg (n=3). A maximum tolerated dose was not reached and no dose limiting toxicities (DLTs) were observed. The most common (≥ 10%) treatment related adverse events (TRAEs) were nausea (24%), fatigue (12%), and vomiting (10%) that were predominantly grade 1 in severity. Two patients experienced grade 3 adverse events (AEs) that were potentially related to ARV-471: 1 patient treated at 180mg had a transient headache lasting 1 day, and 1 patient treated at 360mg had a venous thromboembolism (VTE) a few days after a minor procedure. There were no AEs > grade 3 potentially related to ARV-471. All AEs were manageable with only one patient discontinuing ARV-471 due to a TRAE (grade 3 VTE). ARV-471 demonstrated a dose-related increase in plasma exposure up to 500mg, with doses of 60mg daily and above resulting in steady-state Cmax and AUC24 that exceeded the exposure associated with tumor regression in preclinical models. Analysis of 12 paired biopsies from patients treated at 30 to 360mg daily demonstrated up to 90% ER degradation in tumors expressing WT or mutant ER. Of 34 patients who were evaluable for clinical benefit (confirmed complete response, partial response, or stable disease ≥ 24 weeks) the CBR was 41%. As of the data cutoff date, 6 of the 34 patients were continuing to receive study treatment, including 2 patients who had been on treatment for over 16 months. Two confirmed partial responses were observed among the 28 patients with baseline measurable disease and at least 1 on-treatment tumor assessment. Conclusion: ARV-471 was well tolerated with no DLTs at total daily doses up to 700mg. ARV-471 demonstrated robust ER degradation in paired biopsy samples and encouraging clinical activity (41% CBR) in patients who received prior CDK 4/6 inhibitors. ARV-471 is now being evaluated in the VERITAC Phase 2 monotherapy expansion at 200 mg and 500 mg once daily. Citation Format: Erika Hamilton, Linda Vahdat, Hyo S Han, Jennifer Ranciato, Richard Gedrich, Chi F Keung, Deborah Chirnomas, Sara Hurvitz. First-in-human safety and activity of ARV-471, a novel PROTAC® estrogen receptor degrader, in ER+/HER2- locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD13-08.

Introduction: It is well established that multidisciplinary tumor boards improve the decision-making process for cancer patients. Tumor boards have been shown to improve the accuracy of diagnosis and staging, optimize patient outcomes, increase adherence to guidelines, and educate our peers and trainees. However, over 80% of patients in the United States receive their cancer care in the community setting, where access to multi-disciplinary tumor boards may not be readily available. This may particularly impact underserved populations who often lack the resources to travel to an academic center for second opinions or treatment. The problem is worse in low-resource countries. Virtual expert tumor boards could provide an effective solution. Methods: Preeminent breast oncology faculty from around the Unites States were assembled into virtual tumor board panels via an online platform to discuss challenging cases submitted by community providers and trainees. These tumor boards consisted of a moderator, a breast radiologist, a breast medical oncologist, a breast surgeon, and a breast radiation oncologist. The purpose of this ongoing endeavor is to educate community oncologists on how to best manage challenging cases. Following tumor board discussions, written recommendations were shared with submitting providers within 48 hours and recordings of the discussions were also later provided. After submitting providers watched the recording of their case discussion, we conducted a survey to determine their perceived benefit of the expert panel discussion. Results: From Sept 2020 to June 2021, ten breast cancer panels were virtually convened with 17 expert faculty panelists. During that time, 21 providers submitted 94 cases from the U.S. and around the world to be discussed by the expert panel. Thirty-three percent of the providers who submitted a case to be discussed have subsequently submitted an additional case to a later panel. Surveys were sent to all submitting providers and responses were recorded from 16/21 submitters (76.2%). Conclusion: With more than three out of four submitters responding, we learned that not only is it feasible to convene virtual expert breast tumor boards to discuss challenging cases, but the vast majority of respondents learned new information, changed management of their patients, and wanted to submit additional cases. This effort could raise the level of breast cancer care around the world. Ongoing assessment of educational and patient care impacts will be necessary. QuestionNumber answered (n)Number who answered yes (%)Number who answered no (%)Did you learn something new from the PrecisCa discussion of your case scenario?1614 (87.5)2 (12.5)Will anything you learned from the PrecisCa discussion of your case scenario change the management of this or future patients?1615 (93.8)1 (6.2)Are you likely to submit a future challenging case scenario to PrecisCa?1616 (100)0 (0) Citation Format: Naomi Dempsey, Lauren Chiec, Mikala Lodder, Erin Shonkwiler, Kayla Haines, Reshma Mahtani, William Gradishar, Thomas Buchholz, Anne O'Dea, Norman Wolmark, Sara Hurvitz, Joyce O'Shaughnessy, Maxine Jochelson, Reni Butler, Eleftherios Mamounas, Frank Vicini, Mark Pegram, Chirag Shah, Tari King, Ruth O'Regan, Monica Morrow, Mohammad Jahanzeb. Raising the level of cancer care around the world: The feasibility and perceived benefit of a virtual breast tumor board [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-17-03.

Background Although patients with clinical response of hormone receptor-positive (HR+)/HER2-negative breast cancer (BC) frequently respond to neoadjuvant therapy, fewer than 10% of patients achieve a pathologic complete response (pCR) with standard chemotherapy or endocrine therapy, even in combination with targeted agents such as CDK4/6 inhibitors. Thus, finding more effective therapies for this disease remains an area of unmet need. HER2 amplification is a known driver of endocrine resistance and HER2 may be expressed at a low level (IHC 1+ or 2+) in up to 60% of HR+ BC. Trastuzumab deruxtecan (DS-8201a, T-DXd) is a novel HER2-targeting antibody drug conjugate (ADC) that is FDA approved for HER2-positive metastatic BC and has demonstrated promising clinical efficacy in HER2-low BC with an objective response rate of ~37%. The aim of TALENT (TRIO-US B-12) is to evaluate the clinical activity and toxicity of neoadjuvant T-DXd either alone or in combination with endocrine therapy in patients with HR+/HER2-low early BC. Methods TRIO-US B-12 TALENT (NCT04553770) is an ongoing randomized, multicenter, open-label, two-stage, phase II neoadjuvant trial for participants with early stage, HR+, HER2-low expressing (1+ or 2+ by IHC) BC. Eligible participants include men and women with previously untreated, operable invasive BC greater than 2.0 cm (cT2) in size. Pts with recurrent or metastatic BC, or inflammatory BC are excluded. Pts are randomized 1:1 to receive six cycles of T-DXd (5.4 mg/kg IV q21 days) either alone or in combination with anastrozole AI (1 mg PO QD). Men and pre/peri menopausal women randomized to the AI arm also receive standard of care GnRH agonist. Stratification factors include HER2 expression (1+ or 2+) and menopausal status (men stratified as post-menopausal). Tumor tissue is taken at baseline, cycle 1 day 17-21, and at surgery. Blood samples are taken at four time points for biomarker analysis. The primary endpoint is pCR rate (breast and lymph node) at definitive surgery. In stage I, 58 participants will be randomized (29/arm). If ≥2 participants in an arm achieve pCR, that arm will expand (stage II) to enroll an additional 15 participants (total of 44/arm). A pCR rate of >10% (5/44) would be considered favorable, warranting further evaluation of the treatment in a larger trial. Other endpoints include safety, changes in Ki67 expression, Residual Cancer Burden index, biomarker analysis (including serial cfDNA analysis), and health-related quality of life. As of June 2021, sixteen participants have enrolled. Conclusions To our knowledge this is the first and only ongoing study evaluating T-DXd with or without endocrine therapy for HR+, HER2-low breast cancer in the neoadjuvant setting. The study will shed light on clinical activity and biomarkers, which may guide larger confirmatory studies for patients with HR+, HER2-low early breast cancer. Citation Format: Sara Hurvitz, Aditya Bardia, Merry L. Tetef, Nicholas P. McAndrew, Steven Applebaum, Aashini K. Master, Maggie L. DiNome, Minna K. Lee, Evangelia Kirimis, David D. Kim, Lisa S. Wang, Kyle Greene, Vu Phan, Nihal Abdulla, David Chan, Laura M. Spring, Christine Kivork, James Chauv. Phase II neoadjuvant trial evaluating trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early stage breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-12-05.

Background: The phase 3 ML-3 trial demonstrated significant OS benefit for ribociclib (RIB) + fulvestrant (FUL) over placebo (PBO) + FUL as first- or second- line therapy in postmenopausal pts with HR+/HER2- advanced breast cancer (ABC). Prior treatment ([neo]adjuvant or advanced setting) may impact subsequent therapy outcomes, including OS; therefore, understanding the potential effect of prior treatment is of high clinical interest. Here, we present PFS and OS data from 2 subgroup analyses in ML-3: 1L pts with de novo disease vs late relapse and all pts with vs without prior CT. Methods: ML-3 (NCT02422615) enrolled postmenopausal pts who were randomized 2:1 to receive RIB + FUL or PBO + FUL. Pts with prior ET ([neo]adjuvant or ≤1 prior ET for ABC) and no CT for ABC were included. Pts with de novo disease were defined as initially diagnosed as ABC with no prior treatment for ABC. Pts with late relapse were defined as those who relapsed >12 months from completion of (neo)adjuvant ET with no prior treatment for ABC. Since prior CT for ABC was not allowed in ML-3, the prior CT analysis compares pts with prior (neo)adjuvant CT vs those without prior (neo)adjuvant CT. Results: The data cutoff was October 30, 2020. Within the 1L population, in the de novo vs late relapse analysis, 132 pts (RIB: n = 91; PBO: n = 41) had de novo disease, and 153 had late relapse (RIB: n = 98; PBO: n = 55). Baseline characteristics were generally balanced between the de novo and late relapse groups, with some notable exceptions: a higher proportion of pts with de novo disease were aged RIB + FULPBO + FULHR (RIB vs PBO)De novo/late relapseMedian PFS (95% CI), monthsDe novo35.6. (27.1-42.0)22.1. (14.6-33.1)0.55. (0.35-0.86)Late relapse35.8. (20.0-44.4)22.0. (16.5-27.7)0.60. (0.40-0.89)HR (de novo vs late elapse)0.93. (0.64-1.36)0.996. (0.63-1.57)Median OS (95% CI), monthsDe novo59.9. (52.7-NE)52.9. (39.6-NE)0.67. (0.38-1.19)Late relapseNE. (54.9-NE)52.3. (40.4-NE)0.69. (0.42-1.13)HR (de novo vs late relapse)0.899. (0.552-1.465)0.91. (0.51-1.62)Prior (neo)adjuvant CTMedian PFS (95% CI), monthsWithout prior CT28.3. (23.3-35.6)17.5. (13.6-21.9)0.60. (0.46-0.78)With prior CTa17.9. (14.3-19.9)10.8. (7.2-12.3)0.61. (0.48-0.78)HR (without vs with prior CT)0.76. (0.60-0.94)0.72. (0.55-0.95)Median OS (95% CI), monthsWithout prior CTNE (54.9-NE)44.9 (38.5-58.1)0.70. (0.50-0.97)With prior CTa43.0 (39.1-51.2)40.1 (30.3-48.6)0.76. (0.58-1.01)HR (without vs with prior CT)0.68 (0.52-0.89)0.72 (0.52-1.00)NE, not estimable a Includes 4 patients who received prior CT for ABC (protocol violation). Citation Format: Michelino De Laurentiis, Matteo Lambertini, Stephen Chia, Hope S Rugo, Katarina Petrakova, Cristian Villanueva, Sara Hurvitz, J. Thaddeus Beck, Agnes Lteif, Sina Haftchenary, Uday Deore, Jiwen Wu, Nagi El-Saghir. Analysis of first-line (1L) patients (pts) with de novo disease vs late relapse and all pts with vs without prior chemotherapy (CT) in the MONALEESA-3 (ML-3) trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-11.

Background Selective estrogen receptor degraders (SERDs) block estrogen receptor (ER) associated signaling and have created interest for treating patients (pts) with advanced ER+ breast cancer (BC). Fulvestrant is currently the only SERD available for advanced BC but requires intramuscular administration, limiting the applied dose, exposure and receptor engagement. Amcenestrant (SAR439859) is an oral SERD that binds with high affinity to both wild-type and mutant ER, blocking estradiol binding and promoting up to 98% ER degradation in preclinical studies. In the phase I AMEERA-1 study of pretreated pts with ER+/HER2- advanced BC, amcenestrant 150-600 mg once daily (QD) showed a mean ER occupancy of 94% with plasma concentrations > 100 ng/mL and a favorable safety profile (Bardia, 2019; data on file). Combination therapy with amcenestrant + palbociclib (palbo) was also evaluated as part of this ongoing phase I study. CDK 4/6 inhibitors (CDK4/6i) combined with an aromatase inhibitor (AI), the gold standard for first line treatment for advanced breast cancer, prolong progression free survival (PFS) in pts with no prior treatment for ER+/HER2- advanced BC, but OS benefit has not been shown yet in postmenopausal pts. There remains a clinical need for more effective treatments in this setting. Methods AMEERA-5 (NCT04478266) is an ongoing, prospective, randomized, double-blind phase III study comparing the efficacy and safety of amcenestrant + palbo with that of letrozole + palbo in pts with advanced, locoregional recurrent or metastatic ER+/HER2- BC who have not received prior systemic therapy for advanced disease. The study includes men, pre/peri-menopausal (with goserelin) and post-menopausal women. Pts with progression during or within 12 months of (neo)adjuvant endocrine therapy using any of the following agents are excluded: AI, selective estrogen receptor modulators, CDK4/6i. Pts are randomized 1:1 to either continuous amcenestrant 200 mg or letrozole 2.5 mg QD orally with matching placebos; both combined with palbo 125 mg QD orally (d1-21 every 28-d cycle). Randomization is stratified according to disease type (de novo metastatic vs recurrent disease), the presence of visceral metastasis, and menopausal status. The primary endpoint is investigator assessed progression free survival (PFS) (RECIST v1.1). Secondary endpoints are overall survival, PFS2, objective response rate, duration of response, clinical benefit rate, pharmacokinetics of amcenestrant and palbo, health-related quality of life, time to chemotherapy, and safety. Biomarkers will be measured in paired tumor biopsies and cell free deoxyribonucleic acid (cfDNA) over time. Target enrolment = 1066 pts; enrolment as of 6/2021 = 415 pts. Bardia A, et al., J Clin Oncol. 2019; 37 (15 suppl):1054. Funding: Sanofi. This abstract was accepted and previously presented at the 2021 American Society of Clinical Oncology Annual Meeting. All rights reserved. Citation Format: Aditya Bardia, Javier Cortes, Sara Hurvitz, Suzette Delaloge, Hiroji Iwata, Zhi-Ming Shao, Dheepak Kanagavel, Patrick Cohen, Qianying Liu, Sylvaine Cartot-Cotton, Vasiliki Pelekanou, Joyce O’Shaughnessy. AMEERA-5 : A randomized, double-blind phase 3 study of amcenestrant (SAR439859) + palbociclib versus letrozole + palbociclib for previously untreated ER+/HER2- advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-11-08.

Background: Amplification of the human epidermal growth factor receptor 2 (HER2) gene with consequent HER2 protein overexpression occurs in approximately 20% of breast cancers (BC) and is a major driver of tumor development and progression. The HER2-targeted ADC trastuzumab emtansine (T-DM1) has been approved for the treatment of HER2-positive metastatic BC (mBC) after prior trastuzumab and taxane therapy. However, disease progression occurs in all patients requiring additional therapeutic options. The use of second-generation anti-HER2 ADCs using alternative molecules is being investigated to overcome drug resistance. ARX788 is a next-generation ADC using a technology platform whereby a HER2-specific monoclonal antibody is conjugated with Amberstatin269, a potent cytotoxic tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 lead to its slow release and prolongation of the peak serum pAF-AS269 concentration, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells at a lower effective dose compared to other HER2 ADCs. Here, early evidence of activity of ARX788 in patients previously treated with T-DM1 is shown. Methods: ACE-Breast-03 (NCT04829604) is an ongoing global, phase 2, single-arm study evaluating ARX788 in patients with HER2+ mBC whose disease has progressed following T-DM1, T-DXd, and/or tucatinib-containing regimens. The ARX788 is administered with an initial dose of 1.5 mg/kg Q4W and subsequent doses of 1.3 mg/kg Q4W. Eligibility criteria included central laboratory confirmed HER2+ mBC per ASCO/CAP guidelines, measurable disease, and adequate organ function. Stable treated brain metastases are allowed. Patients with interstitial lung disease (ILD) or pneumonitis in prior 12 months; active ocular infections or any chronic corneal disorder; are excluded. The primary endpoint is overall response rate (ORR). Results: At the data cutoff of 11-Jul-2022, 7 patients were enrolled in ACE-Breast-03 (v1.0) who previously experienced disease progression on T-DM1 and had response-evaluable disease. Pts had a median age of 59 years and had received a median of 5 lines of prior anti-HER2 cancer therapy (range: 2-8). None of the pts in this subset had received T-DXd or tucatinib. 5 pts were previously treated with HER2-targeted TKIs (neratinib and lapatinib), as well as an investigational HER2 ADC and responded to ARX788 (3 PR; 2 SD). Two patients had hormone receptor (HR)-positive disease and 5 had HR-negative mBC. Treatment with ARX788 remains ongoing with the median time of ARX788 therapy of 4.5 months. The confirmed ORR was 57.1% (4/7 pts) and an unconfirmed ORR of 71.4% (5/7 pts) as one pt experienced an unconfirmed response with PR after 2 cycles. The disease control rate (DCR) was 100% (7/7 pts). No drug-related grade ≥3 AEs were reported; 57.1% (4/7 pts) reported ocular AEs including grade 1 events in 3 pts (i.e., dry eye, blurred vision) and a grade 2 event in one pt (lagophthalmos). No pneumonitis or ILD was observed. ARX788 was well-tolerated, and AEs were manageable. Conclusion: In this small cohort of patients previously treated with T-DM1, ARX788 had a manageable AE profile and demonstrated promising clinical activity (confirmed ORR 57%; DCR 100%). Figure 1: ACE-Breast-03 Spider Plot for patients with mBC who were previously treated with T-DM1 Figure 1: ACE-Breast-03 Spider Plot for patients with mBC who were previously treated with T-DM1 ARX788 demonstrated promising clinical activity in patients previously treated with T-DM1. Citation Format: Sara Hurvitz, Kevin Kalinsky, Vinod Ganju, Kashif Ali, Laila Agrawal, William Gradishar, George Sledge, Anu Thummala, Arlene Chan, Sophia Frentzas, Joo Hyuk Sohn, Kyong-Hwa Park, Keon Uk Park, Catherine Shannon, Joshua Drago, Sara Tolaney, Hope Rugo, Michael F. Press, Alex Alika, Dong Xu, Janice Lu, Debu Tripathy. ACE-Breast-03: Efficacy and safety of ARX788 in patients with HER2+ metastatic breast cancer previously treated with T-DM1 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-09.

BACKGROUND Endocrine therapies (ETs) that target estrogen receptor (ER) activity and/or estrogen synthesis are the mainstay of ER+ breast cancer (BC) treatment. Despite best management, ≤20% of patients (pts) with ER+/HER2– early BC (eBC) develop resistance (in some cases due to acquisition of tumor mutations in ESR1 that can drive estrogen-independent transcription and proliferation) and still have high recurrence rates on standard ETs. New treatment alternatives for ER+/HER2– eBC are needed to reduce risk of recurrence and improve survival, tolerability, quality of life, and adherence. Giredestrant, a highly potent, nonsteroidal oral selective ER antagonist and degrader (SERD), achieves robust ER occupancy and is active against tumors that retain ER-sensitivity or have ESR1 mutation(s). It has been demonstrated to be more potent in vitro and achieves higher ER occupancy in vivo than fulvestrant, the only currently approved SERD. Early-phase clinical studies have demonstrated that single-agent giredestrant (30 mg daily) has promising clinical and pharmacodynamic activity and is well tolerated in the ER+/HER2– eBC and metastatic BC settings. TRIAL DESIGN This is a phase III, global, randomized, open-label, multicenter study evaluating efficacy and safety of adjuvant giredestrant vs physician’s choice of adjuvant ET (PCET) in pts with medium- and high-risk stage I–III histologically confirmed ER+/HER2– eBC. Pts are randomized 1:1 to oral 30 mg daily giredestrant or PCET (tamoxifen, anastrozole, letrozole, or exemestane, given according to prescribing information). Stratification factors are risk (medium vs high, based on anatomic [tumor size, nodal status] and biologic features [grade, Ki67, gene signatures if available]); geographic region (US/Canada/Western Europe vs Asia-Pacific vs rest of the world); prior chemotherapy (no vs yes); and menopausal status (pre-/perimenopausal vs postmenopausal). Beginning on Day 1 of Cycle 1, pts will be treated with giredestrant or PCET for ≥5 years. Continuing PCET after 5 years is at discretion of the investigator and per local standard of care. ELIGIBILITY Female/male pts with medium-/high-risk stage I–III ER+/HER2– eBC; prior curative surgery; completion of (neo)adjuvant chemotherapy (if administered) and/or surgery < 12 months prior to enrollment; no prior ET (≤4 weeks of [neo]adjuvant ET is allowed). For men and pre-/perimenopausal women, a luteinizing hormone-releasing hormone agonist will be given per local prescribing information (mandatory for pts in the giredestrant arm). AIMS Primary endpoint: Invasive disease-free survival (IDFS). Secondary endpoints: Overall survival; IDFS (STEEP definition, including second non-primary BC); disease-free survival; distant recurrence-free survival; locoregional recurrence-free interval; safety; pharmacokinetics; pt-reported outcomes. In addition, this study aims to improve health equity in research and expand clinical trial access. The study will also use/develop digital healthcare solutions, which will enable better understanding of pts’ needs and their adherence to ET. STATISTICAL METHODS The primary endpoint analysis will use a stratified log-rank test at an overall 0.05 significance level (two-sided). An interim analysis and a futility analysis are planned, and an independent data monitoring committee will be in place. ACCRUAL 1018/4100 pts have been recruited globally. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number NCT04961996. AB, PS and CG contributed equally. This abstract was originally presented at SABCS 2021 (OT2-11-09). a>Disclosure(s): Peter Schmid, MD, PhD: Astellas Pharma: Contracted Research (Ongoing); AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing); Bayer: Consulting Fees (e.g., advisory boards) (Ongoing), Honoraria (Ongoing); Boehringer Ingelheim: Consulting Fees (e.g., advisory boards) (Ongoing), Honoraria (Ongoing); Celgene: Consulting Fees (e.g., advisory boards) (Ongoing); Eisai: Consulting Fees (e.g., advisory boards) (Ongoing); F. Hoffmann-La Roche Ltd.: Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Genentech: Contracted Research (Ongoing); Medivation Inc.: Contracted Research (Ongoing); Merck: Consulting Fees (e.g., advisory boards) (Ongoing), Honoraria (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing); OncoGenex: Contracted Research (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Honoraria (Ongoing); Puma Biotechnology: Consulting Fees (e.g., advisory boards) (Ongoing), Honoraria (Ongoing); Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing) Charles E. Geyer Jr, MD, FACP: Abbvie: Contracted Research (Terminated, July 1, 2022), Writing assistance (Terminated, July 1, 2022); AstraZeneca: Contracted Research (Ongoing), Writing assistance (Ongoing); Daiichi/Sankyo: Contracted Research (Ongoing); Exact Sciences: Consulting Fees (e.g., advisory boards) (Ongoing); F. Hoffman-La Roche Ltd: Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche) (Ongoing); Genentech: Contracted Research (Ongoing), Writing assistance (Ongoing) Nadia Harbeck, MD, PhD: Amgen: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Daiichi Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Eli Lilly: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Exact Sciences: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); MSD: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Pierre Fabre: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Sandoz: Consulting Fees (e.g., advisory boards) (Ongoing); Seagen: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); WSG: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing) Mothaffar Rimawi, MD: Daiichi Sankyo: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); F. Hoffmann-La Roche Ltd.: Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Genentech: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Macrogenics: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Pfizer: Contracted Research (Ongoing); Seattle Genetics: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing) Sara Hurvitz, MD, FACP: Ambrx: Contracted Research (Ongoing); Amgen: Contracted Research (Ongoing); Arvinas: Contracted Research (Ongoing); Astra Zeneca: Contracted Research (Ongoing); Bayer: Contracted Research (Ongoing); Cytomx: Contracted Research (Ongoing); Daiichi-Sankyo: Contracted Research (Ongoing); Dignitana: Contracted Research (Ongoing); Eli Lilly: Contracted Research (Ongoing); Genentech/Roche: Contracted Research (Ongoing); Gilead: Contracted Research (Ongoing); GSK: Contracted Research (Ongoing); Ideal Implant: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing); Immunomedics: Contracted Research (Ongoing); Macrogenics: Contracted Research (Ongoing); Novartis: Contracted Research (Ongoing); OBI Pharma: Contracted Research (Ongoing); Orinove: Contracted Research (Ongoing); Pfizer: Contracted Research (Ongoing); Phoenix Molecular Designs, Ltd.: Contracted Research (Ongoing); Pieris: Contracted Research (Ongoing); PUMA: Contracted Research (Ongoing); Radius: Contracted Research (Ongoing); Sanofi: Contracted Research (Ongoing); Seattle Genetics/Seagen: Contracted Research (Ongoing); Zymeworks: Contracted Research (Ongoing) Miguel Martín, MD, PhD: AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Daiichi Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); F. Hoffmann-La Roche: Third-party writing assistance for this abstract, furnished by Eleanor Porteous, MSc, of Health Interactions, was provided by Roche (Ongoing); Genentech/Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Gilead: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Lilly/ImClone: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Honoraria (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Honoraria (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Honoraria (Ongoing); Pierre Fabre: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Honoraria (Ongoing); Seagen: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing), Honoraria (Ongoing) Sherene Loi, MBBS (Hons), PhD, FRACP, FAHMS, GAICD: Aduro Biotech, Inc.: Consulting Fees (e.g., advisory boards) (Ongoing); Akamara Therapeutics: Uncompensated scientific advisory board member (Ongoing); AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Uncompensated consultant (Ongoing); BMS: Uncompensated consultant (Ongoing); Breast Cancer Research Foundation, New York: Supported by the Breast Cancer Research Foundation, New York (Ongoing); G1 Therapeutics: Consulting Fees (e.g., advisory boards) (Ongoing); GlaxoSmithKline: Consulting Fees (e.g., advisory boards) (Ongoing); Merck: Uncompensated consultant (Ongoing); National Breast Cancer Foundation of Australia Endowed Chair: Supported by the National Breast Cancer Foundation of Australia Endowed Chair (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Uncompensated consultant (Ongoing); Roche-Genentech: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing), Uncompensated consultant (Ongoing); Seattle Genetics: Uncompensated consultant (Ongoing); Silverback Therapeutics: Consulting Fees (e.g., advisory boards) (Ongoing) Shigehira Saji, MD, PhD: Astra Zeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Bayer: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Boerhringer-ingelheim: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Breast International Group: Executive board member (Ongoing); Chugai: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Daiichi Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Eisai: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Eli Lilly: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); F. Hoffmann-La Roche Ltd.: Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Japan Breast Cancer Research Group: Executive board member (Ongoing); Japanese Breast Cancer Society: Executive board member (Ongoing); Japanese Society of Medical Oncology: Executive board member (Ongoing); Kyowa Kirin: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); MSD: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Nihonkayaku: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Novartis: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Ono: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Taiho: Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); Takeda: Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing) Kyung Hae Jung, MD, MS, PhD: AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing); Celgene: Consulting Fees (e.g., advisory boards) (Ongoing); Daiichi-Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing); Eisai: Consulting Fees (e.g., advisory boards) (Ongoing); Everest Medicine: Consulting Fees (e.g., advisory boards) (Ongoing); Merck: Consulting Fees (e.g., advisory boards) (Ongoing); MSD: Consulting Fees (e.g., advisory boards) (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing); Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Takeda: Consulting Fees (e.g., advisory boards) (Ongoing) Gustavo Werutsky, MD, PhD: AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing); Bayer: Contracted Research (Ongoing); Beigene: Contracted Research (Ongoing); Daiichi Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing); Genentech/Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Fees for Non-CME Services Received Directly from Commercial Interest or their Agents (e.g., speakers’ bureaus) (Ongoing); GSK: Contracted Research (Ongoing); Lilly: Contracted Research (Ongoing), Honoraria (Ongoing); MSD: Honoraria (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Honoraria (Ongoing); Sanofi: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Seattle Genetics: Contracted Research (Ongoing) Daniil L. Stroyakovsky, MD: Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing) Vanesa López-Valverde, PharmD, PhD: F. Hoffmann-La Roche Ltd.: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing), Salary (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing) Michael Davis, PsyD: F. Hoffmann-La Roche Ltd.: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Genentech, Inc.: Salary (Ongoing) Tanja Badovinac Crnjevic, MD, PhD: F. Hoffmann-La Roche Ltd.: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing), Salary (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing) Pablo D. Perez-Moreno, MD: F. Hoffmann-La Roche Ltd.: Ownership Interest (stocks, stock options, patent or other intellectual property or other ownership interest excluding diversified mutual funds) (Ongoing), Third-party writing assistance for this abstract, furnished by Sunaina Indermun, BPharm, PhD, of Health Interactions, was provided by Roche (Ongoing); Genentech, Inc.: Salary (Ongoing) Aditya Bardia, MD, MPH: AstraZeneca: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); BioTheranostics: Consulting Fees (e.g., advisory boards) (Ongoing); Daiichi Sankyo: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Eli Lilly: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Foundation Medicine: Consulting Fees (e.g., advisory boards) (Ongoing); Genentech/Roche: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Immunomedics/Gilead: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Merck: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Novartis: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Pfizer: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Phillips: Consulting Fees (e.g., advisory boards) (Ongoing); Radius Health: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing); Sanofi: Consulting Fees (e.g., advisory boards) (Ongoing), Contracted Research (Ongoing) Citation Format: Peter Schmid, Charles E. Geyer Jr, Nadia Harbeck, Mothaffar Rimawi, Sara Hurvitz, Miguel Martín, Sherene Loi, Shigehira Saji, Kyung Hae Jung, Gustavo Werutsky, Daniil L. Stroyakovsky, Vanesa López-Valverde, Michael Davis, Tanja Badovinac Crnjevic, Pablo D. Perez-Moreno, Aditya Bardia. lidERA Breast Cancer: A phase III adjuvant study of giredestrant (GDC-9545) vs physician’s choice of endocrine therapy in patients with estrogen receptor+, HER2– early breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-03-02.

Background: Although patients (pts) with hormone receptor-positive (HR+)/HER2-negative breast cancer (BC) frequently experience disease response to neoadjuvant therapy, fewer than 10% achieve a pathologic complete response (pCR) with standard chemotherapy or endocrine therapy, even in combination with CDK4/6 inhibitors. Thus, finding more effective therapies for this disease remains an unmet need. HER2 is expressed at a low level (IHC 1+ or 2+) in approximately 60-70% of HR+ BC. Trastuzumab deruxtecan (DS-8201a, T-DXd) is a novel HER2-targeting antibody drug conjugate (ADC) that is FDA approved in the US for HER2-positive and HER2-low metastatic BC (with boxed warnings for interstitial lung disease). However, the efficacy of T-DXd in the neoadjuvant setting is not known. The primary objective of TALENT (TRIO-US B-12, NCT04553770) is to evaluate the clinical activity and safety of neoadjuvant T-DXd alone or in combination with endocrine therapy in pts with HR+/HER2-low early BC. Methods: Men and women with previously untreated, operable invasive early stage, non-recurrent, HR+, HER2-low (IHC 1+ or 2+/ISH- by local or central review) BC measuring > 2 cm were eligible. In stage 1 of clinical trial, participants were randomized 1:1 to receive T-DXd (5.4 mg/kg IV q21 days) alone, Arm A, or in combination with anastrozole AI (1 mg PO QD), Arm B. Originally 6 cycles (cy) were given but in 02/2022, an amendment increased the number of treatment cy from 6 to 8 for newly enrolled pts, or those who had not yet had surgery. Men and pre/peri-menopausal women randomized to Arm B also received a GnRH agonist. Stratification factors were HER2 expression (1+ vs. 2+) and menopausal status (men as postmenopausal). Tumor tissue collected at baseline, cy 1 day 17-21, and at surgery. Breast imaging performed at baseline, cy 2 and pre-surgery/EOT. Primary endpoint is pCR rate (ypT0/is ypN0) at surgery. In stage 1, intent was to randomize 58 pts (if at least 2 pCR occurred in an arm, arm progresses to Stage 2 and an additional 15 pts to be enrolled). Other endpoints include safety, objective response rate (ORR), changes in Ki67 expression, Residual Cancer Burden index, exploratory biomarker analysis, and health-related quality of life. Here we present results from stage 1 of the trial. Results: From 09/21/2020 to 10/13/2022, 58 pts were enrolled and treated (29 Arm A, 29 Arm B) in stage 1 of trial. Five pts came off study before completing study therapy (2 after cy 1, 2 after cy 2, 1 after cy 3). As of data cut-off (10/05/2022), 33 pts completed study treatment and have had surgery (17 Arm A, 16 Arm B), 13 are on treatment and 7 are pending surgery; 27 pts completed 6 cy and 13 completed 8 cy. Baseline characteristics were balanced between arms. 19/58 pts were Stage IIA, 26/58 Stage IIB, 12/58 Stage IIIA, and 1/58 Stage IIIB at baseline. 46/58 pts had baseline HER2 expression (from central review) of 1+, 4/58 were 0, 6/58 were 2+, 1/58 had multicentric lesion 1+ and 2+, and 1/58 had a single lesion with 1+ and 2+. In Arm A, 1/17 pt had pCR after 8 cy, 2/17 pts had RCB-I after 6 cy (17.6% RCB 0/1). In Arm B, 1/16 pt had RCB-I after 8 cy (6.3%). The ORR for response-evaluable pts in Arm A was 75% (12/16, 1 CR, 11 PR) and in Arm B was 63.2% (12/19, 2 CR, 10 PR); 1 patient (Arm B) had PD. ILD occurred in 1 pt (1.7%), Gr 2 and resolved 11 days after stopping therapy. Most common treatment-related Grade ≥ 3 AEs in Arms A and B, respectively, include hypokalemia (1.7%, 5.2%), diarrhea (3.4%, 3.4%), neutropenia (3.4%, 1.7%), fatigue (1.7%, 3.4%), headache (3.4%, 1.7%), vomiting (3.4%, 1.7%), dehydration (1.7%, 1.7%) and nausea (3.4%, 0%). Conclusions: This is the first report of a trial evaluating neoadjuvant T-DXd in HER2 low breast cancer. T-DXd +/- endocrine therapy demonstrates promising clinical activity for pts with HR+ BC. Updated study results will be provided at the time of presentation. Citation Format: Aditya Bardia, Sara Hurvitz, Michael F. Press, Lisa S. Wang, Nicholas P. McAndrew, David Chan, Vu Phan, Deborah Villa, Merry L. Tetef, Erin Chamberlain, Nihal Abdulla, Thomas Lomis, Laura M. Spring, Steven Applebaum, Shaker Dakhil, Brian DiCarlo, David D. Kim, Evangelia Kirimis, William E. Lawler, Aashini K. Master, Kelly McCann, Edwin Hayashi, Christine Kivork, James Chauv. GS2-03 TRIO-US B-12 TALENT: Neoadjuvant trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early stage breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS2-03.

Background: Endocrine therapy remains the mainstay treatment for ER+ BC. CDK4/6 inhibitors induce cell cycle arrest and decrease tumor cell proliferation, as measured by the biomarker Ki67, when used in combination with aromatase inhibitors (AI) such as anastrozole (A). Giredestrant is an oral, well-tolerated, and highly potent selective ER degrader (SERD) that achieves robust ER suppression and has demonstrated antitumor activity in the metastatic setting either as monotherapy or in combination with the CDK4/6 inhibitor palbociclib. The randomized, phase 2 coopERA Breast Cancer study (NCT04436744) evaluated giredestrant in postmenopausal women with untreated ER+/HER2- early BC and met its primary endpoint, demonstrating superior Ki67 suppression with giredestrant vs A after two weeks of single agent treatment. This suppression was maintained at surgery where giredestrant vs A was evaluated in combination with palbociclib. Here, we present gene expression analysis and associations with Ki67 response. Methods: 221 eligible patients with measurable ER+/HER2– untreated early BC and baseline Ki67 ≥ 5% were randomized 1:1 to receive 30 mg oral daily (PO QD) giredestrant or 1 mg PO QD A on Days 1–14 of a neoadjuvant window-of-opportunity phase, followed by four 28-day cycles of PO QD giredestrant or A with 125 mg PO QD palbociclib on Days 1–21 before surgery. FFPE specimens were collected at baseline, week 2 and surgery; and RNA-sequencing (seq) was performed. Gene expression analysis included ER pathway activity, PAM50 intrinsic subtypes, and other pathway analyses, assessed by Ki67 response. Results: 112 and 92 patients had paired tumor samples at baseline/week 2 and baseline/surgery, respectively, that were evaluable for RNA-seq and Ki67. The trend for greater Ki67 protein suppression by giredestrant vs A from baseline to week 2 was maintained in the RNA-seq evaluable subset. Interestingly, the same subset revealed similar suppression of both proliferation gene signatures and ER pathway activity between A and giredestrant. PAM50 subtyping showed that 69% of tumors were luminal (Lum) A and 29% were LumB at baseline. Less than 1% were classified as basal or HER2. Interestingly, giredestrant (G) showed greater suppression of both Ki67 and ER pathway activity vs A in LumB tumors (Ki67: -82% [G] vs -62% [A]; ER activity: -0.83 [G] vs -0.66 [A]) compared to LumA at week 2 (Ki67: -74% [G] vs -71% [A]; ER activity: -0.60 [G] vs -0.70 [A]). Moreover, at week 2, 83% (13/18) of LumB tumors at baseline transitioned into a LumA subtype after giredestrant treatment compared to 46% (5/11) of A-treated tumors. Giredestrant-treated tumors also achieved lower mean ER pathway activity compared to those treated with A at surgery (p=0.023). Gene set enrichment analysis showed downregulation of cell-cycle and ER-related pathways at week 2 and surgery in both treatment arms. A subset of cytokine signaling and immune response pathways were increased at week 2 compared to baseline after treatment with A but not with giredestrant. These pathways were also associated with Ki67 resistance (Ki67 ≥ 7.4%) in A-treated tumors. This was consistent with differential expression analysis of samples collected at week 2, in which cytokine signaling pathways were enriched in A compared to giredestrant. Notably, IL12 signaling was enriched in tumors resistant to A but not giredestrant. Conclusions: Giredestrant has a greater effect on Ki67 protein suppression in ER+/HER2- early BC compared to A, which is more pronounced in LumB tumors. This benefit may involve differential regulation of cytokine and immune responses. These exploratory findings reveal novel mechanisms that may differentiate the activity of SERDs vs AIs, which warrant further validation. Citation Format: Alejandro M. Chibly, Tharu M. Fernando, Ciara Metcalfe, Marc Hafner, Gilbert Owusu-Manu, Sara Hurvitz, Aditya Bardia, Peter A. Fasching, Yeon H. Park, Vanesa Quiroga, Jutta Steinseifer, Pablo Perez-Moreno, Heather M. Moore. PD13-02 Exploratory gene expression analysis of coopERA Breast Cancer (BC): a study evaluating neoadjuvant giredestrant versus anastrozole alone and in combination with palbociclib in ER-positive, HER2-negative untreated early BC [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-02.

Objectives: The addition of a CDK 4/6 inhibitors to endocrine therapy, in the first or second line setting, provides a significant improvement in progression free survival (PFS), and in some cases in overall survival (OS), with a tolerable toxicity profile. Regardless, most patients experience disease progression on these agents and ultimately develop endocrine resistance, thus, emphasizing the critical need for novel treatments. Elacestrant showed a statistically significant improvement in PFS when compared to standard of care endocrine therapy after progression on CDK4/6 inhibitors in combination with endocrine therapy (Bidard et al, 2022). Onapristone is a type I antiprogestin which prevents the progesterone receptor (PgR) from dimerizing and blocks ligand-induced protein kinase-mediated phosphorylation of the PgR. The clinical anticancer activity of onapristone, in immediate release formulation, has been previously documented in patients with hormone therapy-naïve (Robertson et al, 1999) or tamoxifen-resistant (Jonat et al, 2002) breast cancer (BC). More recently, onapristone, in extended release formulation, was evaluated in doses up to 50 mg BID in a phase 1 trial that enrolled 52 heavily pretreated patients with metastatic solid tumors, with no dose limiting toxicity observed. Among the 20 breast cancer patients enrolled, 7 (35%) had stable disease (Cottou et al, 2018). Methods: ELONA is a phase 1b/2, open-label, multicenter study. The phase 1b portion of the study will assess the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of elacestrant plus onapristone to determine the combinations’ recommended phase 2 dose. The primary endpoint of the phase 2 part of the trial is objective response rate and secondary endpoints will include safety, duration of response, clinical benefit rate, PFS, and OS, in addition to pharmacodynamics markers using ctDNA. Eligible patients are pre-, peri- and post-menopausal women and men aged ≥18 years with ER+/PgR+,HER2- tumors and an Eastern Cooperative Oncology Group performance status ≤2 with at least one measurable lesion at baseline, as per RECIST version 1.1. Prior therapy in the metastatic setting includes at least one anti-hormonal therapy in combination with a CDK4/6i. No prior chemotherapy regimen in the metastatic setting is allowed. The phase 1b dose-escalation portion of the study will evaluate dose-limiting toxicities (DLTs) of the combination in up to 4 cohorts of 6 patients each. Citation Format: Erika Hamilton, Lajos Pusztai, Hatem H. Soliman, Sara Hurvitz, Krzysztof Grzegorzewski, Nassir Habboubi, Priya Marreddy, Tarek Sahmoud, Nuhad Ibrahim. ELONA: An open-label, phase 1b-2 study of elacestrant, in combination with onapristone in patients with estrogen receptor-positive, progesterone receptor-positive, HER2-negative advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-04.

Background: Breast cancer (BC) is the most common malignancy in women and metastatic triple negative breast cancer (mTNBC) remains one of the most difficult to treat cancers with few targeted treatment options. RSK is recognized as a critical signaling component in the MAPK/PDK-1 pathways, is an important driver for BC and a signature of poor prognosis. PMD-026 is the first RSK inhibitor to enter clinical trials and is being developed alongside an immunohistochemistry (IHC) companion diagnostic to select patients with increased activated RSK2 in tumor tissue. A Phase 1/1b trial of PMD-026 in patients with metastatic breast cancer (mBC) or metastatic triple negative breast cancer (mTNBC) established safety at a dose of 200 mg Q12h. Efficacy signals in patients with heavily pretreated mBC/mTNBC are explored in this analysis along with evaluation of the effect of food (FE) on systemic exposure to treatment. Methods: PMD-026 was administered to 41 patients as a single agent in this phase 1/1b open-label study, with 30 patients evaluable for efficacy. Exploratory objectives were to identify subgroups of patients who may optimally benefit from PMD-026. Subgroup analysis of patients included 1) comparing BC patients who received ≤5 vs >5 prior therapies; 2) comparing TNBC patients (de novo vs secondary subtypes)1, and 3) comparing patients with low RSK2 H-scores (< 180) vs high (≥180). In addition, PMD 026 PK was evaluated at the 200 mg Q12h dose and a FE sub-study enrolled 12 patients administered a single 200 mg dose. Results: PMD-026 monotherapy was generally well-tolerated in the 41 mBC patients who were enrolled and treated. Kaplan-Meier PFS analysis of 30 evaluable BC patients who were dosed with PMD-026 showed that patients with less prior therapy (≤5) did significantly better (HR, 0.19; 95% CI [0.06–0.52], p=0.0014) than those with > 5 prior therapies. Subgroup analysis of PFS in those with TNBC demonstrated that de novo TNBC (n=17) had longer time on treatment with PMD-026 compared with secondary TNBC (n=9) (HR, 0.31; 95% CI [0.10-0.99], p=0.0476). In those with de novo TNBC with ≤5 prior therapies, a high RSK2 H-score was associated with significantly longer PFS at the RP2D (4.2 vs 1.3 months, HR, 0.17; 95% CI [0.03-0.80], p=0.0254) than patients with a low RSK2 H-score. In patients with CDK4/6 resistant HR+ BC (n=3), PFS was 5.2 (RSK2 high) vs 1.3 months (RSK2 low). Stable disease was observed in 53% (9/17) of patients with de novo TNBC and in 67% (6/9) of de novo TNBC patients with high RSK2. Tumor necrosis or target lesion reduction (< 30%) was observed in 17% of patients (5/30), all of whom had high RSK2 expression. In the FE sub-study, increased interpatient variability in PMD-026 Cmax and Tmax but not AUC, was observed when administered with food, favored dosing in a fasted state, which is consistent with the pH dependent solubility of PMD-026. Notably, all FE patients (12/12) achieved the target concentration of 1µM (IC90 in preclinical studies) within 4 hours when PMD-026 was taken without food. At the RP2D, PMD-026 taken without food showed relatively consistent exposure among patients over 24 hr timeframe. Conclusions: These findings demonstrate that in patients treated with PMD-026 who had received < 5 prior treatment regimens, had de novo TNBC or CDK4/6 refractory HR+ disease and had high RSK2 scores had longer PFS. Overall, PMD-026 is a well-tolerated, orally available RSK2 inhibitor that will be evaluated further for efficacy in TNBC and CDK4/6i refractory HR+ mBC, in a trial that will prospectively enroll patients based on RSK2 activation as defined by the RSK2 IHC H-scores. Clinical trial information: NCT04115306. 1 Patients diagnosed and treated for TNBC from their initial diagnosis (de novo TNBC) vs patients previously treated for hormone receptor positive (HR+) or human epidermal growth factor 2 receptor positive (HER2+) BC, but became HR or HER2 negative (secondary TNBC) Citation Format: Judy S. Wang, Muralidhar Beeram, Pavani Chalasani, Lida Mina, Rebecca A. Shatsky, Sara Hurvitz, Meghna S. Trivedi, Robert Wesolowski, Hyo S. Han, Amita Patnaik, Shakeela Bahadur, My-my Huynh, Aarthi Jayanthan, Gerrit Los, Sandra E. Dunn, Andrew Dorr. High levels of RSK2 in breast cancer patients is associated with longer PFS in patients treated with PMD-026, a first in class RSK inhibitor [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-16.

Background: Elacestrant demonstrated significantly prolonged progression-free survival (PFS) and a manageable safety profile compared with standard of care endocrine therapy in the phase 3 EMERALD trial that enrolled patients with estrogen-receptor positive (ER+)/HER2− mBC following disease progression on prior endocrine and cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy. Benefit was observed in the overall population and in patients with ESR1 mutations. Combining elacestrant with targeted agents utilized in combination with endocrine therapy in mBC is of therapeutic interest. Methods: ELEVATE is a phase 1b/2 trial designed to evaluate the combination of elacestrant with alpelisib, everolimus, palbociclib, abemaciclib, or ribociclib. Eligible patients (pts) are women or men with ER+/HER2− locally advanced or mBC, measurable disease per RECIST v1.1 or ≥1 lytic or mainly lytic bone lesion, ECOG PS ≤1, no inflammatory breast cancer or uncontrolled central nervous system metastases, in addition to treatment-arm specific eligibility criteria as detailed below. In the phase 1b portion, pts who have received prior aromatase inhibitor (AI) and CDK4/6i will be enrolled in three 6-patient cohorts for each combination except abemaciclib (under study in a separate trial). Patients will receive elacestrant with the targeted agent at reduced or full doses. The primary endpoint of phase 1b is to determine the recommended phase 2 dose for each combination. Secondary endpoints are safety, pharmacokinetics, pharmacodynamics, and efficacy (objective response rate [ORR], duration of response [DoR], clinical benefit rate [CBR], PFS, and overall survival [OS]). The phase 2 portion will enroll 5 separate arms: A) pts with PIK3CA mutation(s) and prior AI + CDK4/6i: alpelisib + elacestrant, n=50; B) pts with prior AI + CDK4/6i: everolimus + elacestrant, n=50; C) pts with prior AI + CDK4/6i: abemaciclib or ribociclib (investigator’s [inv] choice) + elacestrant, n=60 (30 per combination); D) pts with prior AI only (no CDK4/6i): palbociclib, abemaciclib or ribociclib (inv choice) + elacestrant, n=90 (n=30 per combination); E) pts with no prior systemic therapy: palbociclib or ribociclib (inv choice) + elacestrant, n=90 (n=45 per combination). No prior fulvestrant or chemotherapy is allowed in any arm and no more than 2 prior hormonal therapies are permitted in arms A-D. Prior therapy restrictions apply to the mBC setting or within 12 months of adjuvant therapy. The primary endpoint for the phase 2 portion is the estimation of PFS at 6 months in arms A, B, and C and at 12 months in arms D and E. Secondary endpoints will include ORR, DoR, CBR, PFS, OS, and safety. The Kaplan-Meier method will be used to estimate PFS. Descriptive statistics will be used to evaluate response and safety. Citation Format: Hope Rugo, Aditya Bardia, Javier Cortés, Giuseppe Curigliano, Erika Hamilton, Sara Hurvitz, Sibylle Loibl, Simona Scartoni, Tarek Sahmoud, Krzysztof Grzegorzewski, Nassir Habboubi, Joyce O’Shaughnessy. ELEVATE: A phase 1b/2, open-label, umbrella study evaluating elacestrant in various combinations in women and men with metastatic breast cancer (mBC). [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-03.

Background: Cardiotoxicity associated with use of trastuzumab (T) in breast cancer has been assessed in multiple studies with short-term follow up. However, long-term risk of clinical heart failure (CHF) with the use of T, either with or without anthracyclines (A), is poorly understood. Since the approval of T for use in early-stage breast cancer (ESBC) in 2006, long-term follow up data is now available in the SEER-Medicare database. Methods: We performed a retrospective cohort study in patients (pts) with ESBC identified in the SEER-Medicare database, diagnosed between 2005-2016, excluding pts with in-situ or metastatic disease at time of diagnosis or a history of CHF prior to diagnosis. Primary exposure variables were identified using HCPCS codes and included receipt of T or A. The reference baseline population used for univariate logistic regression of the primary exposure variables was pts with ESBC who received neither T nor A. For multivariate analyses, to avoid co-linearity in the final model, the exposure variables were categorized as either having or not having the exposure (i.e. with or without T, with or without A). The primary outcome variable was CHF, identified using codes 428.0-9, 402.11, 402.91 (ICD9) and I50.0-9, I110 (ICD10). Covariates used in multivariate logistic regression (MLR) included hypertension (HTN), valve disease, hyperthyroidism, diabetes (DM), emphysema, coronary artery disease (CAD), left sided radiation, age, and race. MLR models were constructed using a stepwise-up approach and confirmed using the stepwise-down method with a cutoff of p< 0.05 for inclusion in the final model. Results: A total of 244,129 pts were identified with a median follow up of 6.7 years (7.7 years in the T cohort). Median age was 68. Other demographics are listed in Table 1. Of these, 10,603 were HER2-positive (HER2+) pts who all received T and all of whom also received some form of chemotherapy. Of the HER2+ pts, 19.1% (2,026) also received A in addition to T as part of their treatment regimen. Pts who received T had significantly higher baseline rates of HTN, valve disease, hyperthyroidism, DM, emphysema, and CAD as compared to pts who did not receive T. Compared to pts who received T without A, pts who received T with A had significantly higher baseline rates of HTN, valve disease, hyperthyroidism, emphysema, and CAD with no difference in baseline rate of DM. Risk of CHF with exposure variables are summarized in Table 2. The overall rate of CHF for the entire 244,129 population was 21.3% with a rate of 20.8% in pts who did not receive any T or A (the baseline population). The rate of CHF in pts who received T without A was 19.1% (OR 0.90, 95% CI 0.85-0.95), and 29.0% for those who received T with A (OR 1.55, 95% CI 1.41-1.71). Associations of covariates of interest with risk of CHF as well as MLR models are summarized in Table 3. After adjusting for all baseline cardiac comorbidities as well as other covariates, receipt of T was associated with a reduced risk of CHF (OR 0.74, 95% CI 0.70-0.79, p< 0.001), and receipt of A remained associated with an increased risk of CHF (OR 1.19, 95% CI 1.15-1.24, p< 0.001). Conclusions: With long-term follow up, the addition of A to T significantly increased the risk of CHF over T without A (from 19.1% to 29.0%) in pts with ESBC. Additionally, pts who received T without A had a similar risk of CHF compared to the baseline population who received neither T nor A. After adjusting for potential confounders in the MLR model, T was associated with a slightly decreased overall risk of CHF, while A remained associated with an increased risk of CHF. Possible explanations for these findings include potential increased cardiac monitoring in the T population which may have led to optimization of cardiac comorbidities, which were higher in the T population at baseline. Taken together, these data indicate concern with use of T plus A in ESBC regarding the long-term development of clinical CHF; especially when non-A regimens with similar efficacy are available. Table 1: Demographics Table 2: Risk of Heart Failure with Primary Exposure Variables Table 3: Univariate and Multivariate Analyses Citation Format: Nicholas P. McAndrew, Karissa Britten, Xiaoyan Wang, Eric Yang, Sara Hurvitz, Dennis Slamon. Long-term heart failure risk of trastuzumab with or without anthracyclines in early stage breast cancer: A SEER-Medicare Database Analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-03-13.

Background: Trastuzumab deruxtecan (T-DXd) is approved in the United States and European Union for use in patients (pts) with HER2+ unresectable/metastatic breast cancer (mBC) after ≥1 prior anti–HER2 regimen(s). Approval was based on the randomized, multicenter, open-label, phase 3 DESTINY-Breast03 study (NCT03529110), in which T-DXd demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with trastuzumab emtansine (T-DM1). At the primary interim analysis (data cutoff May 21, 2021), the risk of disease progression or death was reduced by 72% with T-DXd (P < 0.001; Cortes et al. N Engl J Med 2022). Overall survival (OS) data were immature for both treatment groups; although the prespecified cutoff for significance was not reached (NR), a trend toward benefit with T-DXd was observed. With further follow-up, we report results from the prespecified OS analysis of DESTINY-Breast03 (data cutoff July 25, 2022), including updated efficacy and safety. Methods: Pts with HER2+ mBC previously treated with trastuzumab and a taxane in either the metastatic setting or (neo)adjuvant setting with progression within 6 mo of therapy, who could have received pertuzumab, were randomly assigned 1:1 to receive T-DXd 5.4 mg/kg every 3 weeks (Q3W) or T-DM1 3.6 mg/kg Q3W until disease progression. The primary endpoint was PFS by blinded independent central review (BICR). The key secondary endpoint was OS (80% powered at 2-sided significance level of 5%); other secondary endpoints included objective response rate (ORR), duration of response (DoR), PFS based on investigator assessment, and safety. Results: 524 pts received either T-DXd (n = 261) or T-DM1 (n = 263). As of the updated data cutoff, median duration of study follow-up was 28.4 mo (range, 0.0-46.9 mo) for T-DXd and 26.5 mo (range, 0.0-45.0 mo) for T-DM1. Median treatment duration was 18.2 mo (range, 0.7-44.0 mo) for T DXd and 6.9 mo (range, 0.7-39.3 mo) for T-DM1. The risk of death was reduced by 36% (HR, 0.64; P = 0.0037) with T-DXd; median OS (mOS) was NR (95% CI, 40.5 mo-not evaluable [NE]), with 72 (27.6%) OS events, for T-DXd vs NR (95% CI, 34.0 mo-NE), with 97 (36.9%) OS events, for T-DM1. Landmark 12-mo OS rate was 94.1% (95% CI, 90.4-96.4) for T-DXd vs 86.0% (95% CI, 81.1-89.8) for T-DM1; 24-mo OS rate was 77.4% (95% CI, 71.7-82.1) for T-DXd vs 69.9% (95% CI, 63.7-75.2) for T-DM1. The P value for OS crossed the prespecified boundary (P = 0.013) and was statistically significant. mPFS by BICR was 28.8 mo (95% CI, 22.4-37.9 mo) with T-DXd, compared with 6.8 mo (95% CI, 5.6-8.2 mo) with T-DM1; HR, 0.33; nominal P < 0.000001. Key efficacy and safety results are shown in the table. Grade ≥3 treatment-emergent adverse events were experienced by 56.4% of T-DXd-treated pts and 51.7% of T DM1-treated pts. Drug-related interstitial lung disease/pneumonitis, as evaluated by an independent adjudication committee, was experienced by 39 pts (15.2%) in the T-DXd arm and 8 pts (3.1%) in the T DM1 arm; no adjudicated drug-related grade 4 or 5 events were observed in pts who received T-DXd. Conclusions: Updated results confirm the superiority of T-DXd compared with T-DM1 for pts with HER2+ mBC previously treated with an anti-HER2 therapy, with highly clinically meaningful and statistically significant benefit in OS and PFS and a manageable safety profile with longer treatment duration. Editorial Acknowledgment Under the guidance of authors, assistance in medical writing and editorial support was provided by Laura Halvorson, PhD, and Rachel Hood, PhD, of ApotheCom, and was funded by Daiichi Sankyo. Funding This study was funded by Daiichi Sankyo and AstraZeneca. Table. Summary of Efficacy Results for T-DXd and T-DM1 Citation Format: Sara Hurvitz, Roberto Hegg, Wei-Pang Chung, Seock-Ah Im, William Jacot, Vinod Ganju, Joanne Win Yang Chiu, Binghe Xu, Erika Hamilton, Srinivasan Madhusudan, Hiroji Iwata, Sevilay Altintas, Jan-Willem Henning, Giuseppe Curigliano, José Manuel Pérez-García, Anton Egorov, Yali Liu, Jillian Cathcart, Shahid Ashfaque, Javier Cortés. GS2-02 Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: Updated survival results of the randomized, phase 3 study DESTINY-Breast03 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS2-02.

Background: ARV-471 is a selective, orally administered PROteolysis TArgeting Chimera (PROTAC®) protein degrader that targets wild-type and mutant ER. ARV-471 is being evaluated in patients with ER+/HER2- locally advanced or metastatic breast cancer in a first-in-human phase 1/2 study (NCT04072952). In the phase 1 dose escalation, ARV-471 monotherapy (dose range: 30–700 mg total daily dose) showed a manageable safety profile in patients who had previously received endocrine therapy and a cyclin-dependent kinase (CDK) 4/6 inhibitor. The clinical benefit rate (CBR; rate of confirmed complete or partial response or stable disease ≥24 weeks) was 40% (95% CI: 26–56) in 47 evaluable patients. The phase 2 expansion portion of the study (VERITAC) evaluated 2 doses of ARV-471.Methods: In VERITAC, ARV-471 monotherapy was administered at doses of 200 mg once daily (QD) or 500 mg QD to patients with ER+/HER2- locally advanced/metastatic breast cancer who had received ≥1 prior endocrine therapy for ≥6 months, ≥1 CDK4/6 inhibitor, and ≤1 chemotherapy regimen. The primary endpoint of CBR was evaluated in patients enrolled ≥24 weeks prior to the data cutoff. Results: As of June 6, 2022, 71 patients received ARV-471 (200 mg QD [n=35]; 500 mg QD [n=36]) in VERITAC. Across all treated patients, 69 (97.2%) were female and median age was 60 y (range: 41–86). Patients had received a median of 4 prior regimens in all settings (range: 1–10); 100% had prior CDK4/6 inhibitors, 78.9% had prior fulvestrant, and 73.2% had prior chemotherapy. ARV-471 was well tolerated at both doses, with most treatment-related adverse events (TRAEs) grade 1/2; the most common TRAEs were fatigue and nausea (Table). In all, 3 patients (1 in the 200 mg QD cohort and 2 in the 500 mg QD cohort) discontinued ARV-471 due to treatment-emergent adverse events (TEAEs); 3 patients had ARV-471 dose reductions due to TEAEs (all from 500 mg QD to 400 mg QD). CBR was 37.1% (95% CI: 21–55) in 35 evaluable patients treated at 200 mg QD and 38.9% (95% CI: 23–57) in 36 evaluable patients treated at 500 mg QD. CBR in evaluable patients with mutant ESR1 in the 200 mg QD (n=19) and 500 mg QD (n=22) cohorts was 47.4% (95% CI: 24–71) and 54.5% (95% CI: 32–76), respectively. Conclusions: In the phase 2 VERITAC expansion cohorts of patients with ER+/HER2- locally advanced/metastatic breast cancer and prior CDK4/6 inhibitor treatment, ARV-471 monotherapy showed evidence of clinical activity based on CBR, which was further enhanced in the subgroup with ESR1 mutations. The manageable AE profile observed in the phase 1 portion of the study was maintained during cohort expansion at doses of 200 mg QD and 500 mg QD. Additional analyses are ongoing.Table. TRAEs reported in ≥10% of patients overall aNo grade 3/4 TRAE occurred in >1 patient. AST=aspartate aminotransferase Citation Format: Anne F. Schott, Sara Hurvitz, Cynthia Ma, Erika Hamilton, Rita Nanda, George Zahrah, Natasha Hunter, Antoinette R. Tan, Melinda Telli, Jesus Anampa Mesias, Rinath Jeselsohn, Pamela Munster, Haolan Lu, Richard Gedrich, Cecile Mather, Janaki Parameswaran, Hyo S. Han. GS3-03 ARV-471, a PROTAC® estrogen receptor (ER) degrader in advanced ER-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer: phase 2 expansion (VERITAC) of a phase 1/2 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-03.

Background: CD166 is broadly expressed in normal epithelium and overexpressed in many types of malignancies, including breast cancer. Probody® therapeutic candidates are masked antibodies, conditionally activated by tumor-associated proteases, which restricts their activity to the tumor microenvironment and minimizes ‘off-tumor’ toxicity. CX-2009 is a conditionally activated humanized anti-CD166 monoclonal antibody conjugated to DM4 that showed clinical activity in ABC patients in a phase 1 study (Boni et al. Clin Cancer Res. 2022). This phase 2 study (NCT04596150) evaluates CX-2009 as monotherapy in patients with advanced HR+/HER2− BC (Arm A) and TNBC (Arm B), and in combination with pacmilimab (a conditionally activated PD-L1) in TNBC (Arm C). Methods: Key eligibility criteria for all cohorts include: ECOG 0-1, acceptable end-organ function, measurable disease, willingness to receive ocular prophylaxis for DM-4 related toxicity, and available tumor tissue for CD166 evaluation. Eligibility criteria for HR+ BC include: 2-4 prior regimens (excluding single-agent hormonal therapy with up to 2 prior cytotoxic regimens) and a prior CDK 4/6 inhibitor in the metastatic setting; eligibility criteria for TNBC include CD166 by IHC >1% by central assessment, 1-3 prior regimens in the metastatic setting and prior taxane. All patients initially received 7 mg/kg Q3W; the protocol was subsequently amended to enroll patients at 6 mg/kg Q3W. The primary endpoint was overall response rate (ORR) using RECIST v1.1 assessed by central review. Other key endpoints include ORR by investigator assessment, clinical benefit rate at 24 weeks (CBR24; defined as any response, confirmed or unconfirmed, or SD for 24 weeks), duration of response, and progression-free survival by investigator. Archival tumor specimens and blood samples were collected for correlative research including genomic analyses. Results: As of 13 May 2022, 60 patients were enrolled in Arm A (all patients started at 7 mg/kg); 52 were evaluable for efficacy by investigator. Median duration of follow-up was 29.1 weeks (range: 3.6-60.7). Median age was 60.5 years (36, 83); pts received a median of 3.5 (1, 6) prior treatments for ABC. CD166 H-Score > 200 was reported in 53.3% of patients. Arm A met the primary efficacy endpoint with a confirmed ORR by central radiology of 14.9% (n=47); by investigator, ORR was similar at 15.4% (n=52); an additional 9 patients (17.3%) had an unconfirmed response. CBR24 was 40.4%; using only confirmed responses, CBR24 was 23.1%. Median PFS was 11.4 weeks (95% CI 9.0, 13.9). Common treatment-related all-grade adverse events (TRAEs) included blurred vision (42%), nausea (35%), fatigue (35%), diarrhea (25%), peripheral neuropathy (27%), infusion-related reaction (23%) and decreased appetite (20%). Grade ≥3 ocular and neuropathic TRAEs were 15% and 10%, respectively. AEs resulting in treatment discontinuation (AEDC) were 25%. For Arm B and C, 55 and 10 patients were enrolled (the majority received a starting dose of 6 mg/kg). For Arm B, the futility boundary was crossed (ORR < 10%). Grade ≥3 ocular and neuropathic TRAEs and AEDC at 7 mg/kg in Arm B were similar to Arm A (11%, 11% and 21% respectively); whereas at 6 mg/kg, they were reduced at 3%, 0% and 0%, respectively. Biomarker data and correlation with outcomes will be presented. Conclusions: Praluzatamab ravtansine demonstrated single-agent activity in unselected heavily pretreated patients with HR+/HER2- ABC. Time to event analyses, such as PFS, were confounded by higher-than-expected toxicity at a starting dose of 7 mg/kg. The toxicity profile was generally consistent with a DM4 payload. The lower dose of 6 mg/kg appears to be better tolerated. Additional clinical studies in HR+ABC, incorporating a starting dose of 6 mg/kg and potentially including a biomarker strategy, are warranted. Citation Format: Kathy Miller, Sara Tolaney, Leisha A. Emens, Sung-Bae Kim, Erika Hamilton, Cristina Saura, Lucia Sanz, Valentina Boni, Filipa Lynce, Juan Miguel Cejalvo, Jennifer Crozier, Shirley Wang, Hirdesh Uppal, Alison L. Hannah, Sara Hurvitz. Preliminary results from a phase 2 study of praluzatamab ravtansine (CX-2009) in patients with advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-15.

Purpose: Ribociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase III MONALEESA-7 trial of pre-/perimenopausal patients with hormone receptor (HR)-positive (HR+), HER2-negative (HER2−) advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months). Patients and Methods: Patients were randomized to receive ET [goserelin plus nonsteroidal aromatase inhibitor (NSAI) or tamoxifen] with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan–Meier methods. Results: The intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo [hazard ratio = 0.76; 95% confidence interval (CI), 0.61–0.96]. Kaplan–Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged less than 40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of cyclin-dependent kinase 4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug–drug interactions were observed between ribociclib and either NSAI. Conclusions: Ribociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged less than 40 years, with HR+/HER2− ABC with 53.5 months of median follow-up (ClinicalTrials.gov, NCT02278120).

Background: The HER2 receptor is a cancer driver which is overexpressed on 15-20% of breast cancers. Though historically survival is poor with this disease subtype, HER2+ targeted therapy has improved survival in both early and advanced disease. In spite of this, most patients in the metastatic setting will eventually experience disease progression and death. Therefore, new therapeutic options and innovative treatments are needed for patients with recurrent or refractory disease. ARX788 is a next-generation antibody–drug conjugates (ADC) using a technology platform whereby a HER2 specific monoclonal antibody is conjugated with Amberstatin269, a potent cytotoxic tubulin inhibitor. Site-specific, high homogenous, and stable covalent conjugation in ARX788 leads to slow release and prolonged peak of serum pAF-AS269, which may contribute to the lower systemic toxicity, increased targeted delivery of payload to tumor cells, and lower effective dose compared to other HER2 ADCs.Methods: ACE-Breast-03 (NCT04829604) is a global, single arm, phase 2 study designed to assess anticancer activity and safety of ARX788 in patients with metastatic HER2 positive breast cancer. Patients whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens are eligible. Patients must have adequate organ function and any brain metastasis must demonstrate radiographic stability and lack of steroid dependence. Approximately 200 subjects with advanced HER2-positive breast cancer will be enrolled. ARX788 will be administered as an intravenous (IV) infusion at 1.5 mg/kg as the initial dose on Day 1 of the first 4-week cycle and followed by 1.3 mg/kg at every subsequent 4-week cycle. Efficacy will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 via imaging every 8 weeks (±7 days) on study and endpoints include objective response rate (ORR), duration of response (DOR), time to response (TTR), best overall response (BOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The safety and tolerability profile will be assessed. Blood samples will be collected at specified time points to determine serum concentrations of ARX788 (intact ADC), total antibody, and metabolite pAF-AS269. Biomarkers (e.g., cell-free DNA, serum HER2 extracellular domain, and circulating tumor cells) at baseline and on-treatment will be analyzed for exploratory research. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The study is currently recruiting patients. Please contact breast03trialinquiry@ambrx.com for additional information. Citation Format: Janice Lu, Kevin M Kalinsky, Debu Tripathy, George W Sledge, William Gradishar, Ruth O’Regan, Joyce O’Shaughnessy, Shanu Modi, Joshua Drago, Haeseong Park, Amelia McCartney, Sophia Frentzas, Catherine Shannon, Katharine Cuff, Richard Eek, Miguel Idzwan Martin, Giuseppe Curigliano, Guy Jerusalem, Chiun-Sheng Huang, Michael Press, Matt Li, Dong Xu, Cynthia Song, Richard Huhn, Jinchun Yan, Sara Hurvitz. A global, phase 2 study of ARX788 in patients with HER2-positive metastatic breast cancer whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-02-02.

"Second victims" are clinicians who are traumatized after an unanticipated adverse patient event, medical error, or patient-related injury. Less recognized is the profound sense of betrayal and trauma that can occur in the context of patient deception. The implicit patient-healthcare provider contract assumes that patients are truthful with providers so they may obtain accurate diagnoses and effective treatments. Betrayal by deception can feel like a traumatic death; not of a person, but of a previously intimate and trusting relationship. Healthcare professionals are no better at detecting lies than the lay public and hold inaccurate beliefs about detectable signs of deception. Thus, healthcare professionals may be more vulnerable to betrayal by deception than they realize. The 2 clinical cases presented here reveal the ease with which healthcare providers can be misled, emotionally manipulated by individuals who superficially appear to be psychologically healthy and traumatized by betrayal by deception.

Background: Tucatinib is an oral tyrosine kinase inhibitor highly specific for HER2 that is approved for use in combination with trastuzumab and capecitabine in adults with advanced or metastatic HER2+ breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. In the HER2CLIMB trial, the tucatinib regimen significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with HER2+ metastatic breast cancer (Murthy, NEJM 2020), including in patients with untreated, treated stable, and treated progressing brain metastases (Lin, J Clin Oncol, 2020). With an additional 15.6 months of follow-up, addition of tucatinib continued to show clinically meaningful prolongation of PFS and OS in the total study population (Curigliano, ASCO Meeting, 2021). We report updated results of exploratory efficacy analyses in patients with brain metastases. Methods: All patients in HER2CLIMB had a baseline brain MRI. Patients with brain metastases were eligible and classified as untreated, treated stable, or treated progressing. Patients were randomized 2:1 to receive tucatinib 300 mg twice daily or placebo, in combination with trastuzumab and capecitabine. Following the primary analysis, the protocol was amended to unblind sites to treatment assignment and allowed crossover from the placebo regimen to the tucatinib regimen. Efficacy analyses in patients with brain metastases at baseline were performed at approximately 2 years from the last patient randomized by applying RECIST 1.1 to the brain based on investigator evaluation. OS and CNS-PFS (progression in the brain or death) were evaluated in all patients with brain metastases. Patients without CNS-PFS events were censored at the last brain MRI. Confirmed intracranial (IC) objective response rate (ORR-IC) was evaluated in patients with measurable IC disease. Results: At a median follow-up of 29.6 months, median OS was 21.6 months vs 12.5 months in all patients with brain metastases (HR: 0.60; 95% CI: 0.44, 0.81), 21.4 months vs 11.8 months in patients with untreated/treated progressing brain metastases (HR: 0.52; 95% CI: 0.36, 0.77), and 21.6 months vs 16.4 months in patients with treated stable brain metastases (HR: 0.70; 95% CI: 0.42, 1.16). Median CNS-PFS was 9.9 months vs 4.2 months in all patients with brain metastases (HR: 0.39; 95% CI: 0.27, 0.56), 9.6 months vs 4.0 months in patients with untreated/treated progressing brain metastases (HR: 0.34; 95% CI: 0.22, 0.54), and 13.9 months vs 5.6 months in patients with treated stable brain metastases (HR: 0.41; 95% CI: 0.19, 0.85). ORR-IC was higher in the tucatinib arm (47.3%; 95% CI: 33.7, 61.2) vs the placebo arm (20.0%; 95% CI: 5.7, 43.7) for patients with brain metastases, and median duration of response (DOR) was 8.6 months (95% CI: 5.5, 10.3) vs 3.0 months (95% CI: 3.0, 10.3). Conclusions: With 15.6 months of additional follow-up, the tucatinib-trastuzumab-capecitabine regimen resulted in a robust and durable prolongation of OS for all patients with HER2+ metastatic breast cancer and brain metastases. Additionally, this benefit was maintained in patients with untreated/treated progressing and treated stable brain metastases. Treatment with tucatinib continued to show clinically meaningful benefit in CNS-PFS consistent with the primary analysis. Citation Format: Nancy U Lin, Rashmi K Murthy, Vandana Abramson, Carey Anders, Thomas Bachelot, Philippe Bedard, Virginia Borges, David Cameron, David Cameron, Lisa Carey, A Jo Chien, Giuseppe Curigliano, Michael DiGiovanna, Karen Gelmon, Gabriel Hortobagyi, Sara Hurvitz, Ian Krop, Sherene Loi, Sibylle Loibl, Volkmar Mueller, Mafalda Oliveira, Elisavet Paplomata, Mark Pegram, Dennis Slamon, Amelia Zelnak, Jorge Ramos, Wentao Feng, Eric Winer. Updated results of tucatinib vs placebo added to trastuzumab and capecitabine for patients with previously treated HER2-positive metastatic breast cancer with brain metastases (HER2CLIMB) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-04.

Background: T-DXd is a HER2-targeting antibody-drug conjugate approved for the treatment of pts with advanced HER2+ mBC based on the DESTINY-Breast01 study (NCT03248492). DESTINY-Breast03 (NCT03529110) isa randomized, multicenter, open-label, phase 3 study assessing the efficacy and safety of T-DXd vs. T-DM1 in pts with HER2+ mBC previously treated with trastuzumab and taxane. In the primary analysis, T-DXd demonstrated a clinically meaningful and statistically significant improvement in PFS vs. T-DM1 (Corteset al, ESMO 2021). In this exploratory analysis, we provide additional efficacy and safety data in subgroups, including in pts with brain metastases (BMs). Methods: Pts were randomly assigned 1:1 to receive 5.4 mg/kg T-DXd or 3.6 mg/kg T-DM1 Q3W. Pts with clinically stable BMs were eligible. Lesions were measured per modified Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint was progression-free survival (PFS) determined by blinded independent central review (BICR). PFS and overall response rate (ORR) were analyzed for subgroups.Sites of progression and post-end-of-study therapies were also investigated. Results: At data cutoff (May 21, 2021), 524 pts were randomly assigned to T-DXd (n=261) orT-DM1 (n=263). T-DXd demonstrated superior PFS by BICR vs. T-DM1 (HR, 0.28 [95%CI, 0.22-0.37]; P=7.8 x 10-22); median (m) PFS by BICR was not reached (95% CI, 18.5-NE) for T-DXd compared with 6.8 mo (95% CI, 5.6-8.2) forT-DM1. For pts with stable BMs at baseline (n=82), mPFS was 15.0 mo (95% CI,12.5-22.2) for T-DXd vs. 3.0 mo (95% CI, 2.8-5.8) for T-DM1 (HR, 0.25 [95% CI,0.31-0.45)]. Overall, confirmed ORR for T-DXd was 79.7% vs. 34.2% for T-DM1.For patients with stable BMs at baseline, ORR was 67.4% for T-DXd vs. 20.5% forT-DM1. Consistent PFS and ORR benefit was also observed across other subgroups(Table 1). At data cutoff, 84 (32.2%) pts treated with T-DXd had progressive disease (PD) versus 155 (58.9%) with T-DM1. In pts with stable BMs in the T-DXd arm, 48.8% of pts (21/43) had PD. In pts with stable BMs in the T-DM1 arm, 69.2%of pts (27/39) had PD. Data on sites of progression will be presented. Further analyses are underway and will be presented. Overall, the safety profile of T-DXd was manageable and comparable with its known safety profile. Adjudicated drug-related interstitial lung disease/pneumonitis was reported in 27 (10.5%) pts treated with T-DXd and 5 (1.9%) pts treated with T-DM1 overall, with no grade 4 or 5 events. Additional new safety data will be presented. Conclusion: DESTINY-Breast03,the first-reported randomized phase 3 trial comparing T-DXd to standard of care, met the primary endpoint with T-DXd demonstrating superior PFS vs. T-DM1and T-DXd had a manageable safety profile. In this exploratory analysis, consistent PFS and ORR benefit with T-DXd vs. T-DM1 was observed across subgroups in pts with HER2+ mBC previously treated with trastuzumab and taxane, including in pts with BMs. Table 1.Subgroup Analyses forPFS and ORR of T-DXd versus T-DM1PFS by BICR HR (95% CI)Absolute ORR Difference (T-DXd-T-DM1) (95% CI)All patients (N=524)0.28 (0.22-0.37)45.5 (37.6-53.4)Hormone receptorPositive (n=272)0.32 (0.22-0.46)47.3 (36.1-58.4)Negative (n=248)0.30 (0.20-0.44)43.2 (31.5-55.0)Prior pertuzumabYes (n=320)0.31 (0.22-0.43)46.7 (36.5-56.9)No (n=204)0.30 (0.19-0.47)43.6 (30.5-56.7)Prior lines of therapya0-1 (n=258)0.33 (0.23-0.48)39.3 (27.3-51.2)≥2 (n=266)0.28 (0.19-0.41)51.6 (40.9-62.4)Visceral disease Yes (n=384)0.28 (0.21-0.38)48.3 (39.1-57.6)No (n=140)0.32 (0.17-0.58)39.1 (23.6-54.6)Brain metastases at baseline Yes (n=82)0.25 (0.13-0.45)46.9 (25.6-68.3)No (n=442)0.30 (0.22-0.40)45.5 (36.9-54.1) Citation Format: Sara Hurvitz, Sung-Bae Kim, Wei-Pang Chung, Seock-Ah Im, Yeon Hee Park, Roberto Hegg, Min-Hwan Kim, Ling-Ming Tseng, Vanessa Petry, Chi-Feng Chung, Hiroji Iwata, Erika Hamilton, Giuseppe Curigliano, Binghe Xu, Caleb Lee, Yali Liu, Jillian Cathcart, Emarjola Bako, Sunil Verma, Javier Cortés. Trastuzumab deruxtecan (T-DXd; DS-8201a) vs. trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): subgroup analyses from the randomized phase 3 study DESTINY-Breast03 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS3-01.

The incidence of advanced breast cancer in premenopausal women is increasing, and breast cancer in younger women is often more aggressive and has a worse prognosis compared with breast cancer in older women. Premenopausal women with hormone receptor-positive (HR

Summary Background The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT pathway activation, including triple-negative breast cancer. The LOTUS trial investigated the addition of ipatasertib to paclitaxel as first-line therapy for triple-negative breast cancer. Methods In this randomised, placebo-controlled, double-blind, phase 2 trial, women aged 18 years or older with measurable, inoperable, locally advanced or metastatic triple-negative breast cancer previously untreated with systemic therapy were recruited from 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy, and Belgium. Enrolled patients were randomly assigned (1:1) to receive intravenous paclitaxel 80 mg/m 2 (days 1, 8, 15) with either ipatasertib 400 mg or placebo once per day (days 1–21) every 28 days until disease progression or unacceptable toxicity. Randomisation was by stratified permuted blocks (block size of four) using an interactive web-response system with three stratification criteria: previous (neo)adjuvant therapy, chemotherapy-free interval, and tumour PTEN status. The co-primary endpoints were progression-free survival in the intention-to-treat population and progression-free survival in the PTEN-low (by immunohistochemistry) population. This ongoing trial is registered with ClinicalTrials.gov (NCT02162719). Findings Between Sept 2, 2014, and Feb 4, 2016, 166 patients were assessed for eligibility and 124 patients were enrolled and randomly assigned to paclitaxel plus ipatasertib (n=62) or paclitaxel plus placebo (n=62). Median follow-up was 10·4 months (IQR 6·5–14·1) in the ipatasertib group and 10·2 months (6·0–13·6) in the placebo group. Median progression-free survival in the intention-to-treat population was 6·2 months (95% CI 3·8–9·0) with ipatasertib versus 4·9 months (3·6–5·4) with placebo (stratified hazard ratio [HR] 0·60, 95% CI 0·37–0·98; p=0·037) and in the 48 patients with PTEN-low tumours, median progression-free survival was 6·2 months (95% CI 3·6–9·1) with ipatasertib versus 3·7 months (1·9–7·3) with placebo (stratified HR 0·59, 95% CI 0·26–1·32, p=0·18). The most common grade 3 or worse adverse events were diarrhoea (14 [23%] of 61 ipatasertib-treated patients vs none of 62 placebo-treated patients), neutrophil count decreased (five [8%] vs four [6%]), and neutropenia (six [10%] vs one [2%]). No colitis, grade 4 diarrhoea, or treatment-related deaths were reported with ipatasertib. One treatment-related death occurred in the placebo group. Serious adverse events were reported in 17 (28%) of 61 patients in the ipatasertib group and nine (15%) of 62 patients in the placebo group. Interpretation Progression-free survival was longer in patients who received ipatasertib than in those who received placebo. To our knowledge, these are the first results supporting AKT-targeted therapy for triple-negative breast cancer. Ipatasertib warrants further investigation for the treatment of triple-negative breast cancer. Funding F Hoffmann-La Roche.

Long-term outcomes for women with a diagnosis of human epidermal growth factor receptor 2 (HER2)-driven early-stage breast cancer have significantly improved since the advent of HER2-targeted therapy. Although the first studies in the early-stage setting focused on the adjuvant use of trastuzumab plus chemotherapy, clinical trials increasingly are using a neoadjuvant design to evaluate novel HER2-targeted therapies. Neoadjuvant therapy downstages locally advanced breast cancer, improves rates of breast conservation, and provides information regarding the responsiveness of a cancer to systemic therapy; in addition, studies have shown that the pathologic response to neoadjuvant therapy is correlated with event-free and overall survival. Given these advantages, multiple studies of neoadjuvant therapy, several of which have reported longer-term outcomes, have been conducted to evaluate HER2-targeted therapies. This review summarizes available data from prior and ongoing neoadjuvant trials in HER2-positive breast cancer, focusing on those studies that have reported not only pathologic response rates but also event-free, disease-free, and/or overall survival. The long-term outcomes associated with the achievement of a pathologic complete response are explored, and the comparisons of pathologic complete response rates, event-free survival, and overall survival reported for different HER2-targeted regimens are reviewed.

The elements [ f ′ ] ( f ′ : X ′ → Y ′ ) [f’](f’:X’ \to Y’) of the genus − G ( f ) - G(f) of a map f : X → Y f:X \to Y are equivalence classes of homotopy classes of maps f ′ f’ which satisfy: For every prime p p there exist homotopy equivalences h p : X p ′ → X p {h_p}:{X’_p} \to {X_p} and k p : Y p ′ → Y p {k_p}:{Y’_p} \to {Y_p} so that f p h p ∼ k p f p ′ {f_p}{h_p} \sim {k_p}{f’_p} . The genus of f f under X − G X ( f ) X - {G^X}(f) and the genus of f f over Y − G Y ( f ) Y - {G_Y}(f) are defined similarly. In this paper we prove that under certain conditions on f f , the sets G ( f ) G(f) , G X ( f ) {G^X}(f) and G Y ( f ) {G_Y}(f) are finite and admit an abelian group structure. We also compare the genus of f f to those of X X and Y Y , calculate it for some principal fibrations of the form K ( G , n − 1 ) → X → Y K(G,n - 1) \to X \to Y , and deal with the noncancellation phenomenon.

Let P be the set of primes, l ⊆ P a subset and l′ = P – l Recall that an H0-space is a space the rational cohomology of which is a free algebra.Cassidy and Hilton defined and investigated l′-isolated homomorphisms between locally nilpotent groups. Zabrodsky [8] showed that if X and Y are simply connected H0-spaces either with a finite number of homotopy groups or with a finite number of homology groups, then every rational equivalence f : X → Y can be decomposed into an l-equivalence and an l′-equivalence.In this paper we define and investigate l′-isolated maps between pointed spaces, which are of the homotopy type of path-connected nilpotent CW-complexes. Our definition of an l′-isolated map is analogous to the definition of an l′-isolated homomorphism. As every homomorphism can be decomposed into an l-isomorphism and an l′-isolated homomorphism, every map can be decomposed into an l-equivalence and an l′-isolated map.