Manageable Safety Profile Research Articles

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

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

Abstract PO1-06-10: Overall survival results from EVER-132-001, a phase 2b single-arm study of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer

Abstract Background Breast cancer is the most frequently diagnosed cancer and the 5th most common cause of cancer-related death in Chinese women with over 416,000 new cases and over 117,000 deaths estimated in 2020. Triple-negative breast cancer (TNBC) represents 10%-20% of cases in women with breast cancer. Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate and is approved for second-line or later (2L+) treatment of metastatic (m)TNBC in multiple countries, including the US and China. In the pivotal phase 3 study ASCENT, which enrolled predominantly non-Asian patients (pts), SG demonstrated improved efficacy outcomes vs treatment of physician’s choice (TPC) in pts with mTNBC treated in 2L+, with a manageable safety profile. For pts treated with SG, median progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were improved vs TPC (Bardia A et al, 2021). The single-arm phase 2b EVER-132-001 study was conducted to assess the efficacy and safety of 2L+ SG in Chinese pts with mTNBC. In preliminary findings from EVER-132-001, SG demonstrated substantial clinical activity and a manageable safety profile (Xu B et al, 2023). Here, we present additional efficacy and safety results from EVER-132-001, including the first report of median OS. Methods Pts with mTNBC who had received at least 2 prior lines of chemotherapy for mTNBC received SG (10 mg/kg IV on days 1 and 8, Q3W). The primary end point was ORR per independent review committee (IRC). Secondary end points included duration of response (DoR) per IRC, clinical benefit rate (CBR) per IRC, PFS per IRC, OS, and safety. Results Eighty pts were enrolled, with a median age of 48 years (range 24-70). Pts had received a median of 4 prior treatment regimens (range 2-8), and 59% of pts had ECOG performance status of 1. At the data cutoff, September 19, 2022, with a median follow-up of 14.7 mo (range 1.2-25.3), median OS was 14.7 mo (95% CI 10.3-18.3) and the OS rate at 12 months was 54% (95% CI 42-64) (Table). ORR was 40% (95% CI 29-52) with median DoR of 11.6 mo (95% CI 7.0-13.8), and CBR was 46% (95% CI 35-58) (Table). Median PFS was 5.6 mo (95% CI 4.1-8.3) (Table). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 79% of pts, and TEAEs leading to dose reduction, treatment interruption, and treatment discontinuation occurred in 20%, 48%, and 8% of patients, respectively (Table). The most common TEAEs of any grade were decreased neutrophil count (85%), anemia (84%), and decreased white blood cell count (83%). The most common grade ≥ 3 TEAEs were decreased neutrophil count (64%), decreased white blood cell count (50%), and anemia (23%). Conclusions SG continued to demonstrate substantial clinical activity, with OS, ORR, DoR, CBR, and PFS results in the EVER-132-001 trial, consistent with the phase 3 ASCENT trial of SG in mTNBC. TEAEs were manageable and no new safety signals were identified. These results support the use of SG as a new standard of care for Chinese pts with pretreated mTNBC. Table Citation Format: Fei Ma, Shusen Wang, Zhongsheng Tong, Wei Li, Xinhong Wu, Xiaojia Wang, Tao Sun, Yueyin Pan, Herui Yao, Xian Wang, Ting Luo, Jin Yang, Xiaohua Zeng, Weihong Zhao, Kimberly Komatsubara, Rachel Nakamura, Catherine Lai, Bo Zhang, Xiuyu Cong, Binghe Xu. Overall survival results from EVER-132-001, a phase 2b single-arm study of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-10.

Abstract PS14-05: Safety evaluation from the KEYNOTE-522 study of neoadjuvant pembrolizumab (or placebo) plus chemotherapy followed by adjuvant pembrolizumab (or placebo) in patients with early triple-negative breast cancer (TNBC)

Abstract Background: In KEYNOTE-522 (NCT03036488), neoadjuvant (neoadj) pembrolizumab (pembro) + chemotherapy (chemo) followed by adjuvant (adj) pembro led to statistically significant and clinically meaningful improvements in the primary endpoints, pCR and EFS, vs neoadj placebo (pbo) + chemo followed by adj pbo in patients (pts) with newly diagnosed, high-risk, early TNBC. In the safety population at preplanned interim analysis 4 (IA4), treatment-related AEs in the combined phases (neoadj + adj) occurred in 98.9% of pts with pembro + chemo/pembro and 99.7% of pts with pbo + chemo/pbo; immune-mediated AEs of any grade occurred in 33.5% and 11.3% of pts, respectively. We report additional safety findings, beyond the already reported safety results, on immune-mediated AEs and management in the combined phases from IA4 of KEYNOTE-522. Methods: Eligible pts were randomized 2:1 to receive neoadj pembro 200 mg or pbo Q3W + paclitaxel-carboplatin for 4 cycles and then doxorubicin or epirubicin + cyclophosphamide for 4 cycles. After definitive surgery, pts received radiation therapy as indicated + adj pembro 200 mg or pbo Q3W for up to 9 cycles. Safety was assessed in all randomized pts who received ≥1 dose, underwent surgery, or both. AEs were monitored throughout the study and for 30 d post-treatment (90 d for serious AEs). Results: At IA4 (data cut-off: March 23, 2021), median treatment duration was 13.3 (range, 0-21.9) mo with pembro + chemo/pembro (n = 783) and 13.6 (range, 0-19.8) mo with pbo + chemo/pbo (n = 389). Of 341 pts with immune-mediated AEs and infusion reactions in the pembro + chemo/pembro arm (most events occurred in neoadj phase), 224 had grade 1-2 events and 117 had grade 3–5 events. The most common immune-mediated AEs with pembro + chemo/pembro were hypothyroidism (15.1%) and severe skin reactions (5.7%); infusion reactions occurred in 18.0% of pts (table). Of 118 pts with hypothyroidism, median time to onset was 105 d (range, 7–510 d) and 106 were treated with thyroid replacement, suggesting an endocrine abnormality and need for continued thyroid replacement. Of 45 pts with severe skin reactions, median time to onset was 64 d (range, 4–479 d) and 28 were treated with corticosteroids. Of 141 pts with infusion reactions, median time to onset was 16 d (range, 1–458 d) and 85 were treated with corticosteroids. Other immune-mediated AEs of interest with pembro + chemo/pembro were adrenal insufficiency (2.6%), pneumonitis (2.2%), and hypophysitis (1.9%); most of these events were grade 2–3. All 20 pts with adrenal insufficiency were treated with hormone replacement. Of 17 pts with pneumonitis, median time to onset was 167 d (range, 22-537 d) and 12 were treated with corticosteroids; median episode duration was 92 d. Of 15 pts with hypophysitis, 14 were treated with corticosteroids. Conclusion: In pts with newly diagnosed, high-risk, early TNBC, neoadj pembro + chemo followed by adj pembro had a manageable safety profile that was generally consistent with the known safety profiles of pembro and the chemo regimens. Most immune-mediated AEs and infusion reactions were grade 1-2, manageable with treatment interruption, corticosteroids, and/or hormone replacement therapy, and did not result in treatment discontinuation. Together with the efficacy findings, our results support neoadj pembro + chemo followed by adj pembro as a standard of care regimen for these pts. Table Citation Format: Javier Cortés, Rebecca Dent, Lajos Pusztai, Heather McArthur, Sherko Kuemmel, Carsten Denkert, Yeon Hee Park, Rina Hui, Masato Takahashi, Carlos Barrios, Yalin Zhu, Xiaoli Zhang, Wilbur Pan, Vassiliki Karantza, Joyce O'Shaughnessy, Peter Schmid. Safety evaluation from the KEYNOTE-522 study of neoadjuvant pembrolizumab (or placebo) plus chemotherapy followed by adjuvant pembrolizumab (or placebo) in patients with early triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS14-05.

Abstract PO4-10-06: Cost-effectiveness analysis of ribociclib in the treatment for premenopausal or perimenopausal women with HR+/HER2− advanced breast cancer: a public health care system perspective in Mexico

Abstract BACKGROUND: Ribociclib (RIB) an inhibitor of cyclin-dependent kinase 4 and 6 for the treatment of advanced breast cancer (ABC), has demonstrated significant efficacy in prolonging progression-free survival and overall survival when added to endocrine therapy (ET). Because of the high-cost perception of this therapeutic class, it is crucial to assess their relative value compared to existing standards of care in the local setting. Chemotherapy is used as the first line of treatment in a conservative case in almost three-quarters of ABC patients with positive hormone receptors in the Public Health System in Mexico. Additionally, the high use of chemotherapy presents additional clinical and economic challenges for the Institute. Among the clinical challenges, the toxicity associated with chemotherapy regimens stands out. We evaluated the cost-effectiveness of the inclusion of RIB+ ET to usual care in the treatment of premenopausal or perimenopausal ABC from the perspective of the Public Health System in Mexico. Direct medical costs were considered. METHODS: We developed a partitioned survival model to simulate time to cancer progression and to compare lifetime clinical benefit and cost of standard alternative treatment strategies for patients with metastatic disease. Per approved indication, endocrine treatment-naive patients were assigned to RI plus ET or usual care (different chemotherapy schemes). Costs in Mexican Pesos (MXN) were estimated from the perspective of the Public Health System in Mexico. Costs and clinical benefits were discounted at 5% annually. The model assumptions were informed based on published clinical trial data from the randomized Phase III MONALEESA-7 trial and other peer-reviewed studies and indirect treatment comparisons. We carried out one-way and probabilistic sensitivity analyses to assess the robustness of our results to the changes in model assumptions. RESULTS: Ribociclib reduced monthly direct medical costs associated with the administration of breast cancer treatment and the management of adverse events. Direct drug acquisition costs per month of ribociclib were in the range of the cost of current available and used therapies. Indirect treatment comparisons did not show statistical significance of the benefit of ribociclib vs. standard of care, primarily due to heterogeneity leading to a mixed evaluation vs. two comparator groups according to the statistical significance of the survival improvement. Ribociclib is a 100% oral therapy with a manageable safety profile with dosage adjustments, so it does not require institutional resources for its administration or for managing adverse events. Its consolidated cost at 28 days of treatment is up to 40% less than combined chemotherapy regimens and up to 30% less than monotherapy schemes. Average cost-effectiveness for progression-free survival for ribociclib is among the lowest considering chemotherapy options even though generic versions are available for many of them. For the comparators with comparable efficacy, ribociclib was cost-saving at current public market prices. For the comparators where ribociclib showed a significant benefit, the incremental cost-effectiveness ratio of ribociclib vs. standard of care is also below the threshold of 3 GDPs per capita vs. most options, leading to cost-effectiveness. A longer treatment duration due to progression delay was a main driver of incremental cost. CONCLUSIONS: Ribociclib is cost-saving or cost-effective vs. standard of care in the Public Health System in Mexico. Other variables must be considered to inform clinical and funding decisions, such as disease burden and humanistic impact on this young, economically active population. Citation Format: Saúl Campos-Gomez, Christian Pichardo Piña. Cost-effectiveness analysis of ribociclib in the treatment for premenopausal or perimenopausal women with HR+/HER2− advanced breast cancer: a public health care system perspective in Mexico [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-10-06.

Abstract PS08-08: Updated efficacy and safety of SKB264 (MK-2870) for previously treated metastatic triple negative breast cancer (mTNBC) in Phase 2 study

Abstract Background: Patients (pts) with mTNBC have limited treatment options and poor prognosis. The estimated median overall survival (OS) of pts with mTNBC is 12 to 18 months (mo) after diagnosis. SKB264, an antibody drug conjugate (ADC) composed of an anti-TROP2 antibody coupled to a cytotoxic belotecan-derivative via a novel linker with an average Drug to Antibody Ratio (DAR) of 7.4, has shown promising anti-tumor activity and tolerable safety profile in pts with mTNBC (Yin, Y. et al. SABCS 2022). Here, we report the updated data from a Phase 2 expansion cohort for pts with mTNBC (NCT04152499). Methods: Pts with previously treated mTNBC were enrolled to receive SKB264 at 4 mg/kg Q2W or 5 mg/kg Q2W in a non-randomized manner until disease progression or unacceptable toxicity. Tumor assessment was performed every 8 weeks per RECIST v1.1 assessed by investigator. The primary objective was to assess objective response rate (ORR). Secondary objectives included DoR, PFS, and OS. The TROP2 expression was scored using the semi-quantitative H-score method, and a preliminary cutoff was set as 200. TROP2 expression and its association with anti-tumor activity were retrospectively analyzed. Results: At data cut-off date (May 05, 2023), 59 pts were enrolled (23 in 4 mg/kg, 36 in 5 mg/kg), and 88% (52 pts) had received ≥3 prior lines of therapy for metastatic disease. The median follow-up was 22.8 months (mo; 95% CI, 21.3-25.2). The ORR was 42.4% (25/59, 22 confirmed and 3 unconfirmed) and disease control rate (DCR) was 76.3% (45/59). The median duration of response (DoR) was 11.5 mo (range, 3.7 to 22.1+). Median PFS (mPFS) was 5.7 mo (95% Cl: 3.8, 9.1). Median OS (mOS) was 16.8 mo (95% Cl: 12.7, NE), while 12-mo and 24-mo OS rates were 65.0% and 39.5%, respectively. In the subset of pts with high TROP2 expression (H-score>200, N=32), ORR was 53.1% (including 3 complete response), mDoR was 11.1 mo (range, 3.7 to 22.1+), mPFS was 5.8 mo (95% Cl: 3.7, 13.3), mOS was not reached (95% Cl: 9.7, NE), while 12-mo and 24-mo OS rates were 65.3% and 57.3%, respectively. Treatment-related adverse events (TRAEs) of ≥ Grade 3 severity were reported in 57.6% (34/59) of pts. The most common ≥ Grade 3 TRAEs (≥ 10%) were neutrophil count decreased (25.4%), white blood cell count decreased (23.7%), anemia (22.0%) and platelet count decreased (16.9%). TRAEs leading to dose reduction and dose delay occurred in 13.6% (8/59) and 47.5% (28/59) of pts, respectively. Three pts discontinued treatment due to TRAEs (platelet count decreased, dry eye, anaphylactic shock). No cases of interstitial lung disease (ILD), neuropathy or grade ≥3 diarrhea were observed. Serious TRAEs were reported in 28.8% (17/59) of pts; no deaths associated with TRAEs were observed. Conclusions: The updated data continues to demonstrate that pts with heavily pretreated mTNBC could achieve durable response and a trend of long-term OS benefit from SKB264 treatment, along with a manageable safety profile. Higher response rate was seen in mTNBC pts with high TROP2 expression. A Phase 3 study of SKB264 vs. investigator’s choice of chemotherapy in 3L+ mTNBC (NCT05347134) and a Phase 2 study evaluating SKB264 as monotherapy or combination with anti-PD-L1 antibody in first-line setting (NCT05445908) are ongoing in China. Citation Format: Yongmei Yin, Xinhong Wu, Quchang Ouyang, Min Yan, Lihua Song, YunPeng Liu, Zhongsheng Tong, Cuizhi Geng, Ying Wang, Guohua Yu, Xiang Wang, Ying Cheng, Weihong Zhao, Xiaoping Jin, Yina Diao, Gesha Liu, Mengyu Yang, Yue Yang, Yalan Yang, Lian Lu, Junyou Ge, Jin Li, Qun Li. Updated efficacy and safety of SKB264 (MK-2870) for previously treated metastatic triple negative breast cancer (mTNBC) in Phase 2 study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-08.

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

Abstract Background: Eribulin is a halichondrin non-taxane inhibitor of microtubule dynamics approved in China for advanced breast cancer patients who have received at least two prior chemotherapy treatments. The combination of eribulin and gemcitabine has demonstrated a similar progression-free survival (PFS) benefit as paclitaxel plus gemcitabine, with less neurotoxicity, for patients with MBC who have not received prior cytotoxic chemotherapy. However, the effect of eribulin plus gemcitabine on PFS in second line or beyond remains unclear. Methods: This open-label, single-arm, phase II study (NCT05263882) was conducted at 13 institutions in China. Eligible patients had histologically confirmed HER2-negative MBC and had received at least one prior taxane-containing chemotherapy regimen for advanced disease, and anthracycline-containing regimens in the adjuvant setting. Patients received intravenous infusions of eribulin (1.4 mg/m2) and gemcitabine (1.0 g/m2) on days 1 and 8 of a 21-day cycle. Efficacy outcomes, including PFS, objective response rate (ORR), and disease control rate (DCR), were assessed using RECIST v1.1. Adverse events (AEs) were graded according to NCI-CTC version 5.0. Results: A total of 65 patients were enrolled from November 2021 to May 2023; 47 (72.3%) had HR+/HER2- and 18 (27.7%) had triple-negative MBC. The median patient age was 50 years (range: 31-68), and the sites of metastasis were the bone (70.8%), liver (58.5%), lymph nodes (50.8%), lung (43.1%) and brain (10.8%). Patients had received a median of 3 prior lines of systemic treatment, 2 lines of chemotherapy, and 1 line of endocrine treatment. Among all patients, the ORR was 52.3%, the DCR was 92.3% and the median PFS was 7.6 months (Table). For the HR-positive subgroup, the median PFS was 8.4 months, while for the triple-negative subgroup, it was 7.6 months. Among patients who had received prior CDK4/6 inhibitor treatment, the median PFS was 7.2 months. In the subgroup of patients who had not received CDK4/6 inhibitor treatment, the median PFS had not been reached. The most common grade 3-4 AEs were hematological, including neutropenia (41.6%), leukopenia (33.9%), anemia (23.1%), and thrombocytopenia (15.4%). No grade ≥3 perceived AEs were reported. Conclusion: Eribulin plus gemcitabine was effective in heavily pretreated patients with HER2- MBC, while maintaining a predictable and manageable safety profile. Table. Summary of efficacy outcomes Citation Format: PeiJian Peng, Xiao-Lu Xu, Jin-Cai Zhong, Jin-Hui Ye, Zhi-Hui Wang, Hong Wang, Hong Lin, Cai-Wen Du, Guorong Zou, Jie Ouyang, Ying-Ying Shi, Fei Xu, Geng-Sheng Yu, Yong-Kui Lu, Yong-Xia Wang, Shi-En Cui, Lu-Zhen Li. Efficacy and safety of eribulin plus gemcitabine in second-line or beyond for patients with HER2-negative metastatic breast cancer (MBC): A multi-center, open-label, single-arm, phase II study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-10.

Abstract PO2-02-05: CDK4/6 inhibitor dalpiciclib combined with letrozole as neoadjuvant therapy in postmenopausal patients with hormone receptor-positive, HER2-negative stage II-III breast cancer: a single-arm exploratory trial

Abstract Background: Patients with HR-positive, HER2-negative breast cancer respond poorly to neoadjuvant chemotherapy. The phase 3 DAWNA-1 and DAWNA-2 studies have proved that adding dalpiciclib (a CDK4/6 inhibitor) to endocrine therapy can significantly improve progression-free survival in patients with hormone receptor (HR)-positive, HER2-negative advanced breast cancer. However, the evidence of dalpiciclib in the neoadjuvant setting is limited. This study aimed to explore the efficacy and safety of dalpiciclib plus letrozole as neoadjuvant therapy in in patients with HR-positive, HER2-negative stage II-III breast cancer. Methods: In this multicenter, single-arm exploratory trial (NCT05512780), adult postmenopausal women with HR-positive (estrogen receptor >10%), HER2-negative stage II-III invasive breast cancer were enrolled. Patients received oral dalpiciclib (150 mg on days 1-21 of each 28-day cycle) and oral letrozole (2.5 mg once daily) for 4 cycles, followed by surgery. The primary endpoint was objective response rate (ORR), assessed by investigator according to the Response Evaluation Criteria In Solid Tumors version 1.1. Secondary endpoints included complete cell cycle arrest (CCCA, defined as Ki-67 < 2.7% on day 15 of the first cycle) rate, total pathological complete response (tpCR; ypT0/is ypN0) rate, residual cancer burden (RCB) 0-I rate, and safety. Results: Between June 2022 and January 2023, 41 patients were screened at 9 sites, and 35 patients were enrolled and received at least one dose of study drug. The median age was 66 years (range, 52-83), and the median baseline Ki-67 level was 20% (range, 4%-40%). The majority of patients had T2 disease (65.7%), lymph node-positive disease (88.6%), and stage II disease (IIA: 45.7%; IIB: 40.0%). The ORR was 35.5% (11/31) at 8 weeks and 51.7% (15/29) at 16 weeks in patients with evaluable response. The CCCA rate was 70.0% (21/30) in patients with available data. Four patients refused surgery and chose to continue the drug therapy. Of 27 patients who had undergone surgery, one (3.7%) patient had tpCR and RCB 0. Of 35 patients, the most common adverse events were neutrophil count decreased (74.3%), white blood cell decreased (68.6%), anemia (34.3%), and fatigue (31.4%). The most common grade 3 or higher adverse event was neutrophil count decreased (45.7%). No febrile neutropenia or treatment-related deaths occurred. Conclusions: This is the first prospective study of neoadjuvant dalpiciclib in patients with HR-positive, HER2-negative breast cancer. The findings suggest the promising tumor response to neoadjuvant dalpiciclib plus letrozole in postmenopausal patients with HR-positive, HER2-negative breast cancer, with a manageable safety profile. This combination can effectively suppress the tumor cell proliferation, as reflected by change in Ki-67 level. Citation Format: Lina Zhang, Chao Yang, Jie Ma, Yuntao Li, Ruizhen Luo, Jianjun Han, Xiaochun Wang, Zhisheng Zhang, Li Ma, Haifeng Cai, Xiangshun Kong, Zunyi Wang, Xinping Zhou, Yueping Liu, JiaJie Shi, Yanshou Zhang, Meiqi Wang, Jiaxing Wang, Cuizhi Geng. CDK4/6 inhibitor dalpiciclib combined with letrozole as neoadjuvant therapy in postmenopausal patients with hormone receptor-positive, HER2-negative stage II-III breast cancer: a single-arm exploratory trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-02-05.

Abstract PO2-05-05: ELECTRA: An open-label, multicenter, phase 1b/2 study of elacestrant in combination with abemaciclib in patients with brain metastasis (mets) from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC)

Abstract Background: Currently, there are no approved systemic treatment options specifically for patients with ER+/HER2- BC who have brain metastasis. The prevalence of brain metastases from ER+/HER2- BC is approximately 14% of women (Aversa, 2014). Elacestrant is a next-generation oral SERD that was evaluated in a pivotal phase 3 trial, EMERALD, as monotherapy vs. standard of care (SOC) endocrine therapy. The EMERALD trial reported significantly prolonged progression-free survival (PFS) with elacestrant vs SOC endocrine therapy in patients with ER+/HER2− ESR1 mutated (ESR1-mut) mBC following progression on prior endocrine therapy (Bidard, 2022). Elacestrant was well tolerated with a manageable safety profile. Most adverse events, including nausea, were low-grade and consistent with other endocrine therapies. A clinical study in healthy postmenopausal women demonstrated the ability of elacestrant to cross the blood-brain barrier (Conlan, 2020). Abemaciclib, a CDK4/6i, has been shown to achieve therapeutic concentrations in brain metastases tissue (Tolaney, 2020). Given the lack of current systemic treatments, elacestrant is now being evaluated with abemaciclib in patients with ER+/HER2- BC and brain metastasis (NCT05386108). Methods: ELECTRA (NCT05386108) is an open-label phase 1b/2, multicenter study evaluating elacestrant in combination with abemaciclib in patients with brain metastasis from ER+, HER2- BC. Eligibility are patients with ER+/HER2− locally advanced or mBC and measurable brain metastasis. For phase 1b, the presence of brain metastases is allowed but not required for eligibility. For phase 2, patients must have ≥ 1 active and measurable brain metastasis per RECIST v1.1. Patients must have received prior therapy in the metastatic setting, including ≥ 1 ET, ≤2 chemotherapy regimens, and 0-2 prior CDK4/6i (excluding abemaciclib). The primary objectives of Phase 1b are to determine the recommended Phase 2 dose (RP2D). Phase 1b secondary objectives include safety, PK, objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR), PFS, and overall survival (OS). Phase 2 primary objective is ORR per RECIST version 1.1. Phase 2 secondary objectives include intracranial response rate (RR), DoR, CBR, PFS, OS, PK, and quality of life (QoL). The phase 1b portion evaluated dose-limiting toxicities (DLTs) of the combination during the first cycle (28 days) of treatment in up to three 6-patient cohorts, starting at elacestrant 300 mg daily plus abemaciclib 100 mg twice daily. Here we report initial safety results from the phase 1b portion. Results: As of June 2023, 15 patients have been enrolled in the phase 1b portion of the trial. At dose level 1, elacestrant 300 mg QD + abemaciclib 100 mg BID, no patient experienced DLTs, and the combination was feasible. Dose level 2, elacestrant 400 mg QD + abemaciclib 100 mg BID has been completed, and no patients experienced DLTs. In dose level 1, 4/7 patients remain on treatment at cycle 5. Additional safety and PK data for the cohorts will be provided. Conclusion: In the phase 1b portion of ELECTRA, dose level 1 and dose level 2 have been completed. No patients experienced DLTs in either dose level 1 or dose level 2, and the combination was considered feasible in the respective dose levels. Dose level 3 (elacestrant 400 mg QD + abemaciclib 150 mg BID) is proceeding. Recruitment is actively ongoing, enabling oral-oral combinations to determine a RP2D. Citation Format: Nuhad Ibrahim, Sung-Bae Kim, Nancy Lin, Ahmad Awada, Eva Ciruelos Gil, Giulia Tonini, Bartomeu Piza Vallespir, Kathy Puvana Theall, Erika Hamilton. ELECTRA: An open-label, multicenter, phase 1b/2 study of elacestrant in combination with abemaciclib in patients with brain metastasis (mets) from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-05-05.

Abstract PS17-02: Elacestrant vs standard-of-care in ER+/HER2- advanced or metastatic breast cancer (mBC) with ESR1 mutation: key biomarkers and clinical subgroup analyses from the phase 3 EMERALD trial

Abstract Background: The EMERALD trial reported significantly prolonged progression-free survival (PFS) and a manageable safety profile with elacestrant vs standard of care (SOC) endocrine therapy in patients (pts) with ER+/HER2− ESR1 mutated (ESR1-mut) mBC following progression on prior endocrine therapy (ET). EMERALD is the only pivotal oral SERD clinical trial where prior CDK4/6i usage was mandated. Duration of prior CDK4/6i was shown to be a predictor of efficacy in patients with ESR1 mutations (ESR1-mut) receiving elacestrant, with median PFS (mPFS) for patients with ESR1-mut receiving at least 12 months of CDK4/6i achieved 8.61 months (elacestrant) vs 1.91 months (SOC) (SABCS 2022). This analysis evaluates the clinical benefit of single-agent elacestrant in key clinically relevant subgroups, including biomarkers, usually associated with poorer prognosis. Methods: Patients with ER+/HER2- advanced or mBC who previously had 1-2 lines of endocrine therapy, and prior CDK4/6i, were randomized 1:1 to receive elacestrant or SOC (aromatase inhibitor or fulvestrant). A subgroup analysis was performed on patients with ESR1-mut, by prior duration of CDK4/6i plus ET with at least 12 months in the advanced or metastatic setting, with concomitant presence of liver and/or lung metastases, PIK3CA mutations, TP53 mutation, and HER2 low expression. Results: Overall, 478 patients were randomized to elacestrant (n=239) or SOC (n=239), 228 pts (47.7%) had ESR1-mut, and 159 pts (71.6%) received at least 12 months of prior CDK4/6i. Out of these 159 pts, 113 pts (71%) had liver and/or lung metastases, 62 pts (39%) had a PIK3CA-mut, 61 pts (38%) had TP53m, and 77 pts (48%) had HER2 low expression. A clinically meaningful improvement in PFS favoring elacestrant compared to SOC was consistent across all relevant subgroups in pts with ESR1-mut. Conclusions: Elacestrant showed significantly greater PFS when prior treatment duration with CDK4/6i was at least 12 months, suggesting prior exposure to CDK4/6i is a surrogate marker for endocrine sensitivity. In this population, elacestrant demonstrated superior efficacy, compared to SOC, even in patients with concomitant PIK3CA or TP53 mutations, expression of HER2 low, or presence of liver and/or lung metastases. These results suggest an active ER-driven pathway for this group despite the presence of other resistance mechanisms, where single-agent oral elacestrant could be an attractive option compared to combination therapies or intravenous HER2 low-targeted ADCs. NCT number: NCT03778931 Table. a. Includes E545K, H1047R, E542K amongst others b. HER2 IHC 1+, and 2+ with no ISH amplification Citation Format: Aditya Bardia, Joyce O'Shaughnessy, Francois-Clement Bidard, Patrick Neven, José Ángel García-Sáenz, Philippe Aftimos, Javier Cortés, Janice Lu, Giulia Tonini, Kathy Puvana Theall, Alessandro Paoli, Virginia Kaklamani. Elacestrant vs standard-of-care in ER+/HER2- advanced or metastatic breast cancer (mBC) with ESR1 mutation: key biomarkers and clinical subgroup analyses from the phase 3 EMERALD trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS17-02.

Abstract PS14-08: Safety evaluation from the KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy in patients with previously untreated, locally recurrent inoperable or metastatic triple-negative breast cancer

Abstract Background: In KEYNOTE-355 (NCT02819518), pembrolizumab (pembro) + chemotherapy (chemo) led to statistically significant and clinically meaningful improvements in PFS and OS (primary endpoints) vs placebo (pbo) + chemo in patients (pts) with previously untreated PD-L1 positive advanced TNBC (combined positive score ≥10). In the overall safety population at final analysis, treatment-related AEs occurred in 96.3% of pts in the pembro + chemo arm and 95.0% of pts in the pbo + chemo arm; immune-mediated AEs occurred in 26.5% and 6.4% of pts, respectively. We report additional safety information, beyond the already reported safety results, on immune-mediated AEs and management from the final analysis of KEYNOTE-355. Methods: Eligible pts were randomized 2:1 to receive pembro 200 mg or pbo Q3W for up to 35 cycles + investigator’s choice of nab-paclitaxel, paclitaxel, or gemcitabine-carboplatin. Safety was assessed in all randomized pts who received ≥1 dose of study treatment. AEs were monitored throughout the study and for 30 d post-treatment (90 d for serious AEs). Results: At final analysis (data cut-off: June 15, 2021), median treatment duration was 6.1 (range, 0.0–48.8) mo in the pembro + chemo arm (n = 562) and 5.3 (range, 0.0–51.5) mo in the pbo + chemo arm (n = 281). Of 157 pts with immune-mediated AEs and infusion reactions in the pembro + chemo arm, 125 had grade 1-2 events and 32 had grade 3-4 events; none were grade 5. The most common immune-mediated AEs with pembro + chemo were hypothyroidism (15.8%) and hyperthyroidism (4.3%); infusion reactions occurred in 3.7% of pts (table). Of 89 pts with hypothyroidism, median time to onset was 105 d (range, 19–707 d) and 70 were treated with thyroid replacement, suggesting an endocrine abnormality and need for continued thyroid replacement. Of 24 pts with hyperthyroidism, median time to onset was 53.5 d (range, 20–209 d) and 2 were treated with corticosteroids. Of 21 pts with infusion reactions, median time to onset was 147 d (range, 1–729 d) and 10 were treated with corticosteroids. Other immune-mediated AEs of interest in the pembro + chemo arm were pneumonitis (2.5%) and adrenal insufficiency (1.4%); most of these events were grade 2–3. Of 14 pts with pneumonitis, median time to onset was 99.5 d (range, 29–288 d) and 11 were treated with corticosteroids; median episode duration was 56 d. All 8 pts with adrenal insufficiency were treated with hormone replacement. There were no reports of hypophysitis. Conclusion: In pts with previously untreated advanced TNBC, pembro + chemo had a manageable safety profile that was generally consistent with the known safety profiles of pembro and the chemo regimens. Most immune-mediated AEs and infusion reactions were grade 1-2, manageable with treatment interruption, corticosteroids, and/or hormone replacement therapy, and did not result in discontinuation of study treatment. Together with the efficacy findings, our results support pembro + chemo as a standard of care regimen for these pts. Table. Citation Format: Hope Rugo, Peter Schmid, Zbigniew Nowecki, David Cescon, Seock-Ah Im, Mastura Yusof, Carlos Gallardo, Hiroji Iwata, Carlos Barrios, Sherene Loi, Xuan Zhou, Xiaoli Zhang, Wilbur Pan, Vassiliki Karantza, Javier Cortés. Safety evaluation from the KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy in patients with previously untreated, locally recurrent inoperable or metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS14-08.

Abstract RF02-05: Report on Cohort Expansion of Phase I Study to Investigate the Safety, Tolerability, Pharmacokinetics and Antitumor Activity of BB-1701 in Patients with Locally Advanced/Metastatic HER2 Low Breast Cancer

Abstract Background: BB-1701 is an antibody-drug conjugate (ADC) consisting of a humanized IgG1κ monoclonal anti-HER2 antibody with the same sequence as trastuzumab and eribulin linked together by a cathepsin-cleavable valine-citrulline linker. Eribulin is an inhibitor of microtubule approved for the treatment of metastatic breast cancer and advanced liposarcoma, following prior therapies. When BB-1701 targets HER2 expressing cancer cells and it is internalized, free eribulin is cleaved from the ADC by cathepsin b and causes cytotoxicity to cancer cells. The neighboring cells were affected with bystander effects, like cytotoxicity on tumor cells and non-cytotoxic effects on microenvironment, by free eribulin released from dying cancer cells. Here, we report preliminary results from the ongoing cohort expansion of a phase I study of BB-1701 in patients with HER2 low breast cancer (ClinicalTrials.gov Identifier: NCT 04257110). Methods: Patients ≥ 18 years of age with confirmed locally advanced/metastatic HER2 low breast cancer (IHC 2+ and FISH negative or IHC 1+), that had progressed on at least two lines of prior standard therapies, with ECOG PS ≤ 2 and measurable disease (RECIST 1.1) were enrolled. HER2 expressions was determined by IHC and FISH before enrollment. Total of four dose levels of BB-1701 (1.0 mg/kg Q3W, 1.2 mg/kg Q3W, 1.4 mg/kg Q3W and 1.6 mg/kg Q3W) were administered during the cohort expansion. The safety, tolerability and preliminary anti-tumor activity of BB-1701 were assessed during study. Radiographic assessment was conducted every 6 weeks. Results: As of 30 June 2023, 40 patients with HER2 low breast cancer were enrolled in the four dose levels, 5 patients at 1.0 mg/kg Q3W, 20 patients at 1.2 mg/kg Q3W, 5 patients at 1.4 mg/kg Q3W and 10 patients at 1.6 mg/kg Q3W. Median age was 55 years (range 30-74), 97.5% were female, and 30.0%/70.0% patients were ECOG PS 0/1. The median prior lines of systemic therapy were 3 (range 2 – 9). All subjects experienced at least one treatment emergent adverse events and treatment-related adverse events (TRAEs) occurred in 30 subjects. The most common all grade TRAEs (≥20%) were peripheral neuropathy, aspartate aminotransferase increased, alanine aminotransferase increased, anemia, white blood cell count decreased. Grade 3 TRAEs were peripheral neuropathy (3 subjects), peripheral sensory neuropathy (2 subjects), neutrophil count decreased (2 subjects), platelet count decreased (1 subject), white blood cell count decreased (1 subject). There were no grade 4 or grade 5 events. The treatment related serious adverse events (SAEs) were peripheral sensory neuropathy (1 subject) and infusion related reaction (1 subject). There was no interstitial lung disease reported. No patients discontinued the study treatment due to AE. Of the 40 patients enrolled, 38 patients were evaluable for antitumor activity. At 1.0 mg/kg dose level, of 5 patients treated, 2 achieved partial response (PR), 2 had stable disease (SD), best overall response rate (BOR) was 40.0% (2/5) and disease control rate (DCR) was 80.0% (4/5). At 1.2 mg/kg dose level, of 18 patients treated, 5 achieved PR, 11 had SD with BOR of 27.8% (5/18) and DCR of 88.9% (16/18). At 1.4 mg/kg dose level, of 5 patients treated, 2 achieved PR, 2 had SD with BOR of 40.0% (2/5), and DCR was 80.0% (4/5). One patient who achieved PR was previously progressed on sacituzumab govitecan. At 1.6 mg/kg dose level, of 10 patients treated, 1 achieved CR, 3 achieved PR, 2 had SD with BOR of 40.0% (4/10), and DCR of 60.0% (6/10). Among these patients, the patient who achieved CR was previously treated by disitamab vedotin, and one patient who achieved PR was previously treated by trastuzumab deruxtecan. Conclusions: BB-1701 has demonstrated promising preliminary antitumor activity in HER2 low breast cancer including patients who received prior anti-HER2 ADCs, and a manageable safety profile. Citation Format: Fei Ma, Pamela Munster, Xiaoxiang Guan, Jingfen Wang, Herui Yao, Erika Hamilton, Xian Wang, Yehui Shi, Xinjun Liang, Nong Xu, Huoling Tang, Yuhong Zhou, Ziping Wei. Report on Cohort Expansion of Phase I Study to Investigate the Safety, Tolerability, Pharmacokinetics and Antitumor Activity of BB-1701 in Patients with Locally Advanced/Metastatic HER2 Low Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF02-05.

Abstract PO1-04-03: Phase I/II Trial of Ibrutinib Plus Trastuzumab in HER2-Positive Metastatic Breast Cancer

Abstract Background: Ibrutinib is a first-in-class inhibitor of Bruton’s tyrosine kinase that has demonstrated potent inhibition of ErbB/HER family receptor tyrosine kinases in preclinical models. Ibrutinib also displays immunomodulatory effects, shifting the profile of the immune response from Th2-type to Th1-type cytokines (Dubovsky et al. 2013), resulting in enhanced antitumor immunity. As there is a need for novel HER2-targeted therapies following progression on established anti-HER2–directed therapies, and as combining multiple HER2-directed agents is more effective than single-agent therapy (Blackwell et al. 2012), this study explored the safety and efficacy of ibrutinib in combination with trastuzumab in patients (pts) with HER2-positive metastatic breast cancer (MBC) (NCT03379428). Trial design: Phase I was a dose-escalation study to define the recommended Phase II dose (RP2D) of ibrutinib plus trastuzumab. The primary objective of Phase II was to define the clinical benefit rate (CBR = complete response [CR] + partial response [PR] + stable disease [SD] ≥ 6 months) of ibrutinib plus trastuzumab; secondary objectives were to determine objective response rate (ORR = CR + PR), overall survival (OS), progression-free survival (PFS), and safety/tolerability. Pts had HER2-positive MBC with measurable disease per RECIST v1.1, disease progression on or within 6 months of completing ado-trastuzumab emtansine (T-DM1) therapy, and ≤4 (Phase I) or ≤5 (Phase II) prior chemotherapy regimens for MBC, with no limit on prior endocrine therapies. Results: 26 pts were treated in Phases I and II: median age, 65.1 y; 15.4% Asian, 15.4% Black, 46.2% Caucasian, 19.2% Hispanic, and 3.8% Other; 46.2% with ECOG performance status (PS) of 0, 42.3% with PS of 1, and 7.7% with PS of 2. Median prior lines of therapy for MBC was 2 (range: 0, 6); median prior lines of therapy in any setting was 4 (range: 1, 9). In any setting, 88.5% of pts had prior treatment (Tx) with trastuzumab, 80.8% had prior Tx with pertuzumab, and 100% had prior Tx with T-DM1. 0% of pts had brain, 38.5% had bone, 23.1% had liver, and 42.3% had lung metastases. All pts were HER2+ by local pathology, 61.5% positive by IHC and 42.3% by FISH; 12 pts had ER+ and/or PR+ and 14 pts had ER-/PR- cancers. The starting dose of ibrutinib for Phase I was 560 mg. Of the 3 pts enrolled at this dose level, all experienced grade 3 or higher adverse events (AEs), with 2 of the pts experiencing serious AEs (grade 4 alanine aminotransferase [ALT] increased and grade 5 respiratory failure). As such, 420 mg of ibrutinib was selected as the RP2D. At the time of data extraction, across Phase I/II, 16 pts (61.5%) experienced a Tx-related adverse event (TRAE). The most common (≥5%) TRAEs of any grade were bruising and rash (each 19.2%); fatigue and thrombocytopenia (each 15.4%); anemia, diarrhea, and edema (each 11.5%); and ALT increased, aspartate aminotransferase increased, blurred vision, ecchymoses, mucositis, nausea, pruritus, and vomiting (each 7.7%). A total of 5 pts (19.2%) experienced grade 3 or 4 TRAEs; no grade 5 TRAEs were reported. 26 pts were treated with ibrutinib and trastuzumab, and 26 pts were in the evaluable population. 1 pt had CR for an ORR of 3.8% (95% CIs: 0.1, 19.6); 9 pts had SD, and 4 pts had SD for ≥6 months for a CBR of 19.2% (95% CIs: 6.6, 39.4). Median OS was 27.1 months (range: 0.30, 27.1), and median PFS was 2.0 months (range: 0.03, 27.1). The PFS rate at 12 months was 34.6% (95% CIs: 15.6, 54.6). Conclusion: Ibrutinib plus trastuzumab had a manageable safety profile; however, the CBR did not reach the protocol-specified goal of 28%, and these results do not support further clinical investigation. An in-depth evaluation of the immune effects of ibrutinib in these pts is ongoing. Citation Format: Joyce O'Shaughnessy, Andrea Glidden, Tracy Locke, Amy Scales. Phase I/II Trial of Ibrutinib Plus Trastuzumab in HER2-Positive Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-03.

A Practical Review of Encorafenib and Binimetinib Therapy Management in Patients with BRAF V600E-Mutant Metastatic Non-Small Cell Lung Cancer.

According to current guidelines, targeted therapy with a combination of BRAF plus MEK inhibitors is the preferred first-line treatment for patients with BRAF V600E-mutant metastatic non-small cell lung cancer (NSCLC). In the open-label, single-arm, phase2 PHAROS trial (NCT03915951), the combination of encorafenib, a potent BRAF inhibitor, and binimetinib, a potent MEK inhibitor, demonstrated durable antitumor activity with a manageable safety profile in this patient population. On the basis of the results of this study, the combination of encorafenib plus binimetinib was approved by the US Food and Drug Administration on October 11, 2023, for patients with BRAF V600E-mutant metastatic NSCLC. In this review, we summarize the efficacy and safety of encorafenib plus binimetinib from the PHAROS study. In addition, we discuss strategies to manage adverse reactions with this combination therapy with the intent of minimizing unnecessary treatment discontinuations in these patients.

Abstract PO2-05-04: ELEVATE: A phase 1b/2, open-label, umbrella study evaluating elacestrant in various combinations in patients (pts) with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (mBC)

Abstract Background: ER+/HER2- breast cancer (BC) is the most prevalent BC subtype. Endocrine therapy (ET) is the mainstay of treatment; however, development of resistance to this therapeutic approach is common in the metastatic setting. After progression on first-line treatment, both ET monotherapy and combination therapy options are available. Combinations such as everolimus + exemestane and alpelisib + fulvestrant can be associated with higher efficacy, but also significant toxicity with discontinuation rates around 25%. Also, for second-line treatment, pts who did not receive prior treatment with a CDK4/6i, the combination of fulvestrant with a CDK4/6i (palbociclib, abemaciclib, and ribociclib) are among the recommended treatment options for this pt population (NCCN, 2022). However, fulvestrant has low bioavailability and an IM injection burden. The crosstalk between the three pathways ER, PI3K/AKT/mTOR and cyclin-dependent kinases (CDK4/6) provide a rationale for the combination of elacestrant, a next-generation oral SERD, with inhibitors of these pathways that are natural targets to overcome endocrine resistance. The EMERALD trial reported significantly prolonged progression-free survival (PFS) with elacestrant vs SOC ET in pts with ER+/HER2− ESR1 mutated (ESR1-mut) mBC following disease progression on prior ET (Bidard, 2022). Elacestrant was well tolerated with a manageable safety profile. Most adverse events, including nausea, were low-grade and consistent with other endocrine therapies. The replacement of the fulvestrant backbone with elacestrant in combination with targeted agents enabling oral-oral combinations is of therapeutic interest. Methods: ELEVATE (NCT05563220) is a phase 1b/2 clinical trial that will evaluate the safety and efficacy of elacestrant combined with alpelisib, everolimus, palbociclib, abemaciclib, and ribociclib. Eligible pts must be adults with confirmed ER+/HER2− advanced or mBC, > 1 measurable lesion as per RECIST v1.1, and adequate bone marrow or organ function. The main objectives for Phase 1b are to determine the RP2D of elacestrant combined with other targeted agents. The RP2D of elacestrant and abemaciclib will be determined in the ELECTRA study (NCT05386108). The Phase 2 portion will evaluate the efficacy of elacestrant combined with other study drugs for PFS; secondary objectives include PK of the various combinations, ORR, DoR, CBR, PFS, and OS. Here we report the initial dosing from the Phase 1b portion. Results: As of June 2023, 11 pts were enrolled in the phase 1b portion of the trial, cohort 1 for all combinations: 5 pts in the elacestrant and everolimus (300 mg elacestrant QD/everolimus 5 mg QD) and 3 pts in the elacestrant and alpelisib (300 mg elacestrant QD/alpelisib 250 mg QD) and 2 patients for palbociclib and 1 patient in the ribociclib combinations. Further patient accrual is expected in phase 1b cohorts of various combinations during the second half of 2023; both safety and PK data will be provided. Conclusion: In the Phase 1b portion of ELEVATE, elacestrant is being combined with various targeted agents enabling oral-oral combinations to determine a RP2D. Recruitment is actively ongoing; safety and PK results will be presented at the meeting from the completed phase 1b cohorts. Citation Format: Hope Rugo, Aditya Bardia, Javier Cortés, Giuseppe Curigliano, Erika Hamilton, Sara Hurvitz, Sibylle Loibl, Sara Tolaney, Virginia Kaklamani, Giulia Tonini, Shannon Matheny, Kathy Puvana Theall, Joyce O'Shaughnessy. ELEVATE: A phase 1b/2, open-label, umbrella study evaluating elacestrant in various combinations in patients (pts) with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (mBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-05-04.

Abstract PO4-17-02: A multicenter, prospective, observational study of patients receiving trastuzumab deruxtecan for the treatment of HER2-positive and HER2-low unresectable and/or metastatic breast cancer: DESTINY-Breast-RESPOND

Abstract Background: Approximately 20% of breast cancer (BC) cases are human epidermal growth factor receptor 2-positive (HER2+; immunohistochemistry [IHC] 3+, IHC 2+/in-situ hybridization [ISH]+), and up to ~50% of patients with primary or metastatic BC (mBC) have HER2-low tumors (IHC 1+, IHC 2+/ISH−), a new therapeutically targetable subset of BC. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate approved in the USA, EU, and other countries for the treatment of adult patients with unresectable or metastatic HER2+ BC who have received a prior anti-HER2-based regimen, or with unresectable or metastatic HER2-low BC who have received a prior chemotherapy (CTx) in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant CTx. Approvals followed positive results from the DESTINY-Breast03 and DESTINY-Breast04 clinical trials. In DESTINY-Breast03, T-DXd improved median progression-free survival (mPFS) compared with trastuzumab emtansine (28.8 vs 6.8 months, respectively; P< 0.0001) in previously treated (prior trastuzumab and taxane) patients with HER2+ mBC. In DESTINY-Breast04, T-DXd significantly improved mPFS vs physician’s choice of CTx (9.9 vs 5.1 months, respectively; P< 0.001) in all randomized patients with HER2-low mBC who were previously treated with one or two lines of CTx. Alongside these efficacy benefits, T-DXd has demonstrated an acceptable and generally manageable safety profile. To optimize care and maximize treatment benefit, insights into real-world T-DXd use and safety events of interest, including patient management and experience, are needed. This study aims to describe the effectiveness and tolerability of T-DXd in patients with HER2+ or HER2-low unresectable and/or mBC in a real-world setting. Trial design: DESTINY-Breast-RESPOND (NCT05592483) is a multicenter (120 sites planned as of June 2023), multi-country (HER2+ cohort: several regions globally; HER2-low cohort: North America only), prospective, observational study characterizing real-world clinical use, effectiveness, tolerability, and patient experience among adults who initiated T-DXd monotherapy, per standard of care, for HER2+ (second line or earlier) and HER2-low unresectable and/or mBC (T-DXd not provided by study sponsor). The decision to initiate T-DXd will be made by the physician prior to, and independent from, participation in this study. Approximately 750 patients with HER2+ and 250 patients with HER2-low disease will be enrolled. Patients must have received prior treatment with a trastuzumab-containing regimen in the metastatic setting or have evidence of disease progression within 6 months of neoadjuvant or adjuvant treatment (HER2+ cohort), or prior CTx in the metastatic setting or have evidence of disease progression within 6 months of adjuvant CTx (HER2-low cohort). Data will be collected via chart abstraction, patient-reported outcome questionnaires on tolerability and safety (PGI-TT, NCI PRO-CTCAE, and EORTC IL19), and a daily patient nausea/vomiting symptom diary. Endpoints will be analyzed separately for HER2+ and HER2-low cohorts. The primary endpoint of interest is time to next treatment from T-DXd initiation, a measure of real-world effectiveness. Other important endpoints include treatment patterns, safety events of interest (nausea/vomiting, fatigue, alopecia, interstitial lung disease/pneumonitis, left ventricular ejection fraction decrease) and their management, time to T-DXd discontinuation, and patient-reported tolerability. Patients will be observed until end of study (~60% of patients receive subsequent treatment or have died), withdrawal from study, or loss to follow up, whichever occurs first. Citation Format: Joyce O'Shaughnessy, Reva Basho, Maryam Lustberg, Gary H Lyman, Manoj Prahladan, Gareth D. James, Della Varghese, Flavia Lujan, Hans Tesch. A multicenter, prospective, observational study of patients receiving trastuzumab deruxtecan for the treatment of HER2-positive and HER2-low unresectable and/or metastatic breast cancer: DESTINY-Breast-RESPOND [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-17-02.

Abstract PO1-20-13: TROPION-Breast04: A phase 3 study of neoadjuvant datopotamab deruxtecan (Dato-DXd) + durvalumab followed by adjuvant durvalumab vs the standard of care in treatment-naive early-stage triple negative or HR-low/HER2– breast cancer

Abstract Background: The current standard of care for patients (pts) with treatment-naive Stage II–III triple-negative breast cancer (TNBC) is neoadjuvant pembrolizumab + anthracycline/taxane/platinum-based chemotherapy followed by surgery and adjuvant pembrolizumab monotherapy. However, among pts who received the combination of pembrolizumab and chemotherapy in the KEYNOTE-522 trial (NCT03036488), 28% ultimately discontinued therapy due to treatment-related adverse events, and 37% had residual disease at the time of surgery, which was associated with poor outcomes. Consequently, there remains an unmet need to develop a treatment approach that improves pathologic complete response (pCR) rates and long-term survival while reducing chemotherapy-associated toxicity in pts with early-stage TNBC. Dato-DXd is a TROP2-directed antibody-drug conjugate that consists of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to a potent topoisomerase I (Topo-I) inhibitor via a plasma stable tetrapeptide-based tumor-selective cleavable linker. Dato-DXd monotherapy has demonstrated a manageable safety profile and encouraging preliminary efficacy in pts with metastatic TNBC in the Phase 1 TROPION-PanTumor01 study (NCT03401385), with a confirmed objective response rate (ORR) of 32% in all pts and 44% in Topo-I inhibitor-naive pts with measurable disease at baseline. The combination of Dato-DXd with durvalumab has demonstrated durable responses in unresectable locally advanced or metastatic TNBC in the Phase 1b/2 BEGONIA study (NCT03742102), with an ORR of 79%, median duration of response of 15.5 months and median progression-free survival of 13.8 months. The ongoing Phase 3 TROPION-Breast03 trial (NCT05629585) is evaluating Dato-DXd ± durvalumab versus standard-of-care therapy as adjuvant treatment in pts with Stage I–III TNBC with residual invasive disease at the time of surgery after neoadjuvant treatment. The TROPION-Breast04 trial aims to determine if improved efficacy and safety can be achieved with neoadjuvant Dato-DXd + durvalumab followed by adjuvant durvalumab, compared with the pembrolizumab-based standard of care regimen in pts with previously untreated TNBC or hormone receptor-low (estrogen and/or progesterone receptor 1% to <10%; neither hormone receptor may be ≥10%)/HER2-negative (HR-low/HER2–) breast cancer. Trial design: TROPION-Breast04 (NCT06112379) is an ongoing Phase 3, 2-arm, parallel-group, randomized, open-label, multicenter, global trial. Approximately 1728 adults (aged ≥18 years) with previously untreated histologically confirmed Stage II–III unilateral or bilateral primary invasive TNBC or HR-low/HER2– breast cancer per AJCC edition 8 as assessed by the investigator, and an ECOG PS of 0 or 1, will be randomized 1:1 into one of two arms: neoadjuvant Dato-DXd + durvalumab followed by adjuvant durvalumab-based therapy, or neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab-based therapy (full treatment details are provided in the Table). Randomization will be stratified by lymph node status, tumor stage, HR status, and geographic region. Pts with distant disease and any prior surgery, radiotherapy, or systemic anticancer therapy will be excluded from the study. The primary endpoints are pCR and event-free survival. The key secondary endpoint is overall survival; others are distant disease-free survival, patient reported outcomes, pharmacokinetics, immunogenicity, and safety/tolerability. TROPION-Breast04 opened for enrolment in November 2023. Citation Format: Heather McArthur, Sara Tolaney, Sibylle Loibl, Rebecca Dent, Peter Schmid, Jamil Asselah, Erwei Song, Naoki Niikura. TROPION-Breast04: A phase 3 study of neoadjuvant datopotamab deruxtecan (Dato-DXd) + durvalumab followed by adjuvant durvalumab vs the standard of care in treatment-naive early-stage triple negative or HR-low/HER2– breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-13.

Abstract PS02-02: Patient-reported outcomes from the Phase 3 CAPItello-291 trial investigating capivasertib and fulvestrant for patients with aromatase inhibitor-resistant HR-positive/HER2-negative advanced breast cancer

Abstract Background: In the Phase 3 CAPItello-291 trial, adding capivasertib (C), a pan-AKT inhibitor, to fulvestrant (F) in patients (pts) with aromatase inhibitor-resistant, HR+/HER2− (HER2− defined as IHC 0, or 1+ or IHC2+/ISH–) advanced breast cancer significantly improved PFS vs placebo (P) + F in the overall (HR 0.60, 95% CI 0.51, 0.71, p< 0.001) and AKT pathway-altered populations (HR 0.50, 95% CI 0.38, 0.65, p< 0.001). The safety profile of C-F was manageable; diarrhea (mostly grade 1) was the most frequent adverse event. Global health status (GHS)/health-related quality of life (HRQoL) was maintained from baseline in both arms; time to deterioration (TTD) favored C-F. We report results from additional patient-reported outcomes (PRO). Methods: Pts were randomized 1:1 to receive F (500 mg IM on days 1 and 15 of cycle 1 and day 1 of each subsequent 28-day cycle) with either P or C (400 mg BID; 4 days on, 3 days off). PRO measures assessed HRQoL, disease-related symptoms, functioning, and patient-reported treatment tolerability using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), EORTC QLQ Breast Cancer 23 items (EORTC QLQ-BR23), PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and Patient Global Impression of Treatment Tolerability (PGI-TT). PROs were assessed at pre-specified timepoints. Change from baseline was assessed using Mixed Model Repeat Measures (on-treatment scores) for EORTC QLQ-C30 and summarized for EORTC QLQ-BR23; TTD was assessed using the stratified log-rank test for both. Results: Overall, 708 pts were randomized to C-F (n=355) or P-F (n=353). Overall compliance rates with EORTC QLQ-C30 and PGI-TT were 84.5% and 80.6% with C-F and 81.8% and 81.7% with P-F, respectively. Baseline compliance rates with the EORTC QLQ-C30 and PGI-TT were 88.2% and 82.8% with C-F and 87.3% and 83.1% with P-F, respectively. Mean changes from baseline in EORTC QLQ-C30 functional and symptom domain scores were maintained with C-F and P-F, except for diarrhea in the C-F arm, where scores worsened by >10 points (table). TTD analysis showed that HRs favored C-F vs P-F for all functional and symptom domains, except diarrhea (HR 2.75; 95% CI 2.01, 3.81), which favored P-F (table). Median TTD of diarrhea was shorter with C-F vs P-F in line with the C-F safety profile. Diarrhea with C-F was generally manageable, and discontinuations due to diarrhea were low (2.0%; n=7/355). For PGI-TT, most pts reported that they were ‘not at all’ or ‘a little bit’ bothered by the side effects of cancer therapy. Over the first 6 months, the proportion of pts reporting to be ‘somewhat’, ‘quite a bit’, or ‘very much’ bothered by side effects was higher for C-F vs P-F, with between-arm differences being highest in the first 2 cycles. Results from EORTC QLQ-BR23 domains will be presented at the meeting. Conclusions: Pts treated with C-F maintained HRQoL for longer than pts treated with P-F on all EORTC QLQ-C30 functional and symptom domain scores, except diarrhea. Worsening of diarrhea was observed with C-F, consistent with the safety profile of C, but events appeared tolerable and did not negatively impact GHS/HRQoL. Together with the clinical efficacy and manageable safety profile of C-F, the PRO results from the CAPItello-291 trial further support a positive benefit–risk profile of the combination in this population. https://clinicaltrials.gov/: NCT04305496. Funding: CAPItello-291 is sponsored by AstraZeneca. Editorial acknowledgment: AstraZeneca-funded medical writing support was provided by Suzanne Patel, Ph.D., from BOLDSCIENCE Inc. Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited). Citation Format: Hope Rugo, Mafalda Oliveira, Sacha Howell, Florence Dalenc, Javier Cortés, Henry Gómez, Xichun Hu, Komal Jhaveri, Petr Krivorotko, Sibylle Loibl, Serafin Morales Murillo, Meena Okera, Yeon Park, Joo Hyuk Sohn, Eriko Tokunaga, Masakazu Toi, Samih Yousef, Lyudmila Zhukova, Marta Fulford, Haylee Andrews, Ian Wadsworth, Celina D’Cruz, Nicholas Turner. Patient-reported outcomes from the Phase 3 CAPItello-291 trial investigating capivasertib and fulvestrant for patients with aromatase inhibitor-resistant HR-positive/HER2-negative advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS02-02.

Impact of prior treatment on selinexor, bortezomib, dexamethasone outcomes in patients with relapsed/refractory multiple myeloma: Extended follow-up subgroup analysis of the BOSTON trial.

To analyze the impact of prior therapies on outcomes with selinexor, bortezomib, and dexamethasone (SVd) versus bortezomib and dexamethasone (Vd) in 402 patients with relapsed/refractory multiple myeloma (RRMM) in the phase 3 BOSTON trial. Post hoc analysis of progression-free survival (PFS), overall survival (OS), and safety for lenalidomide-refractory, proteasome inhibitor (PI)-naïve, bortezomib-naïve, and one prior line of therapy (1LOT) patient subgroups. At a median follow-up of over 28 months, clinically meaningful improvements in PFS were noted across all groups with SVd. The median SVd PFS was longer in all subgroups (lenalidomide-refractory: 10.2 vs. 7.1 months, PI-naïve: 29.5 vs. 9.7; bortezomib-naïve: 29.5 vs. 9.7; 1LOT: 21.0 vs. 10.7; p < .05). The lenalidomide-refractory subgroup had longer OS with SVd (26.7 vs. 18.6 months; HR 0.53; p = .015). In all subgroups, overall response and ≥very good partial response rates were higher with SVd. The manageable safety profile of SVd was similar to the overall patient population. With over 2 years of follow-up, these clinically meaningful outcomes further support the use of SVd in patients who are lenalidomide-refractory, PI-naïve, bortezomib-naïve, or who received 1LOT (including a monoclonal antibody) and underscore the observed synergy between selinexor and bortezomib.

Comprehensive multi-omics analysis of resectable locally advanced gastric cancer: Assessing response to neoadjuvant camrelizumab and chemotherapy in a single-center, open-label, single-arm phase II trial.

The current standard of care for locally advanced gastric cancer (GC) involves neoadjuvant chemotherapy followed by radical surgery. Recently, neoadjuvant treatment for this condition has involved the exploration of immunotherapy plus chemotherapy as a potential approach. However, the efficacy remains uncertain. A single-arm, phase 2 study was conducted to evaluate the efficacy and tolerability of neoadjuvant camrelizumab combined with mFOLFOX6 and identify potential biomarkers of response through multi-omics analysis in patients with resectable locally advanced GC. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints included the R0 rate, near pCR rate, progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). Multi-omics analysis was assessed by whole-exome sequencing, transcriptome sequencing, and multiplex immunofluorescence (mIF) using biopsies pre- and post-neoadjuvant therapy. This study involved 60 patients, of which 55 underwent gastrectomy. Among these, five (9.1%) attained a pathological complete response (pCR), and 11 (20.0%) reached near pCR. No unexpected treatment-emergent adverse events or perioperative mortality were observed, and the regimen presented a manageable safety profile. Molecular changes identified through multi-omics analysis correlated with treatment response, highlighting associations between HER2-positive and CTNNB1 mutations with treatment sensitivity and a favourable prognosis. This finding was further supported by immune cell infiltration analysis and mIF. Expression data uncovered a risk model with four genes (RALYL, SCGN, CCKBR, NTS) linked to poor response. Additionally, post-treatment infiltration of CD8+ T lymphocytes positively correlates with pathological response. The findings suggest the combination of PD-1-inhibitor and mFOLFOX6 showed efficacy and acceptable toxicity for locally advanced GC. Extended follow-up is required to determine the duration of the response. This study lays essential groundwork for developing precise neoadjuvant regimens.

Subgroup analyses from the phase 3 ASCENT study of sacituzumab govitecan in metastatic triple-negative breast cancer

In this post hoc analysis of the ASCENT study, we compared outcomes with sacituzumab govitecan (SG) vs single-agent chemotherapy in clinically important subgroups of patients with metastatic triple-negative breast cancer (mTNBC). Patients with mTNBC refractory to/relapsing after ≥2 prior chemotherapies (≥1 in the metastatic setting) were randomized 1:1 to receive SG or treatment of physician’s choice (TPC) until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) per RECIST 1.1 by central review in patients without brain metastases. Patients with brain metastases were allowed if metastases were stable ≥4 weeks. In the intention-to-treat (ITT) population, 19% of patients were age ≥65 years; 12% were Black, and 12% had brain metastases. SG improved PFS and overall survival (OS), respectively, vs TPC in patients age ≥65 years (7.1 vs 2.4 months and 14.7 vs 8.9 months), or of Black race (5.4 vs 2.2 months and 13.8 vs 8.5 months), consistent with outcomes in the ITT population. Patients with brain metastases had numerically higher median PFS with SG vs TPC, but median OS was similar between treatment groups. SG was well tolerated and had a manageable safety profile consistent with the full safety population across all subgroups; neutropenia and diarrhea were the most common treatment-emergent adverse events. These findings confirm the meaningful clinical benefit of SG vs standard chemotherapy in patient subgroups with high unmet needs. SG should be considered an effective and safe treatment option for patients with mTNBC eligible for second-line or later therapy. ClinicalTrials.gov Number: NCT02574455.