Background Entinostat is a novel, potent, once weekly, orally bioavailable, class I selective histone deacetylase (HDAC) inhibitor. In a previous Phase II study, the combination of entinostat with exemestane showed significant improvement of overall survival in patients with advanced hormone receptor (HR) positive breast cancer. To verify and further confirm the benefit of HDAC inhibitor in combination with exemestane we designed a randomized, controlled trial to assess the efficacy and safety in a larger population of Chinese patients with advanced, HR positive breast cancer. Methods We carried out the randomized, double-blind, placebo-controlled, Phase III trial at 35 sites in China. Eligible patients were women (aged ≥18 years) with HR positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer, whose disease had relapsed or progressed after at least one endocrine therapy (either in advanced or metastatic or adjuvant setting), and who had at least one measurable lesion, adequate organ function, ECOG performance status of 0-1, and adequate haematological and biochemical parameters. Patients were randomly assigned (2:1) via an interactive web-response system to orally take 5 mg entinostat or placebo. Both groups received oral administration of 25 mg exemestane daily. Randomization was stratified according to previous usage of CDK4/6 (yes vs no), fulvestrant (yes vs no), chemotherapy (yes vs no), and the presence of visceral metastases (yes vs no). Patients, investigators, study site staff, and the sponsor were masked to treatment assignment. The primary endpoint was Independent Radiographic Committee (IRC)-assessed progression free survival (PFS). Efficacy and safety analyses were done in all patients who received at least one dose of any study treatment. The study has reached the required number of events for final analysis of the primary endpoint. The trial is no longer enrolling patients, but follow-up for investigation of overall survival is ongoing. This study was registered with ClinicalTrials.gov with the number of NCT03538171. Results From April 16th, 2019 to May 13th, 2020, 354 patients were enrolled and randomly assigned as 235 to the entinostat group and 119 to the placebo group. IRC-assessed median PFS was 6.32 months (95% CI 5.30-9.11) in the entinostat group and 3.72 months (95% CI 1.91-5.49) in the placebo group (HR 0.74 [95% CI 0.57-0.96]; p<0.001). The most common Grade 3 or 4 adverse events in the entinostat group vs placebo group were neutropenia (103 [43.8%] vs 119 [0.8%] ), thrombocytopenia (20 [8.5%] vs 1 [0.8%]), and leucopenia (15 [6.4%] vs 0). Serious adverse events occurred in 28 out of 235 patients (11.9%) in the entinostat group and 11 out of 119 patients (9.2%) in the placebo group. Conclusions Entinostat and exemestane combination treatment significantly improved PFS compared with exemestane alone in patients with advanced, HR positive, HER2 negative breast cancer that progressed after previous endocrine therapy. Entinostat and exemestane combination was generally tolerated and can offer meaningful clinical benefit in these patients with unmet medical need. This phase III trial was sponsored by Taizhou EOC Pharma Co., Ltd. Citation Format: Binghe Xu, Qingyuan Zhang, Xichun Hu, Qing Li, Tao Sun, Wei Li, Quchang Ouyang, Jingfen Wang, Zhongsheng Tong, Min Yan, Huiping Li, Xiaohua Zeng, Changping Shan, Xian Wang, Xi Yan, Jian Zhang, Yue Zhang, Jiani Wang, Liang Zhang, Ying Lin, Jifeng Feng, Qianjun Chen, Jian Huang, Yongkui Lu, Hongsheng Li, Jinsheng Wu, Jing Cheng, Yanrong Hao, Cuizhi Geng, Min Lu, Yanping Li, Xi Chen, Lihua Song, Xueying Wu, Changlu Hu, Xinhong Wu, Xiaojia Wang, Yueyin Pan, Yuehong Cui, Guohua Yu, Sanyuan Sun. A randomized control phase III trial of entinostat, a once weekly, class I selective histone deacetylase inhibitor, in combination with exemestane in patients with hormone receptor positive 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 GS1-06.

Background: Pyrotinib, a newly-developed irreversible pan-ErbB inhibitor, has shown promising antitumor activity and acceptable tolerability in phase 1-3 studies. However, findings from randomized clinical trials may have limited generalizability to patients treated in routine clinical practice. Herein, we conducted this multicenter real-world study to examine the treatment patterns, effectiveness and safety of pyrotinib-based therapy in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients in China.Methods: This is a China-based, observational study of HER2-positive BC patients receiving pyrotinib-based therapy (NCT04158505). Both early stage and advanced disease were included. Demographics, treatment patterns, and diarrhea management were summarized. The data cutoff date was April 30, 2021, and the study is ongoing to enroll. Real-world progression-free survival (PFS) and overall survival (OS) will be analyzed. Results: Between October 2019 and April 2021, a total of 907 patients (45 in the neoadjuvant setting [median age, 51 years] and 862 in the advanced setting [median age, 54 years]) from 65 sites received at least one dose of pyrotinib. Considering the limited sample size of early stage patients so far, we focused on advanced BC patients in this report. Of 862 patients with advanced disease, 44.2% had visceral metastases, 12.5% had brain metastases, 31.1%, 35.7%, and 33.2% received pyrotinib-based therapy as first-line, second-line, and third- or later-line treatment, respectively. The majority of patients (82.5%) were trastuzumab-exposed, and 10.2% were lapatinib-treated before receiving pyrotinib. Among 744 patients with available treatment information, 75.8% started with standard dose of pyrotinib (400 mg). Pyrotinib plus capecitabine (372 [50.0%]) was the most commonly used regimen for advanced disease, followed by pyrotinib plus chemotherapy other than capecitabine (189 [25.4%]), pyrotinib plus trastuzumab and chemotherapy (100 [13.4%]), and pyrotinib alone (77 [10.3%]). At the time of data cutoff, there were 164 (19.0%) progression or death events in 862 patients with advanced disease, and the median PFS and OS was not mature for the whole population. The median PFS for patients receiving second-line pyrotinib-based therapy was 11.7 months (95% CI, 8.8-not reached). The most common adverse event was diarrhea. Any grade and grade ≥3 diarrhea occurred in 70.5% and 14.9% of 907 patients, respectively. Diarrhea in eight (0.9%) patients with advanced disease were deemed as serious adverse events. Eighty-nine (9.8%) patients received diarrhea prophylaxis, and 436 (48.1%) used antidiarrhea drugs after diarrhea occurred. Montmorillonite powder (6.0% and 33.6%) were the most commonly used drug for both diarrhea prophylaxis and treatment, followed by loperamide (3.9% and 27.9%).Conclusions: In real world, a high percentage of physicians chose to use pyrotinib-based therapy in front lines when treating HER2-positive advanced BC patients, which might maximize its antitumor activity. Diarrhea is manageable in the real-world setting. Citation Format: Yiqun Li, Zhongsheng Tong, Quchang Ouyang, Xinhong Wu, Wei Li, Li Cai, Zhiyong Yu, Zhengxiang Han, Xiaojia Wang, Man Li, Jin Yang, Li Li, Zhaofeng Niu, Haibo Wang, Qitang Wang, Yi Li, Yuee Teng, Shiguang Zhu, Binghe Xu. Treatment patterns and adverse events of pyrotinib-based therapy in HER2-positive breast cancer patients in China: Results from a multicenter, real-world study [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 P2-13-40.

Pyrotinib, an irreversible pan‐ErbB inhibitor, has been approved for treating HER2‐positive advanced breast cancer in China. We conducted a nationwide, prospective observational study to examine the real‐world data of pyrotinib‐based therapy in this population. Patients from 61 sites across China were included. Pyrotinib‐based regimens were prescribed at local physician's discretion. Demographics, treatment patterns, prognosis and safety were evaluated. The primary outcome was real‐world progression‐free survival (rwPFS). Of 1129 patients, pyrotinib‐based therapy was prescribed as first‐, second‐ and third‐ or later‐line treatment in 437 (38.7%), 476 (42.2%) and 216 (19.1%) patients, respectively. Median rwPFS (mrwPFS) was 14.3 (95% CI, 13.3‐15.2) months in the total population, with the longest mrwPFS of 17.8 (95% CI, 15.2‐24.9) months in the first‐line setting, followed by 14.4 (95% CI, 12.9‐15.3) months in the second‐line setting. Patients with third‐ or later‐line treatment also achieved a mrwPFS of 9.3 (95% CI, 8.4‐11.8) months. Patients with trastuzumab‐ or trastuzumab‐pertuzumab‐treated disease achieved a mrwPFS of 14.3 and 13.6 months, respectively. Dual HER2 blockade with pyrotinib plus trastuzumab showed a mrwPFS of 16.2 months in the total population, with data not mature in the first‐line setting. For patients with baseline brain metastases, the mrwPFS was 11.7 months. The most common adverse event was diarrhea (any grade, 73.5%; grade ≥ 3, 15.3%). In real world, pyrotinib‐based therapy shows promising effectiveness in the first‐, as well as second‐ and later‐line treatment, with acceptable tolerability. Further investigations regarding front‐line use or novel combinations of pyrotinib might facilitate to maximize its anti‐tumor potential.

Background: The therapeutic options for patients (pts) with previously treated metastatic TNBC are limited compared with other breast cancer subtypes. SKB264 is an antibody drug conjugate (ADC) composed of an anti-TROP2 antibody coupled to the cytotoxic belotecan-derivative via a novel linker. Here, we present results from a Phase 2 expansion cohort for pts with mTNBC (NCT04152499). Methods: Pts with previously treated mTNBC were enrolled to receive SKB264 4 mg/kg Q2W or 5 mg/kg Q2W in a non-randomized fashion until disease progression/unacceptable toxicity. The assessment for tumor response was performed every 8 weeks per RECIST v1.1 assessed by investigator. The TROP2 expression was scored using the semi-quantitative H-score method, and cut off point was set to 200. TROP2 expression and its association with anti-tumor activity was retrospectively analyzed. Results: At data cut-off date (May 15, 2022), 59 pts were enrolled (23 in 4 mg/kg, 36 in 5 mg/kg), 88% of them (52 pts) had received ≥3 prior therapies for metastatic disease. Among 53 patients with tissue available for TROP2 testing, 29 patients (55%) had TROP2 high (H-score >200-300) tumors. The median follow up was 9.6 months. Of 55 pts (21 in 4 mg/kg and 34 in 5 mg/kg) evaluable for response assessment (≥1 on-study scan), the confirmed ORR (cORR) was 40% (22/55) and disease control rate (PR+CR+SD) was 80% (44/55). The cORR was 55% (16/29) in the subset of patients with high TROP2 expression. The median duration of response (DoR) was not reached with range from 1.0+ to 11.0+ months and the 6-month DoR rate was 82%. Median PFS was 5.7 months (95% Cl: 3.9, 7.6). Treatment-related adverse events (TRAEs) of ≥ Grade 3 were reported in 55.9% (33/59) of pts. The most common ≥ Grade 3 TRAEs (≥ 10%) were neutrophil count decreased (23.7%), anemia (20.3%) and platelet count decreased (16.9%). TRAEs led to dose reduction in 15.2% (9/59) of pts and to discontinuation in 6.8% (4/59) of pts. No treatment-related AEs leading to death or interstitial lung disease (ILD) were reported. Safety and anti-tumor activities of SKB264 by dose level will be presented. Conclusions: SKB264 demonstrates a manageable safety profile and promising antitumor activity in pts with heavily pretreated mTNBC. SKB264 toxicity was mainly hematologic. A Phase 3 study of SKB264 vs investigator selected chemo alone in pts with locally advanced inoperable or metastatic TNBC was initiated (NCT05347134). 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, Qun Li, Yina Diao, Gesha Liu, Junyou Ge, Jin Li. Efficacy and safety of SKB264 for previously treated metastatic triple negative breast cancer in Phase 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 OT1-03-02.

Background: SHR-A1811 is an ADC comprised of a humanized anti-HER2 monoclonal antibody (trastuzumab), a cleavable linker, and a DNA topoisomerase I inhibitor payload. Here we assessed SHR-A1811 in HER2-expressing/mutated unresectable, advanced, or metastatic solid tumors. Methods: Pts were eligible if they had HER2 positive breast cancer (BC), HER2 positive gastric/GEJ carcinoma, HER2 low-expressing BC, HER2-expressing/mutated NSCLC, or other HER2-expressing/mutated solid tumors, and were refractory or intolerant to standard therapy. SHR-A1811 at doses of 1.0-8.0 mg/kg was given Q3W (IV). The primary endpoints were DLT, safety, and the RP2D. Results: From Sep 7, 2020 to Sep 28, 2022, 250 pts who had undergone a median of 3 prior treatment lines in the metastatic setting received at least one dose of SHR-A1811 in dose escalation, PK expansion, and indication expansion part. As of data cutoff on Sep 28, 2022, 1 pt experienced DLT. Treatment-related adverse events (TRAEs) were reported in 243 (97.2%) pts. Grade ≥3 TRAEs, serious TRAEs, and treatment-related deaths were reported in 131 (52.4%), 31 (12.4%), and 3 (1.2%) pts, respectively. Interstitial lung disease (AESI) was reported in 8 (3.2%) pts. Exposures of SHR-A1811, total antibody, and the payload were generally proportional to dose from 3.2 to 8.0 mg/kg. ORR was 61.6% (154/250, 95% CI 55.3-67.7) in all pts. Objective responses were observed in pts with HER2 positive BC (88/108, ORR 81.5%, 95% CI 72.9-88.3), HER2-low BC (43/77, ORR 55.8%, 95% CI 44.1-67.2), urothelial carcinoma (7/11), colorectal cancer (3/10), gastric/GEJ carcinoma (5/9), biliary tract cancer (5/8), NSCLC (1/3), endometrial cancer (1/2), and H&N cancer (1/1). Subgroup analyses of ORR are shown in Table 1. The 6-month PFS rate was 73.9% in all pts. Conclusions: SHR-A1811 was well-tolerated and showed promising antitumor activity in heavily pretreated advanced solid tumors. Table 1. Subgroup analyses of ORR No. of prior treatment lines in metastatic setting in all pts (N=250) HER2 positive BC (N=108) HER2-low BC (N=77) Other tumor types (N=65) ≤3 81.8% (45/55) 58.7% (27/46) 36.7% (18/49) >3 81.1% (43/53) 51.6% (16/31) 31.3% (5/16) Prior anti-HER2 therapies in pts with BC (N=185)* HER2 positive BC (N=108) HER2-low BC (N=77) All BC (N=185) Any 82.2% (88/107, 73.7-89.0) 68.8% (11/16, 41.3-89.0) 80.5% (99/123, 72.4-87.1) Trastuzumab 81.9% (86/105, 73.2-88.7) 75.0% (9/12, 42.8-94.5) 81.2% (95/117, 72.9-87.8) Pertuzumab 83.0% (39/47, 69.2-92.4) 100% (5/5, 47.8-100) 84.6% (44/52, 71.9-93.1) Pyrotinib 86.9% (53/61, 75.8-94.1) 71.4% (5/7, 29.0-96.3) 85.3% (58/68, 74.6-92.7) Lapatinib 80.0% (28/35, 63.1-91.6) 100% (1/1, 2.5-100) 80.6% (29/36, 64.0-91.8) T-DM1 82.4% (14/17, 56.6-96.2) 100% (3/3, 29.2-100) 85.0% (17/20, 62.1-96.8) Other HER2-ADC (except T-DM1)** 60.0% (9/15, 32.3-83.7) 50.0% (2/4, 6.8-93.2) 57.9% (11/19, 33.5-79.8) ORR in pts with tumor types other than BC (N=65) HER2 IHC3+ or IHC2+/ISH+ (N=36) HER2 IHC2+/ISH- or IHC1+ or unknown (N=29) All other tumor types (N=65) % (n/N) 38.9% (14/36) 31.0% (9/29) 35.4% (23/65) ORR was shown as % (n/N, 95% CI) or % (n/N). *ORR is calculated using the number of subjects previously treated with anti-HER2 cancer therapy in advanced/metastatic setting as denominator; 2-sided 95% CIs are estimated using Clopper-Pearson method. **Includes RC48-ADC, A166, DP303c, MRG002, ARX788, TAA013, DX126-262, PF-06804103, and BAT8001. Citation Format: Herui Yao, Min Yan, Zhongsheng Tong, Xinhong Wu, Min-Hee Ryu, Jee Hyun Kim, John Park, Yahua Zhong, Weiqing Han, Caigang Liu, Mark Voskoboynik, Qun Qin, Jian Zhang, Minal Barve, Ana Acuna-Villaorduna, Vinod Ganju, Seock-Ah Im, Changsheng Ye, Yongmei Yin, Amitesh C. Roy, Li-Yuan Bai, Yung-Chang Lin, Chia-Jui Yen, Hui Li, Ki Young Chung, Shanzhi Gu, Jun Qian, Yuee Teng, Yiding Chen, Yu Shen, Kaijing Zhao, Shangyi Rong, Xiaoyu Zhu, Erwei Song. Safety, tolerability, pharmacokinetics, and antitumor activity of SHR-A1811 in HER2-expressing/mutated advanced solid tumors: A global phase 1, multi-center, first-in-human study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT175.