Secondary prevention of cancer therapy-induced thrombocytopenia with hetrombopag in breast cancer: a multicenter, randomized, exploratory phase II trial

Secondary prevention of cancer therapy-induced thrombocytopenia with hetrombopag in breast cancer: a multicenter, randomized, exploratory phase II trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Secondary prevention of cancer therapy-induced thrombocytopenia with hetrombopag in breast cancer: a multicenter, randomized, exploratory phase II trial Huihui Sun, Huimin Lv, Wenyan Chen, Yanxia Zhao, Mengwei Zhang, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8976504/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background: Cancer therapy-induced thrombocytopenia (CTIT) is a common complication of anti-tumor therapy, leading to treatment delays or interruptions, increased bleeding risk and compromised outcomes. In the present study, we aimed to evaluate the efficacy and safety of hetrombopag, an oral thrombopoietin receptor agonist, for managing and preventing CTIT in patients with breast cancer. Methods: In this multi-center, randomized phase II clinical trial (NCT05394285), breast cancer patients with platelet counts <50×10⁹/L during anti-tumor treatment (Cycle 1) were enrolled. Those patients were randomly assigned (1:1)to receive either hetrombopag or subcutaneous recombinant human thrombopoietin (rhTPO) until their platelet counts >100×10⁹/L, which was defined as the thrombocytopenia treatment phase (TTP). During the secondary prevention phase (SPP), all cases as self-control received hetrombopag for 14 days starting on day 1 of the subsequent anti-tumor treatment cycle (Cycle 2). The primary endpoint was the response rate of the SPP. Secondary endpoints comprised the response rate of TTP (key secondary endpoint), other platelet-related parameters, and safety outcomes. Results: Between September 2022 and May 2025, 67 patients with breast cancer were enrolled. After excluding one patient who withdrew informed consent, 66 patients were randomized. During the trial, 6 patients discontinued participation in the SPP, the remaining 60 patients constituted the per-protocol set (PPS). The majority of patients in the PPS (n=47) received antibody-drug conjugates (ADCs) treatment. For the primary endpoint, the response rate was 85.0% (51/60) in the PPS, and 89.4% (42/47) among patients receiving ADCs. Regarding the key secondary endpoint during the TTP, the response rates were 87.9% (29/33) in patients receiving hetrombopag and 81.8% (27/33) in those receiving rhTPO. No treatment-emergent severe adverse events were observed. Conclusions: Hetrombopag represents a promising and well-tolerated strategy for the secondary prevention and management of CTIT in breast cancer patients, particularly in patients received ADCs. Cancer therapy-induced thrombocytopenia secondary prevention breast cancer hetrombopag recombinant human thrombopoietin Figures Figure 1 Figure 2 Introduction Cancer therapy-induced thrombocytopenia (CTIT) is a common complication of anti-tumor treatment and may lead to treatment delays or interruptions, increased bleeding risk, and compromised outcomes[ 1 ]. This concept encompasses thrombocytopenia induced by various treatments, such as chemotherapy (CIT), immune checkpoint inhibitors, targeted therapy including antibody-drug conjugates (ADCs), and radiotherapy[ 2 ]. In breast cancer, CTIT presents a major clinical challenge. With traditional chemotherapy, gemcitabine-based regimens are particularly associated with grade ≥ 3 thrombocytopenia, with an approximate incidence of 14% for monotherapy[ 3 ] and up to 32% for combination with cisplatin[ 4 ]. This challenge extends to certain ADCs, a transformative class of agents with rapidly expanding clinical utility in breast cancer. Trastuzumab Emtansine (T-DM1), a pioneering ADC targeting the human epidermal growth factor receptor 2 (HER2), was initially approved based on the results of the phase III EMILIA trial[ 5 ] and remains a cornerstone in adjuvant therapy for HER2-positive breast cancer following the KATHERINE trial[ 6 ]. However, its clinical utility is limited by high-grade thrombocytopenia, with a meta-analysis reporting a 32% incidence of grade ≥ 3 events, often requiring treatment modification or even discontinuation[ 7 ]. The subsequent development of trastuzumab deruxtecan (T-DXd), a later-generation ADC, is characterized by breakthrough efficacy across the spectrum of HER2 expression (low and positive) and disease stages (early and advanced) in breast cancer[ 8 – 11 ]. Nevertheless, thrombocytopenia remains a relevant adverse event with T-DXd, occurring in approximately 20% of patients, including severe (grade ≥ 3) events in about 10%. Although recombinant human thrombopoietin (rhTPO) is approved for the treatment of CTIT, there is currently no evidence supporting its use for prevention[ 12 ]. Thrombopoietin receptor agonists (TPO-RAs) represent a promising therapeutic strategy for CTIT by binding to the transmembrane domain of TPO receptor, which activates downstream signaling cascades to promote the proliferation and differentiation of megakaryocyte progenitor cells[ 13 ]. However, current evidence for TPO-RAs is limited to the treatment of established CIT[ 14 – 16 ], creating a critical gap in evidence for their use in preventing CTIT within the increasingly prevalent ADC-based regimens for breast cancer. Hetrombopag, a novel oral TPO-RA developed in China, has demonstrated efficacy against CIT in a phase II trial involving patients with solid tumors[ 17 ]. Building on this evidence, this prospective study is the first to evaluate the efficacy and safety of hetrombopag as a secondary prevention strategy for CTIT in breast cancer patients. Methods Study design and participants This multicenter, open-label, randomized, phase II study (NCT05394285) of hetrombopag for the treatment and prevention of CTIT in breast cancer patients was conducted at four qualified tertiary hospitals in China. The study protocol received approval from regulatory authorities and ethics committees at all anticipating centers. Written informed consents were received from all patients before enrollment. Patients aged 18–75 years with pathologically confirmed breast cancer who received anti-tumor treatment and had severe thrombocytopenia were eligible for inclusion. Severe thrombocytopenia was defined as a platelet count (PLT) < 50×10⁹/L during the qualifying cycle (Cycle 1). PLT values were obtained in accordance with standard clinical practice prior to informed consent. Additionally, patients were required to be scheduled to receive the same anti-tumor regimen and dose in the subsequent cycle (Cycle 2). All participants were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, a life expectancy ≥ 12 weeks, and no serious complications. Key exclusion criteria included a history of haematological malignancy or bone marrow metastasis; clinically active bleeding within 2 weeks; receipt of radiotherapy or any platelet-boosting therapy within 1 month; arterial or venous thrombosis within 6 months before enrollment; significant hepatic or renal dysfunction or other severe complications. Randomization and interventions Randomization was generated using a computer-generated randomization table by an interactive web response system. Both study participants and the research team were aware of the group assignments after randomization. Eligible patients were randomized in a 1:1 ratio to the hetrombopag group or the rhTPO group. The period from the start of thrombocytopenia treatment to PLT > 100×10⁹/L was defined as the thrombocytopenia treatment phase (TTP). In the TTP, patients in the hetrombopag group received hetrombopag (7.5 mg, orally, daily), and patients in the rhTPO group received rhTPO (15000 U, subcutaneously, daily). In the secondary prevention phase (SPP), all patients received hetrombopag at an initial dose of 7.5 mg once daily for 14 consecutive days, starting on day 1 following the initiation of Cycle 2. Regarding dose adjustment of hetrombopag, the daily dose was reduced to 5.0 mg when PLT were between 200×10⁹/L and 400×10⁹/L. If PLT reached ≥ 400×10⁹/L, hetrombopag was withheld until PLT dropped to < 200×10⁹/L, and then resumed at a daily dose of 5.0 mg. Any days of treatment interruption were counted toward the total 14-day treatment course. Platelet counts were monitored every other day during both the TTP and SPP, with additional assessments performed at the investigator’s discretion. Platelet transfusion might be considered when PLT < 10×10⁹/L or when there was a risk of bleeding. The detail study design is shown in Fig. 1 . Study endpoints Patients who completed at least two consecutive cycles of anti-tumor therapy (Cycle 1 and Cycle 2) were included in the primary endpoint analysis. Efficacy endpoints were assessed during the defined observation period spanning from the time of randomization to the initiation of Cycle 3 therapy. The choice to extend hetrombopag prophylaxis beyond the core study period was guided by patient preferences, and data were systematically collected to enable subsequent post hoc analysis. Response rate was defined as the proportion of patients who met the following criteria until the start of the subsequent cycle: 1. received the standard anti-tumor treatment without dose modification (defined as a dose reduction of ≥ 20% or a delay of ≥ 5 days) due to thrombocytopenia, 2. no platelet transfusion, and 3. no severe thrombocytopenia (defined as a PLT < 25×10⁹/L, or a PLT < 50×10⁹/L persisting for ≥ 7 consecutive days). The primary endpoint was the response rate during the SPP, defined as the proportion of responders until the start of Cycle 3. Subgroup analysis based on different anti-tumor treatment regimens was performed in post hoc analysis. The key secondary endpoint was the response rate during the TTP, defined as the proportion of responders until the start of Cycle 2. Other secondary endpoints included the nadir and peak PLT, as well as the incidence and duration of PLT < 25×10 9 /L and PLT < 50×10 9 /L during the TTP and the SPP, respectively. Adverse events were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 5.0. Bleeds were classified according to the WHO bleeding assessment scale (grade 0, no bleeding; grade 1, petechiae; grade 2, mild blood loss; grade 3, gross blood loss; and grade 4, debilitating blood loss). Statistical analyses Full analysis set (FAS) included all randomly assigned patients. The per-protocol set (PPS) included all subjects who completed protocol-specified treatments without serious protocol violations. The proportion of responders was present as binary categories. For patients lacking efficacy data due to treatment interruption, additional patients were incorporate to complete the study. Descriptive statistical analyses were used to summarize other secondary outcomes. Results were presented as the number (percentage), mean±standard (deviation), or median (Min, Max). Data analyses were performed using SAS software (version 9.4). A comprehensive description of the study protocol is available in Supplementary Appendix 1. Results Patient characteristics Between September 2022 and May 2025, a total of 67 female breast cancer patients were initially enrolled in the study. After excluding 1 patient who withdrew informed consent, 66 patients comprised the FAS. They were randomly assigned to receive either hetrombopag (n = 33) or rhTPO (n = 33). Patients in the FAS had a median age of 54.4 years (range, 29–73) and an ECOG performance status of 0 or 1. The cohort comprised 19 patients with early-stage breast cancer and 47 with metastatic disease. Among those with metastatic disease, 38 had visceral metastases and 16 had ≥ 3 metastatic lesions. The median number of prior therapy lines was 3 (range, 0–10), and 23 patients had received more than 3 lines of systemic therapy. The average baseline PLT was 37.5 (15–49) ×10⁹/L, with 39.0 (23–49) ×10⁹/L in the hetrombopag group and 36.0 (15–49) ×10⁹/L in the rhTPO group, respectively. Furthermore, 9 patients (13.6%) had baseline PLT ≤ 25×10⁹/L, including 2 (6.1%) in the hetrombopag group and 7 (21.2%) in the rhTPO group. A total of 51 patients (77.3%) received ADCs, comprising 23 patients in the hetrombopag group and 28 patients in the rhTPO group. Fourteen patients (21.2%) were treated with chemotherapy-based regimens (CBRs), while one patient (1.5%) received a combination of abemaciclib (a CDK4/6 inhibitor) and fulvestrant (an endocrine agent) along with inetetamab (a macromolecular monoclonal antibody). Detailed patient characteristics are presented in Table 1 . Table 1 Baseline characteristics Characteristics Hetrombopag group (n = 33) rhTPO, group (n = 33) All patients (N = 66) Age, years 55.6 (32, 69) 52.5 (29, 73) 54.4 (29, 73) Sex, n (%) Female 33 (100.0) 33 (100.0) 66 (100.0) Stage, n (%) Early-stage 8 (24.2) 11 (33.3) 19 (28.8) Metastatic 25 (75.8) 22 (66.7) 47 (71.2) Visceral metastases Yes 19 (57.6) 19 (57.6) 38 (57.6) No 6 (18.2) 3 (9.1) 9 (13.6) Number of metastatic lesions 1 7 (21.2) 6 (18.2) 13 (19.7) 2 8 (24.2) 10 (30.3) 18 (54.5) ≥ 3 10 (30.3) 6 (18.2) 16 (24.2) Number of previous therapy lines, n (%) ≤ 3 13 (39.4) 11 (33.3) 24 (36.4) > 3 12 (36.4) 11 (33.3) 23 (34.8) Baseline platelet count×10⁹/L (median, range) 39.0 (23, 49) 36.0 (15, 49) 37.5 (15, 49) Baseline platelet count×10⁹/L, n (%) PLT ≤ 25 2 (6.1) 7 (21.2) 9 (13.6) 25 < PLT < 50 31 (93.9) 26 (78.8) 57 (86.4) Regimen, n (%) ADCs 23 (69.7) 28 (84.8) 51 (77.3) T-DM1 21 (63.6) 26 (78.8) 47 (71.2) T-DXd 2 (6.1) 2 (6.1) 4 (6.1) CBRs 10 (30.3) 4 (12.1) 14 (21.2) Monotherapy chemotherapy 1 (3.0) 1 (3.0) 2 (3.0) Combination chemotherapy 9 (27.3) 3 (9.1) 12 (18.2) Abemaciclib, fulvestrant and inetetamab 0 1 (3.0) 1 (1.5) ADCs: antibody-drug conjugates; CBRs: chemotherapy-based regimens; T-DM1: trastuzumab emtansine; T-DXd: trastuzumab deruxtecan Primary endpoint: the response rate during the SPP After excluding 6 patients who failed to complete cycle 2 anti-tumor therapy in accordance with the study protocol (2 due to disease progression, 4 due to withdrawal of informed consent), the remaining 60 patients constituted the PPS for primary analysis. Among them, 47 patients were treated with ADCs, while 12 patients were treated with CBRs. The response rate during the SPP was 85.0% (51/60). Post hoc analysis showed that the response rate in patients treated with ADCs (89.4%, 42/47) was numerically higher than that among patients treated with CBRs (75.0%, 9/12) (Table 2 ). After receiving prophylactic hetrombopag during the SPP, the median nadir PLT was 56.5×10 9 /L, with only one patient requiring platelet transfusion. Treatment adjustments due to thrombocytopenia occurred in 10% of patients and were numerically lower in the ADC group than in the CBR group (4.3% vs 25.0%). The detailed response items and other PLT parameters are shown in Table 3 . Table 2 The response rate during the SPP. Primary endpoint Response (n) Non-response (n) Response rate (%) PPS (N = 60) 51 9 85.0 Regimen ADC (n = 47) 42 5 89.4 CBR (n = 12) 9 3 75.0 PPS: protocol set; ADC: antibody-drug conjugate; CBR: chemotherapy-based regimen Table 3 The response items and other PLT parameters during the SPP Other endpoints ADC (N = 47) CBR (N = 12) PPS (N = 60) Response items Treatment modification due to thrombocytopenia (n, %) 2 (4.3%) 3 (25%) 6 (10.0%) Platelet transfusion requirement (n, %) 0 1 (8.3%) 1 (1.7%) Grade 4 thrombocytopenia (PLT < 25×10⁹/L; n, %) 4 (8.5%) 2 (16.7%) 6 (10.0%) Persistent thrombocytopenia (PLT < 50×10⁹/L for ≥ 7 consecutive days; n, %) 2 (4.3%) 1 (8.3%) 3 (5.0%) Other PLT parameters PLT nadir (×10⁹/L; median, range) 55 (19, 236) 70.5 (20, 188) 56.5 (19, 331) PLT maxmium (×10⁹/L; median, range) 179 (70, 445) 185 (87, 651) 179.5 (51, 445) Median duration of grade 4 thrombocytopenia (PLT < 25×10⁹/L; days) 2.0 3.0 2.0 Grade 3/4 thrombocytopenia (PLT < 50×10⁹/L; n, %) 18 (38.3%) 5 (41.7%) 23 (38.3%) Median duration of grade 3/4 thrombocytopenia (PLT < 50×10⁹/L; days) 2.5 3.0 3.0 PPS: protocol set; ADC: antibody-drug conjugate; CBR: chemotherapy-based regimen Secondary endpoints: the response rate during the TTP In the FAS, the response rate was 84.8% (56/66), with similar rates in the hetrombopag and rhTPO groups (87.9% [29/33] vs. 81.8% [27/33]). Post hoc analysis showed a response rate of 90.2% (46/51) in ADC-treated patients, with rates of 95.7% (22/23) and 85.7% (24/28) in the hetrombopag and rhTPO groups, respectively. In the CBR subgroup, the response rate was 71.4% (10/14), with 70.0% (7/10) in the hetrombopag group and 75.0% (3/4) in the rhTPO group. Detailed data are showed in Fig. 2 . The median duration of the TTP was 6 days in the hetrombopag group and 7 days in the rhTPO group. Moreover, the median nadir and peak PLT, the incidence and the duration of grade 3/4 thrombocytopenia were comparable between the two groups (Table 4 ). Table 4 Platelet parameters and thrombocytopenia occurrence in FAS during the TTP Secondary endpoints during the TTP Hetrombopag group (n = 33) rhTPO group (n = 33) FAS (N = 66) PLT nadir (×10⁹/L; median, range) 53.0 (12, 164) 47.0 (10, 90) 49.5 (10, 164) PLT maxmium (×10⁹/L; median, range) 125.0 (81, 552) 135.0 (96, 212) 126.5 (81, 552) Grade 4 thrombocytopenia (PLT < 25×10⁹/L; n, %) 3 (9.1) 4 (12.1) 7 (10.6) Median duration of grade 4 thrombocytopenia (PLT < 25×10⁹/L; days) 3.0 3.5 3.0 Grade 3/4 thrombocytopenia (PLT < 50×10⁹/L; n, %) 14 (42.4) 19 (57.6) 33 (50.0) Median duration of grade 3/4 thrombocytopenia (PLT < 50×10⁹/L; days) 2.0 2.0 2.0 Median duration of the TTP (days) 6.0 7.0 7.0 Post hoc analysis of platelet parameters and the incidence of thrombocytopenia were performed in the ADC and CBR subgroups. In patients treated with ADC, the nadir PLT was significantly higher in the hetrombopag group compared to the rhTPO group (67 vs. 44×10 9 /L), accompanied by a reduced incidence of grade 3/4 thrombocytopenia (Table 5 ). This favorable trend was not evident in patients treated with CBR (Supplementary Appendix 2). These findings indicated that hetrombopag may be more effective in managing ADC-induced thrombocytopenia compared to that induced by other medications. Table 5 Platelet parameters and thrombocytopenia occurrence in ADC-treated patients during the TTP Secondary endpoints Hetrombopag group (n = 23) rhTPO group (n = 28) ADC (N = 51) PLT nadir (×10⁹/L; median, range) 67.0 (21, 118) 44.0 (10, 90) 52.0 (10, 118) PLT maxmium (×10⁹/L; median, range) 120.0 (89, 552) 135.5 (96, 212) 125.0 (89, 552) Grade 4 thrombocytopenia (PLT < 25×10⁹/L; n, %) 1 (4.3) 3 (10.7) 4 (7.8) Median duration of grade 4 thrombocytopenia (PLT < 25×10⁹/L; days) 3.0 3.0 3.0 Grade 3/4 thrombocytopenia (PLT < 50×10⁹/L; n, %) 6 (26.1) 17 (60.7) 23 (45.1) Median duration of grade 3/4 thrombocytopenia (PLT < 50×10⁹/L; days) 2.0 2.0 2.0 Median duration of TTP (days) 6.0 7.0 6.0 Safety During the SPP, 12 patients underwent dose adjustments of hetrombopag. Of these, 9 patients reduced their dose to 5.0 mg for PLT ranging from 200 to 400×10⁹/L. The remaining 3 patients temporarily discontinued treatment (2 days for two patients each; 3 days for one patient) when their PLT reached ≥ 400×10⁹/L and resumed hetrombopag at 5 mg once PLT dropped to < 200×10⁹/L. In the FAS population, the most common treatment-emergent adverse events (TEAEs) of any grade were leukopenia (34, 51.5%) and anemia (34, 51.5%), followed by elevated aspartate aminotransferase (31, 47.0%), elevated glutamyltransferase (31, 47.0%), neutropenia (29, 43.9%) and elevated blood lactate dehydrogenase (22, 33.3%). The most common grade 3 or higher TEAEs were leukopenia (4, 6.1%) and elevated aspartate aminotransferase (4, 6.1%), followed by neutropenia (3, 4.5%), elevated alanine aminotransferase (3, 4.5%), elevated glutamyltransferase (3, 4.5%), and anemia (2, 3.0%). All TEAEs were predominantly associated with the anti-tumor agents and were considered unrelated to the thrombopoietic agents. Six patients (9.1%) experienced bleeding, all classified as WHO grade 1, including hemoptysis, epistaxis, skin petechiae and ecchymosis. There were no arterial or venous thrombosis events during the study. Detailed data are presented in Table 6 . Table 6 Adverse events among FAS population. Adverse events Hetrombopag (n = 33) rhTPO (n = 33) FAS (N = 66) Ang grades ≥ 3 grade Ang grades ≥ 3 grade Ang grades ≥ 3 grade Leukopenia 17 (51.5%) 3 (9.1%) 17 (51.5%) 1 (3.0%) 34 (51.5%) 4 (6.1%) Neutropenia 15 (45.5%) 3 (9.1%) 14 (42.4%) 0 29 (43.9%) 3 (4.5%) Anemia 16 (48.5%) 2 (6.1%) 18 (54.5%) 0 34 (51.5%) 2 (3.0%) Elevated alanine aminotransferase 9 (27.3%) 0 11 (33.3%) 3 (9.1%) 20 (30.3%) 3 (4.5%) Elevated aspartate aminotransferase 16 (48.5%) 1(3.0%) 15 (45.5%) 3 (9.1%) 31 (47.0%) 4 (6.1%) Elevated bilirubin 1 (3.0%) 0 1 (3.0%) 0 2 (3.0%) 0 Elevated glutamyltransferase 14 (42.4%) 2 (6.1%) 17 (51.5%) 1 (3.0%) 31 (47.0%) 3 (4.5%) Elevated blood lactate dehydrogenase 12 (36.4%) 0 10 (30.3%) 0 22 (33.3%) 0 Elevated blood creatinine 2 (6.1%) 0 5 (15.2%) 0 7 (10.6%) 0 Hypokalaemia 3 (9.1%) 0 0 0 3 (4.5%) 0 Hyponatremia 1 (3.0%) 0 0 0 1 (1.5%) 0 Hypocalcaemia 1 (3.0%) 0 1 (3.0%) 0 2 (3.0%) 0 AEs of special interest 0 0 0 0 0 0 Bleeding 4 (12.1%) 0 2 (6.1%) 0 6 (9.1%) 0 Thrombosis 0 0 0 0 0 0 Follow-up: additional cycles Among the 51 responders who completed the protocol-defined prevention phase, 12 patients chose to continue hetrombopag prophylaxis. Of these, six patients with early-stage breast cancer successfully completed the planned adjuvant T-DM1 treatment course (an additional 12 cycles). The remaining six patients (five on T-DM1 and one on chemotherapy) with advanced breast cancer received secondary prevention for variable durations: three for only 2 additional cycles, two for 6 cycles (both discontinued due to financial pressure), and one for 20 cycles until disease progression. Follow-up data about the remaining patients are showed in Supplementary Appendix 3. Discussion This phase II study is the first clinical trial to assess hetrombopag for the secondary prevention of CTIT in patients with breast cancer, demonstrating an 85.0% response rate in the PPS population. Furthermore, hetrombopag was well tolerated in this cohort, with no increased incidence of thromboembolic events or other serious adverse events. Proactive prevention of thrombocytopenia, rather than reactive correction, better optimizes patient safety and facilitates timely completion of scheduled therapy, yet relevant research remains limited. A phase II randomized controlled trial (RCT) evaluated dose-ranging eltrombopag (50, 75, 100 mg) for CIT prevention in advanced solid tumor patients receiving carboplatin/paclitaxel, but failed to show significant pre-chemotherapy platelet elevation versus placebo[ 14 ]. Subsequently, a phase I study of once-daily eltrombopag (100 mg) in gemcitabine-treated advanced solid tumors demonstrated potential for preventing thrombocytopenia, with a significantly higher median PLT nadir than placebo[ 18 ]. A phase II study further confirmed that eltrombopag reduced chemotherapy modifications (delays, dose reductions, or discontinuation) due to thrombocytopenia (87% vs. 69%) compared with placebo[ 15 ]. A recent phase II study of hetrombopag demonstrated that a continuous oral dose of 7.5 mg is an effective and well-tolerated option for managing CIT in patients with solid tumors[ 17 ]. Therefore, the present study designed a SPP involving daily oral administration of hetrombopag at 7.5 mg for 14 consecutive days to prevent CTIT in breast cancer patients. Under this protocol, hetrombopag secondary prophylaxis allowed 90% of patients to complete their planned treatment without modifications due to thrombocytopenia. Notably, the post hoc analysis showed a significantly higher completion rate in the ADC group compared to the CBR group (95.7% vs. 75.0%). Moreover, with hetrombopag support, six patients completed 14 cycles of adjuvant T-DM1. These findings suggest hetrombopag may be an effective option for preventing CTIT in breast cancer patients, especially among patients receiving ADC treatment. The precise mechanism underlying ADC-induced thrombocytopenia remains unclear. T-DM1 may potentially impede the maturation and function of megakaryocytes (MK) through a cytotoxic impact following the intracellular liberation of DM[ 19 ]. Although both T-DXd and T-DM1 target HER2, T-DXd elicits lower incidence of thrombocytopenia, which may be attributed to the markedly reduced cytotoxicity of its payload DXd on MK relative to DM[ 20 ]. As the progenitor cells responsible for platelet production, the MK undergo differentiation, maturation, proliferation, and ultimately fragmentation to release platelets[ 21 ]. Hetrombopag may facilitate megakaryopoiesis by activating TPO receptors, offering a plausible mechanistic basis for the clinical activity observed in this study. Current management options for correcting thrombocytopenia remain limited. Platelet transfusion, a common intervention for severe thrombocytopenia, is constrained by supply shortages, infection risks, and transient efficacy[ 22 ]. Despite approval for this condition, platelet growth factors (rhTPO, interleukin-11) are often limited clinically by parenteral administration and associated adverse effects (fluid retention, allergic reactions)[ 23 ]. Consequently, an unmet clinical need persists for more convenient, well-tolerated, and effective agents. TPO-RAs, originally approved for hematologic disorders, have emerged as a promising alternative and are under investigation for CIT. Romiplostim, a peptide-based TPO-RA, has been evaluated for treating CIT in solid tumor patients. Previous retrospective studies have indicated its efficacy in elevating platelet counts[ 24 – 26 ], with the findings of prospective trials likewise demonstrating its superiority over placebo in normalizing platelet levels[ 27 – 29 ]. However, concerns regarding romiplostim-associated bone marrow fibrosis have limited its clinical adoption, spurring the development of small-molecule, non-peptide TPO-RAs. A phase II trial showed eltrombopag may improve platelet counts in chronic myeloid leukemia[ 30 ], and another phase II trial confirmed its efficacy for thrombocytopenia in hematological malignancies versus placebo[ 31 ]. An international phase III trial demonstrated that avatrombopag significantly increased the nadir PLT in solid tumor patients with CIT compared with control (51.5×10⁹/L vs. 29.1×10⁹/L).[ 16 ]. Additionally, a phase II study of hetrombopag for CIT revealed a superior response rate versus placebo (85.7% vs. 48.4%) during the correction phase in patients with advanced solid tumors[ 17 ], this finding was supported by preliminary results from an expanded phase III trial[ 32 ]. However, there remains a paucity of positive-controlled studies evaluating the efficacy of TPO-RAs. Our study represented the first RCT to directly compare hetrombopag with rhTPO, demonstrating the non-inferiority of hetrombopag to rhTPO for correction of thrombocytopenia (87.9% vs. 81.8%). Furthermore, post hoc analysis showed a higher response rate in the hetrombopag group compared with the rhTPO group in ADC-induced thrombocytopenia (95.7% vs. 85.7%). In contrast, no apparent advantage of hetrombopag over rhTPO was observed in the CBR population (70.0% vs. 75.0%), likely due to the limited sample size and the pan-hematopoietic bone marrow suppression effects of CIT in this cohort. Hematological suppression and elevated transaminases, well-recognized adverse events of anti-tumor therapy, occurred at comparable rates in the hetrombopag and rhTPO groups, further confirming that such toxicities are not uniquely attributable to hetrombopag. A total of six participants experienced minor bleeding events in this study, which were associated with thrombocytopenia and clinically manifested as mild epistaxis or cutaneous petechiae. In addition, thrombotic risk may be influenced by patient age, comorbidities, and concomitant medications. Research on romiplostim indicated a thrombosis incidence of around 10%[ 28 ]. Subsequent investigations on other TPO-RAs demonstrated a significant decrease in thrombotic events, with a rate of 5% reported for eltrombopag[ 15 ] and no events observed in a hetrombopag trial[ 17 ]. A meta-analysis further confirmed that TPO-RAs are not associated with an increased risk of thrombotic events[ 33 ], which aligns with the safety profile observed in the present study. Our findings should be interpreted with several limitations in mind. First, the two-cycle study duration and moderate sample size restrict robust assessment of sustained efficacy and long-term safety profiles. While follow-up data provided valuable reference, further validation in large-scale prospective trials with extended follow-up is warranted. Additionally, the absence of stratification by anti-tumor regimens prior to randomization may have resulted in imbalances in key prognostic factors across the study arms. To mitigate this limitation, a dedicated single-arm, multicenter trial evaluating hetrombopag for the prevention of T-DM1-associated thrombocytopenia is currently ongoing at our center (NCT07198672), designed to validate and strengthen the translational significance of our findings. Conclusion As the first prospective trial to evaluate hetrombopag for preventing CTIT in breast cancer patients, this multicenter, exploratory study demonstrated that hetrombopag may be a promising and well-tolerated option for the secondary prevention and management of CTIT. Moreover, encouraging efficacy was observed in patients receiving ADCs, which prompts the need for large-scale, prospective studies with extended cycles and longer follow-up to confirm these findings. Declarations Acknowledgements We thank all the patients who participated in this study and their families, as well as the investigators and staff at each study site. For this investigator-initiated trial, the authors acknowledge Henan Cancer Hospital for providing research facilities and equipment. The study drug (hetrombopag) was supplied by Jiangsu Hengrui Pharmaceuticals Co., Ltd. This study was funded by the XINRUI Project for Tumor Translational Medicine Research (hx2416, M.Y.). Data Availability Statement Data supporting the findings of this study are available from the corresponding author upon reasonable request. Conflict of Interest Statement The authors declare no financial or non-financial conflicts of interest in relation to the work described in this manuscript. Ethics Statement - Approval of the research protocol by an Institutional Reviewer Board: The study protocol was approved by the Ethics Committee of Henan Cancer Hospital (approval number: 2022-214-012) and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. - Informed Consent: Written informed consent was obtained from all participants before enrollment. - Registry and the Registration No. of the study/trial: This clinical trial was registered at clinicaltrial.gov (NCT05394285). Author Contributions Huihui Sun and Huimin Lv contributed equally to this work. Min Yan, Huihui Sun, and Huimin Lv conceived and designed the study. Huihui Sun, Huimin Lv, Wenyan Chen, Yanxia Zhao, Mengwei Zhang, and Limin Niu collected and interpreted the data. Huihui Sun and Huimin Lv drafted the original draft. Min Yan supervised the study and critically revised the manuscript. All authors participated in the enrollment and management of patients. All authors had full access to the data, reviewed and edited the manuscript, and had final responsibility for the decision to submit for publication References Yan D, Yang J, Gao Y, Zhang P, Zhang C, Cheng Y, Zhang X, Fan C, Wang K, Zhu S et al : Combination of Thrombopoietin Receptor Agonist and Recombinant Human Thrombopoietin for Treating Cancer Therapy Induced Thrombopenia . Blood 2022, 140 (Supplement 1):8420-8421. Mei J, Jiao F, Li Y, Cui J, Yang H, Wang L: Application of thrombopoietic agents in cancer therapy-induced thrombocytopenia: A comprehensive review . Blood reviews 2025, 70 :101257. Rha SY, Moon YH, Jeung HC, Kim YT, Sohn JH, Yang WI, Suh CO, Kim GE, Roh JK, Chung HC: Gemcitabine monotherapy as salvage chemotherapy in heavily pretreated metastatic breast cancer . Breast cancer research and treatment 2005, 90 (3):215-221. Hu XC, Zhang J, Xu BH, Cai L, Ragaz J, Wang ZH, Wang BY, Teng YE, Tong ZS, Pan YY et al : Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-label, multicentre, phase 3 trial . The Lancet Oncology 2015, 16 (4):436-446. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E et al : Trastuzumab emtansine for HER2-positive advanced breast cancer . The New England journal of medicine 2012, 367 (19):1783-1791. von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Schneeweiss A, Redondo A et al : Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer . The New England journal of medicine 2019, 380 (7):617-628. Shen K, Ma X, Zhu C, Wu X, Jia H: Safety and Efficacy of Trastuzumab Emtansine in Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: a Meta-analysis . Scientific reports 2016, 6 :23262. Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, Andre F, Iwata H, Ito Y, Tsurutani J et al : Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer . The New England journal of medicine 2020, 382 (7):610-621. Hurvitz SA, Hegg R, Chung WP, Im SA, Jacot W, Ganju V, Chiu JWY, Xu B, Hamilton E, Madhusudan S et al : Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial . Lancet (London, England) 2023, 401 (10371):105-117. Tolaney SM, Jiang Z, Zhang Q, Barroso-Sousa R, Park YH, Rimawi MF, Saura C, Schneeweiss A, Toi M, Chae YS et al : Trastuzumab Deruxtecan plus Pertuzumab for HER2-Positive Metastatic Breast Cancer . The New England journal of medicine 2025. Li J, Hao C, Wang H, Pan Y, Jiang Z: DESTINY-Breast09, new breakthroughs in first-line therapy for HER2-positive advanced breast cancer . 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Winer ES, Safran H, Karaszewska B, Bauer S, Khan D, Doerfel S, Burgess P, Kalambakas S, Mostafa Kamel Y, Forget F: Eltrombopag for thrombocytopenia in patients with advanced solid tumors receiving gemcitabine-based chemotherapy: a randomized, placebo-controlled phase 2 study . International journal of hematology 2017, 106 (6):765-776. Al-Samkari H, Kolb-Sielecki J, Safina SZ, Xue X, Jamieson BD: Avatrombopag for chemotherapy-induced thrombocytopenia in patients with non-haematological malignancies: an international, randomised, double-blind, placebo-controlled, phase 3 trial . The Lancet Haematology 2022, 9 (3):e179-e189. Qin S, Wang Y, Yao J, Liu Y, Yi T, Pan Y, Chen Z, Zhang X, Lu J, Yu J et al : Hetrombopag for the management of chemotherapy-induced thrombocytopenia in patients with advanced solid tumors: a multicenter, randomized, double-blind, placebo-controlled, phase II study . Therapeutic advances in medical oncology 2024, 16 :17588359241260985. Winer ES, Safran H, Karaszewska B, Richards DA, Hartner L, Forget F, Ramlau R, Kumar K, Mayer B, Johnson BM et al : Eltrombopag with gemcitabine-based chemotherapy in patients with advanced solid tumors: a randomized phase I study . Cancer medicine 2015, 4 (1):16-26. Uppal H, Doudement E, Mahapatra K, Darbonne WC, Bumbaca D, Shen BQ, Du X, Saad O, Bowles K, Olsen S et al : Potential mechanisms for thrombocytopenia development with trastuzumab emtansine (T-DM1) . Clinical cancer research : an official journal of the American Association for Cancer Research 2015, 21 (1):123-133. Jia G, Jiang Y, Li X: Targeted drug conjugates in cancer therapy: Challenges and opportunities Pharmaceutical Science Advances 2024, 2 (1):100048-. Kudo T, Sato T, Hagiwara K, Kozuma Y, Yamaguchi T, Ikehara Y, Hamada M, Matsumoto K, Ema M, Murata S et al : C1galt1-deficient mice exhibit thrombocytopenia due to abnormal terminal differentiation of megakaryocytes . Blood 2013, 122 (9):1649-1657. Rodeghiero F: Introduction to a review series on the treatment of thrombocytopenic disorders: something old, something new . Haematologica 2022, 107 (6):1239-1242. Kaye JA: Clinical development of recombinant human interleukin-11 to treat chemotherapy-induced thrombocytopenia . Current opinion in hematology 1996, 3 (3):209-215. Al-Samkari H, Marshall AL, Goodarzi K, Kuter DJ: The use of romiplostim in treating chemotherapy-induced thrombocytopenia in patients with solid tumors . Haematologica 2018, 103 (4):e169-e172. Parameswaran R, Lunning M, Mantha S, Devlin S, Hamilton A, Schwartz G, Soff G: Romiplostim for management of chemotherapy-induced thrombocytopenia . Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 2014, 22 (5):1217-1222. Miao J, Leblebjian H, Scullion B, Parnes A: A single center experience with romiplostim for the management of chemotherapy-induced thrombocytopenia . American journal of hematology 2018, 93 (4):E86-e88. Al-Samkari H, Parnes AD, Goodarzi K, Weitzman JI, Connors JM, Kuter DJ: A multicenter study of romiplostim for chemotherapy-induced thrombocytopenia in solid tumors and hematologic malignancies . Haematologica 2021, 106 (4):1148-1157. Soff GA, Miao Y, Bendheim G, Batista J, Mones JV, Parameswaran R, Wilkins CR, Devlin SM, Abou-Alfa GK, Cercek A et al : Romiplostim Treatment of Chemotherapy-Induced Thrombocytopenia . Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2019, 37 (31):2892-2898. Raj S, Trent J, Araujo D, Patel S, Zhou X, Benjamin R: Evaluation of AMG 531 in chemotherapy-induced thrombocytopenia (CIT): Results of a phase I/II study . Journal of Clinical Oncology 2009, 27 :e20616-e20616. Shoukier M, Borthakur G, Jabbour E, Ravandi F, Garcia-Manero G, Kadia T, Matthews J, Masarova L, Naqvi K, Sasaki K et al : The effect of eltrombopag in managing thrombocytopenia associated with tyrosine kinase therapy in patients with chronic myeloid leukemia and myelofibrosis . Haematologica 2021, 106 (11):2853-2858. Mittelman M, Platzbecker U, Afanasyev B, Grosicki S, Wong RSM, Anagnostopoulos A, Brenner B, Denzlinger C, Rossi G, Nagler A et al : Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): a randomised, placebo-controlled, phase 2 trial . The Lancet Haematology 2018, 5 (1):e34-e43. Qin S, Zhang Y, Li H, Mao Y, Yang W, Xie Z, Liu Y, Wan L, Zhang Y, Zhang X et al : Hetrombopag for the treatment of chemotherapy-induced thrombocytopenia in advanced solid tumors: A multicenter, randomized, double-blind, placebo-controlled phase III trial . Blood 2025, 146 (Supplement 1):1256-1256. Soff GA, Ray-Coquard I, Rivera LJM, Fryzek J, Mullins M, Bylsma LC, Park JK: Systematic literature review and meta-analysis on use of Thrombopoietic agents for chemotherapy-induced thrombocytopenia . PloS one 2022, 17 (6):e0257673. Additional Declarations No competing interests reported. Supplementary Files SupplementaryAppendix1.docx SupplementaryAppendix2.docx SupplementaryAppendix3.png Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 07 May, 2026 Reviews received at journal 17 Apr, 2026 Reviewers agreed at journal 10 Apr, 2026 Reviewers invited by journal 08 Apr, 2026 Editor assigned by journal 27 Feb, 2026 Submission checks completed at journal 27 Feb, 2026 First submitted to journal 26 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8976504","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":621823453,"identity":"d4afecec-4292-465b-b2cb-cfd1f0df48b2","order_by":0,"name":"Huihui Sun","email":"","orcid":"","institution":"Henan Cancer Hospital, China","correspondingAuthor":false,"prefix":"","firstName":"Huihui","middleName":"","lastName":"Sun","suffix":""},{"id":621823463,"identity":"ef5280bd-0084-45e9-9220-5cf7a17e6be0","order_by":1,"name":"Huimin Lv","email":"","orcid":"","institution":"Henan Cancer Hospital, 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10:09:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8976504/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8976504/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107484653,"identity":"34415694-ee84-48cb-ace7-99d260e35b27","added_by":"auto","created_at":"2026-04-22 02:32:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":283004,"visible":true,"origin":"","legend":"\u003cp\u003eStudy design\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8976504/v1/c0f8d1db2f6a5e03e756e33d.png"},{"id":107482485,"identity":"e829e33f-a6c5-4fad-bdf0-718d9ca06812","added_by":"auto","created_at":"2026-04-22 02:23:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":69203,"visible":true,"origin":"","legend":"\u003cp\u003eResponse rates during the TTP.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8976504/v1/9d43b496c8f651217dd00ddb.png"},{"id":107487190,"identity":"963d8341-758c-41b1-8860-e53c75a8f554","added_by":"auto","created_at":"2026-04-22 02:39:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2160535,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8976504/v1/efeb100c-0789-4a5e-9ea7-44621e265f59.pdf"},{"id":107245111,"identity":"19bc866a-c3ac-4a15-87cb-bd58ef9f5030","added_by":"auto","created_at":"2026-04-19 07:57:34","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":550528,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryAppendix1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8976504/v1/57db08f9d390492555ebcac0.docx"},{"id":107245112,"identity":"973e461d-dbc3-4247-9735-7b5331c07352","added_by":"auto","created_at":"2026-04-19 07:57:34","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":12609,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryAppendix2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8976504/v1/b1c476ee0497eff0ea453cf4.docx"},{"id":107482181,"identity":"ba04a9d4-ebe2-4f23-9099-722920d74163","added_by":"auto","created_at":"2026-04-22 02:22:26","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":376715,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryAppendix3.png","url":"https://assets-eu.researchsquare.com/files/rs-8976504/v1/047b7082a5a5dad1fad3aa58.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eSecondary prevention of cancer therapy-induced thrombocytopenia with hetrombopag in breast cancer: a multicenter, randomized, exploratory phase II trial\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCancer therapy-induced thrombocytopenia (CTIT) is a common complication of anti-tumor treatment and may lead to treatment delays or interruptions, increased bleeding risk, and compromised outcomes[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This concept encompasses thrombocytopenia induced by various treatments, such as chemotherapy (CIT), immune checkpoint inhibitors, targeted therapy including antibody-drug conjugates (ADCs), and radiotherapy[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn breast cancer, CTIT presents a major clinical challenge. With traditional chemotherapy, gemcitabine-based regimens are particularly associated with grade\u0026thinsp;\u0026ge;\u0026thinsp;3 thrombocytopenia, with an approximate incidence of 14% for monotherapy[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] and up to 32% for combination with cisplatin[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This challenge extends to certain ADCs, a transformative class of agents with rapidly expanding clinical utility in breast cancer. Trastuzumab Emtansine (T-DM1), a pioneering ADC targeting the human epidermal growth factor receptor 2 (HER2), was initially approved based on the results of the phase III EMILIA trial[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] and remains a cornerstone in adjuvant therapy for HER2-positive breast cancer following the KATHERINE trial[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, its clinical utility is limited by high-grade thrombocytopenia, with a meta-analysis reporting a 32% incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 events, often requiring treatment modification or even discontinuation[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The subsequent development of trastuzumab deruxtecan (T-DXd), a later-generation ADC, is characterized by breakthrough efficacy across the spectrum of HER2 expression (low and positive) and disease stages (early and advanced) in breast cancer[\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Nevertheless, thrombocytopenia remains a relevant adverse event with T-DXd, occurring in approximately 20% of patients, including severe (grade\u0026thinsp;\u0026ge;\u0026thinsp;3) events in about 10%.\u003c/p\u003e \u003cp\u003eAlthough recombinant human thrombopoietin (rhTPO) is approved for the treatment of CTIT, there is currently no evidence supporting its use for prevention[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Thrombopoietin receptor agonists (TPO-RAs) represent a promising therapeutic strategy for CTIT by binding to the transmembrane domain of TPO receptor, which activates downstream signaling cascades to promote the proliferation and differentiation of megakaryocyte progenitor cells[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, current evidence for TPO-RAs is limited to the treatment of established CIT[\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], creating a critical gap in evidence for their use in preventing CTIT within the increasingly prevalent ADC-based regimens for breast cancer.\u003c/p\u003e \u003cp\u003eHetrombopag, a novel oral TPO-RA developed in China, has demonstrated efficacy against CIT in a phase II trial involving patients with solid tumors[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Building on this evidence, this prospective study is the first to evaluate the efficacy and safety of hetrombopag as a secondary prevention strategy for CTIT in breast cancer patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003eThis multicenter, open-label, randomized, phase II study (NCT05394285) of hetrombopag for the treatment and prevention of CTIT in breast cancer patients was conducted at four qualified tertiary hospitals in China. The study protocol received approval from regulatory authorities and ethics committees at all anticipating centers. Written informed consents were received from all patients before enrollment.\u003c/p\u003e \u003cp\u003ePatients aged 18\u0026ndash;75 years with pathologically confirmed breast cancer who received anti-tumor treatment and had severe thrombocytopenia were eligible for inclusion. Severe thrombocytopenia was defined as a platelet count (PLT)\u0026thinsp;\u0026lt;\u0026thinsp;50\u0026times;10⁹/L during the qualifying cycle (Cycle 1). PLT values were obtained in accordance with standard clinical practice prior to informed consent. Additionally, patients were required to be scheduled to receive the same anti-tumor regimen and dose in the subsequent cycle (Cycle 2). All participants were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0\u0026ndash;1, a life expectancy\u0026thinsp;\u0026ge;\u0026thinsp;12 weeks, and no serious complications.\u003c/p\u003e \u003cp\u003eKey exclusion criteria included a history of haematological malignancy or bone marrow metastasis; clinically active bleeding within 2 weeks; receipt of radiotherapy or any platelet-boosting therapy within 1 month; arterial or venous thrombosis within 6 months before enrollment; significant hepatic or renal dysfunction or other severe complications.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRandomization and interventions\u003c/h3\u003e\n\u003cp\u003eRandomization was generated using a computer-generated randomization table by an interactive web response system. Both study participants and the research team were aware of the group assignments after randomization. Eligible patients were randomized in a 1:1 ratio to the hetrombopag group or the rhTPO group. The period from the start of thrombocytopenia treatment to PLT\u0026thinsp;\u0026gt;\u0026thinsp;100\u0026times;10⁹/L was defined as the thrombocytopenia treatment phase (TTP). In the TTP, patients in the hetrombopag group received hetrombopag (7.5 mg, orally, daily), and patients in the rhTPO group received rhTPO (15000 U, subcutaneously, daily). In the secondary prevention phase (SPP), all patients received hetrombopag at an initial dose of 7.5 mg once daily for 14 consecutive days, starting on day 1 following the initiation of Cycle 2.\u003c/p\u003e \u003cp\u003eRegarding dose adjustment of hetrombopag, the daily dose was reduced to 5.0 mg when PLT were between 200\u0026times;10⁹/L and 400\u0026times;10⁹/L. If PLT reached\u0026thinsp;\u0026ge;\u0026thinsp;400\u0026times;10⁹/L, hetrombopag was withheld until PLT dropped to \u0026lt;\u0026thinsp;200\u0026times;10⁹/L, and then resumed at a daily dose of 5.0 mg. Any days of treatment interruption were counted toward the total 14-day treatment course.\u003c/p\u003e \u003cp\u003ePlatelet counts were monitored every other day during both the TTP and SPP, with additional assessments performed at the investigator\u0026rsquo;s discretion. Platelet transfusion might be considered when PLT\u0026thinsp;\u0026lt;\u0026thinsp;10\u0026times;10⁹/L or when there was a risk of bleeding. The detail study design is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eStudy endpoints\u003c/h3\u003e\n\u003cp\u003ePatients who completed at least two consecutive cycles of anti-tumor therapy (Cycle 1 and Cycle 2) were included in the primary endpoint analysis. Efficacy endpoints were assessed during the defined observation period spanning from the time of randomization to the initiation of Cycle 3 therapy. The choice to extend hetrombopag prophylaxis beyond the core study period was guided by patient preferences, and data were systematically collected to enable subsequent post hoc analysis.\u003c/p\u003e \u003cp\u003eResponse rate was defined as the proportion of patients who met the following criteria until the start of the subsequent cycle: 1. received the standard anti-tumor treatment without dose modification (defined as a dose reduction of \u0026ge;\u0026thinsp;20% or a delay of \u0026ge;\u0026thinsp;5 days) due to thrombocytopenia, 2. no platelet transfusion, and 3. no severe thrombocytopenia (defined as a PLT\u0026thinsp;\u0026lt;\u0026thinsp;25\u0026times;10⁹/L, or a PLT\u0026thinsp;\u0026lt;\u0026thinsp;50\u0026times;10⁹/L persisting for \u0026ge;\u0026thinsp;7 consecutive days). The primary endpoint was the response rate during the SPP, defined as the proportion of responders until the start of Cycle 3. Subgroup analysis based on different anti-tumor treatment regimens was performed in post hoc analysis.\u003c/p\u003e \u003cp\u003eThe key secondary endpoint was the response rate during the TTP, defined as the proportion of responders until the start of Cycle 2. Other secondary endpoints included the nadir and peak PLT, as well as the incidence and duration of PLT\u0026thinsp;\u0026lt;\u0026thinsp;25\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L and PLT\u0026thinsp;\u0026lt;\u0026thinsp;50\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L during the TTP and the SPP, respectively. Adverse events were graded according to the National Cancer Institute\u0026rsquo;s Common Terminology Criteria for Adverse Events, version 5.0. Bleeds were classified according to the WHO bleeding assessment scale (grade 0, no bleeding; grade 1, petechiae; grade 2, mild blood loss; grade 3, gross blood loss; and grade 4, debilitating blood loss).\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eFull analysis set (FAS) included all randomly assigned patients. The per-protocol set (PPS) included all subjects who completed protocol-specified treatments without serious protocol violations. The proportion of responders was present as binary categories. For patients lacking efficacy data due to treatment interruption, additional patients were incorporate to complete the study. Descriptive statistical analyses were used to summarize other secondary outcomes. Results were presented as the number (percentage), mean\u0026plusmn;standard (deviation), or median (Min, Max). Data analyses were performed using SAS software (version 9.4). A comprehensive description of the study protocol is available in Supplementary Appendix 1.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eBetween September 2022 and May 2025, a total of 67 female breast cancer patients were initially enrolled in the study. After excluding 1 patient who withdrew informed consent, 66 patients comprised the FAS. They were randomly assigned to receive either hetrombopag (n\u0026thinsp;=\u0026thinsp;33) or rhTPO (n\u0026thinsp;=\u0026thinsp;33).\u003c/p\u003e \u003cp\u003ePatients in the FAS had a median age of 54.4 years (range, 29\u0026ndash;73) and an ECOG performance status of 0 or 1. The cohort comprised 19 patients with early-stage breast cancer and 47 with metastatic disease. Among those with metastatic disease, 38 had visceral metastases and 16 had\u0026thinsp;\u0026ge;\u0026thinsp;3 metastatic lesions. The median number of prior therapy lines was 3 (range, 0\u0026ndash;10), and 23 patients had received more than 3 lines of systemic therapy. The average baseline PLT was 37.5 (15\u0026ndash;49) \u0026times;10⁹/L, with 39.0 (23\u0026ndash;49) \u0026times;10⁹/L in the hetrombopag group and 36.0 (15\u0026ndash;49) \u0026times;10⁹/L in the rhTPO group, respectively. Furthermore, 9 patients (13.6%) had baseline PLT\u0026thinsp;\u0026le;\u0026thinsp;25\u0026times;10⁹/L, including 2 (6.1%) in the hetrombopag group and 7 (21.2%) in the rhTPO group.\u003c/p\u003e \u003cp\u003eA total of 51 patients (77.3%) received ADCs, comprising 23 patients in the hetrombopag group and 28 patients in the rhTPO group. Fourteen patients (21.2%) were treated with chemotherapy-based regimens (CBRs), while one patient (1.5%) received a combination of abemaciclib (a CDK4/6 inhibitor) and fulvestrant (an endocrine agent) along with inetetamab (a macromolecular monoclonal antibody). Detailed patient characteristics are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHetrombopag group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;33)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003erhTPO, group\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;33)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAll patients\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;66)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55.6 (32, 69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e52.5 (29, 73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e54.4 (29, 73)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e33 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e66 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEarly-stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (24.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19 (28.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (75.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e47 (71.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisceral metastases\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (57.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19 (57.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38 (57.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (18.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9 (13.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of metastatic lesions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (21.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (18.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13 (19.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (24.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10 (30.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18 (54.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (30.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (18.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16 (24.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of previous therapy lines, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (39.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24 (36.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (36.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23 (34.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline platelet count\u0026times;10⁹/L (median, range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39.0 (23, 49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36.0 (15, 49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e37.5 (15, 49)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline platelet count\u0026times;10⁹/L, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT\u0026thinsp;\u0026le;\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (21.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9 (13.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u0026thinsp;\u0026lt;\u0026thinsp;PLT\u0026thinsp;\u0026lt;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (93.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26 (78.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e57 (86.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegimen, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eADCs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (69.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28 (84.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e51 (77.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT-DM1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (63.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26 (78.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e47 (71.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT-DXd\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2 (6.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4 (6.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCBRs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (30.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4 (12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14 (21.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMonotherapy chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2 (3.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCombination chemotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12 (18.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbemaciclib, fulvestrant and inetetamab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1 (1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eADCs: antibody-drug conjugates; CBRs: chemotherapy-based regimens; T-DM1: trastuzumab emtansine; T-DXd: trastuzumab deruxtecan\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePrimary endpoint: the response rate during the SPP\u003c/h3\u003e\n\u003cp\u003eAfter excluding 6 patients who failed to complete cycle 2 anti-tumor therapy in accordance with the study protocol (2 due to disease progression, 4 due to withdrawal of informed consent), the remaining 60 patients constituted the PPS for primary analysis. Among them, 47 patients were treated with ADCs, while 12 patients were treated with CBRs. The response rate during the SPP was 85.0% (51/60). Post hoc analysis showed that the response rate in patients treated with ADCs (89.4%, 42/47) was numerically higher than that among patients treated with CBRs (75.0%, 9/12) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAfter receiving prophylactic hetrombopag during the SPP, the median nadir PLT was 56.5\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, with only one patient requiring platelet transfusion. Treatment adjustments due to thrombocytopenia occurred in 10% of patients and were numerically lower in the ADC group than in the CBR group (4.3% vs 25.0%). The detailed response items and other PLT parameters are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe response rate during the SPP.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary endpoint\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eResponse (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-response (n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eResponse rate (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePPS (N\u0026thinsp;=\u0026thinsp;60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e85.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRegimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eADC (n\u0026thinsp;=\u0026thinsp;47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e89.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCBR (n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e75.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003ePPS: protocol set; ADC: antibody-drug conjugate; CBR: chemotherapy-based regimen\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe response items and other PLT parameters during the SPP\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther endpoints\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eADC (N\u0026thinsp;=\u0026thinsp;47)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCBR (N\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePPS (N\u0026thinsp;=\u0026thinsp;60)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResponse items\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment\u0026nbsp;modification\u0026nbsp;due\u0026nbsp;to thrombocytopenia (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6\u0026nbsp;(10.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet transfusion requirement (n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u0026nbsp;(1.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 4 thrombocytopenia (PLT\u0026thinsp;\u0026lt;\u0026thinsp;25\u0026times;10⁹/L; n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (8.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6\u0026nbsp;(10.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePersistent thrombocytopenia (PLT\u0026thinsp;\u0026lt;\u0026thinsp;50\u0026times;10⁹/L for \u0026ge;\u0026thinsp;7 consecutive days; n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u0026nbsp;(5.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther PLT parameters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT nadir (\u0026times;10⁹/L; median, range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 (19, 236)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70.5 (20, 188)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e56.5\u0026nbsp;(19, 331)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT maxmium (\u0026times;10⁹/L; median, range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e179 (70, 445)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e185 (87, 651)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e179.5\u0026nbsp;(51, 445)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian duration of grade 4 thrombocytopenia (PLT\u0026thinsp;\u0026lt;\u0026thinsp;25\u0026times;10⁹/L; days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 3/4 thrombocytopenia (PLT\u0026thinsp;\u0026lt;\u0026thinsp;50\u0026times;10⁹/L; n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (38.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (41.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23 (38.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian duration of grade 3/4 thrombocytopenia (PLT\u0026thinsp;\u0026lt;\u0026thinsp;50\u0026times;10⁹/L; days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003ePPS: protocol set; ADC: antibody-drug conjugate; CBR: chemotherapy-based regimen\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eSecondary endpoints: the response rate during the TTP\u003c/h3\u003e\n\u003cp\u003eIn the FAS, the response rate was 84.8% (56/66), with similar rates in the hetrombopag and rhTPO groups (87.9% [29/33] vs. 81.8% [27/33]). Post hoc analysis showed a response rate of 90.2% (46/51) in ADC-treated patients, with rates of 95.7% (22/23) and 85.7% (24/28) in the hetrombopag and rhTPO groups, respectively. In the CBR subgroup, the response rate was 71.4% (10/14), with 70.0% (7/10) in the hetrombopag group and 75.0% (3/4) in the rhTPO group. Detailed data are showed in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe median duration of the TTP was 6 days in the hetrombopag group and 7 days in the rhTPO group. Moreover, the median nadir and peak PLT, the incidence and the duration of grade 3/4 thrombocytopenia were comparable between the two groups (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePlatelet parameters and thrombocytopenia occurrence in FAS during the TTP\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary\u0026nbsp;endpoints\u0026nbsp;during the\u0026nbsp;TTP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHetrombopag\u0026nbsp; group (n\u0026thinsp;=\u0026thinsp;33)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003erhTPO\u0026nbsp; group (n\u0026thinsp;=\u0026thinsp;33)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFAS (N\u0026thinsp;=\u0026thinsp;66)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT nadir (\u0026times;10⁹/L; median, range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e53.0\u0026nbsp;(12,\u0026nbsp;164)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e47.0\u0026nbsp;(10,\u0026nbsp;90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e49.5\u0026nbsp;(10,\u0026nbsp;164)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT maxmium (\u0026times;10⁹/L; median, range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e125.0\u0026nbsp;(81,\u0026nbsp;552)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e135.0\u0026nbsp;(96,\u0026nbsp;212)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e126.5\u0026nbsp;(81,\u0026nbsp;552)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 4 thrombocytopenia (PLT\u0026thinsp;\u0026lt;\u0026thinsp;25\u0026times;10⁹/L; n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u0026nbsp;(9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u0026nbsp;(12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7\u0026nbsp;(10.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian duration of grade 4 thrombocytopenia (PLT\u0026thinsp;\u0026lt;\u0026thinsp;25\u0026times;10⁹/L; days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 3/4 thrombocytopenia (PLT\u0026thinsp;\u0026lt;\u0026thinsp;50\u0026times;10⁹/L; n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14\u0026nbsp;(42.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19\u0026nbsp;(57.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e33\u0026nbsp;(50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian duration of grade 3/4 thrombocytopenia (PLT\u0026thinsp;\u0026lt;\u0026thinsp;50\u0026times;10⁹/L; days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian duration\u0026nbsp;of\u0026nbsp;the TTP\u0026nbsp;(days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePost hoc analysis of platelet parameters and the incidence of thrombocytopenia were performed in the ADC and CBR subgroups. In patients treated with ADC, the nadir PLT was significantly higher in the hetrombopag group compared to the rhTPO group (67 vs. 44\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L), accompanied by a reduced incidence of grade 3/4 thrombocytopenia (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). This favorable trend was not evident in patients treated with CBR (Supplementary Appendix 2). These findings indicated that hetrombopag may be more effective in managing ADC-induced thrombocytopenia compared to that induced by other medications.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePlatelet parameters and thrombocytopenia occurrence in ADC-treated patients during the TTP\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary\u0026nbsp;endpoints\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHetrombopag\u0026nbsp;\u0026nbsp; group (n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003erhTPO\u0026nbsp; group (n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eADC (N\u0026thinsp;=\u0026thinsp;51)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT nadir (\u0026times;10⁹/L; median, range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e67.0\u0026nbsp;(21,\u0026nbsp;118)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e44.0\u0026nbsp;(10,\u0026nbsp;90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e52.0\u0026nbsp;(10,\u0026nbsp;118)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT maxmium (\u0026times;10⁹/L; median, range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e120.0\u0026nbsp;(89,\u0026nbsp;552)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e135.5\u0026nbsp;(96,\u0026nbsp;212)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e125.0\u0026nbsp;(89,\u0026nbsp;552)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 4 thrombocytopenia (PLT\u0026thinsp;\u0026lt;\u0026thinsp;25\u0026times;10⁹/L; n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u0026nbsp;(4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3\u0026nbsp;(10.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4\u0026nbsp;(7.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian duration of grade 4 thrombocytopenia (PLT\u0026thinsp;\u0026lt;\u0026thinsp;25\u0026times;10⁹/L; days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 3/4 thrombocytopenia (PLT\u0026thinsp;\u0026lt;\u0026thinsp;50\u0026times;10⁹/L; n, %)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u0026nbsp;(26.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17 (60.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23\u0026nbsp;(45.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian duration of grade 3/4 thrombocytopenia (PLT\u0026thinsp;\u0026lt;\u0026thinsp;50\u0026times;10⁹/L; days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian duration\u0026nbsp;of\u0026nbsp;TTP\u0026nbsp;(days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eDuring the SPP, 12 patients underwent dose adjustments of hetrombopag. Of these, 9 patients reduced their dose to 5.0 mg for PLT ranging from 200 to 400\u0026times;10⁹/L. The remaining 3 patients temporarily discontinued treatment (2 days for two patients each; 3 days for one patient) when their PLT reached\u0026thinsp;\u0026ge;\u0026thinsp;400\u0026times;10⁹/L and resumed hetrombopag at 5 mg once PLT dropped to \u0026lt;\u0026thinsp;200\u0026times;10⁹/L.\u003c/p\u003e \u003cp\u003eIn the FAS population, the most common treatment-emergent adverse events (TEAEs) of any grade were leukopenia (34, 51.5%) and anemia (34, 51.5%), followed by elevated aspartate aminotransferase (31, 47.0%), elevated glutamyltransferase (31, 47.0%), neutropenia (29, 43.9%) and elevated blood lactate dehydrogenase (22, 33.3%). The most common grade 3 or higher TEAEs were leukopenia (4, 6.1%) and elevated aspartate aminotransferase (4, 6.1%), followed by neutropenia (3, 4.5%), elevated alanine aminotransferase (3, 4.5%), elevated glutamyltransferase (3, 4.5%), and anemia (2, 3.0%). All TEAEs were predominantly associated with the anti-tumor agents and were considered unrelated to the thrombopoietic agents.\u003c/p\u003e \u003cp\u003eSix patients (9.1%) experienced bleeding, all classified as WHO grade 1, including hemoptysis, epistaxis, skin petechiae and ecchymosis. There were no arterial or venous thrombosis events during the study. Detailed data are presented in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse events among FAS population.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAdverse\u0026nbsp;events\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eHetrombopag\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;33)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003erhTPO\u0026nbsp;(n\u0026thinsp;=\u0026thinsp;33)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eFAS\u0026nbsp;(N\u0026thinsp;=\u0026thinsp;66)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAng\u0026nbsp;grades\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u0026nbsp;grade\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAng\u0026nbsp;grades\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u0026nbsp;grade\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAng\u0026nbsp;grades\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u0026nbsp;grade\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (51.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (9.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (51.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (3.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e34 (51.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4 (6.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (45.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (9.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14 (42.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e29 (43.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3 (4.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (48.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (6.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (54.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e34 (51.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2 (3.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated alanine\u0026nbsp;aminotransferase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (27.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (9.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20 (30.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3 (4.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated aspartate\u0026nbsp;aminotransferase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (48.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(3.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (45.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (9.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e31 (47.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4 (6.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated bilirubin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (3.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (3.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated glutamyltransferase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (42.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (6.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (51.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (3.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e31 (47.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3 (4.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated blood\u0026nbsp;lactate\u0026nbsp;dehydrogenase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (36.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (30.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e22 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated blood\u0026nbsp;creatinine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (6.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (15.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7 (10.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypokalaemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (9.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 (4.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyponatremia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (1.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypocalcaemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (3.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (3.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAEs\u0026nbsp;of\u0026nbsp;special\u0026nbsp;interest\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBleeding\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (12.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (6.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6 (9.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eFollow-up: additional cycles\u003c/h2\u003e \u003cp\u003eAmong the 51 responders who completed the protocol-defined prevention phase, 12 patients chose to continue hetrombopag prophylaxis. Of these, six patients with early-stage breast cancer successfully completed the planned adjuvant T-DM1 treatment course (an additional 12 cycles). The remaining six patients (five on T-DM1 and one on chemotherapy) with advanced breast cancer received secondary prevention for variable durations: three for only 2 additional cycles, two for 6 cycles (both discontinued due to financial pressure), and one for 20 cycles until disease progression. Follow-up data about the remaining patients are showed in Supplementary Appendix 3.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis phase II study is the first clinical trial to assess hetrombopag for the secondary prevention of CTIT in patients with breast cancer, demonstrating an 85.0% response rate in the PPS population. Furthermore, hetrombopag was well tolerated in this cohort, with no increased incidence of thromboembolic events or other serious adverse events.\u003c/p\u003e \u003cp\u003eProactive prevention of thrombocytopenia, rather than reactive correction, better optimizes patient safety and facilitates timely completion of scheduled therapy, yet relevant research remains limited. A phase II randomized controlled trial (RCT) evaluated dose-ranging eltrombopag (50, 75, 100 mg) for CIT prevention in advanced solid tumor patients receiving carboplatin/paclitaxel, but failed to show significant pre-chemotherapy platelet elevation versus placebo[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Subsequently, a phase I study of once-daily eltrombopag (100 mg) in gemcitabine-treated advanced solid tumors demonstrated potential for preventing thrombocytopenia, with a significantly higher median PLT nadir than placebo[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. A phase II study further confirmed that eltrombopag reduced chemotherapy modifications (delays, dose reductions, or discontinuation) due to thrombocytopenia (87% vs. 69%) compared with placebo[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. A recent phase II study of hetrombopag demonstrated that a continuous oral dose of 7.5 mg is an effective and well-tolerated option for managing CIT in patients with solid tumors[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Therefore, the present study designed a SPP involving daily oral administration of hetrombopag at 7.5 mg for 14 consecutive days to prevent CTIT in breast cancer patients. Under this protocol, hetrombopag secondary prophylaxis allowed 90% of patients to complete their planned treatment without modifications due to thrombocytopenia. Notably, the post hoc analysis showed a significantly higher completion rate in the ADC group compared to the CBR group (95.7% vs. 75.0%). Moreover, with hetrombopag support, six patients completed 14 cycles of adjuvant T-DM1. These findings suggest hetrombopag may be an effective option for preventing CTIT in breast cancer patients, especially among patients receiving ADC treatment.\u003c/p\u003e \u003cp\u003eThe precise mechanism underlying ADC-induced thrombocytopenia remains unclear. T-DM1 may potentially impede the maturation and function of megakaryocytes (MK) through a cytotoxic impact following the intracellular liberation of DM[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Although both T-DXd and T-DM1 target HER2, T-DXd elicits lower incidence of thrombocytopenia, which may be attributed to the markedly reduced cytotoxicity of its payload DXd on MK relative to DM[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. As the progenitor cells responsible for platelet production, the MK undergo differentiation, maturation, proliferation, and ultimately fragmentation to release platelets[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Hetrombopag may facilitate megakaryopoiesis by activating TPO receptors, offering a plausible mechanistic basis for the clinical activity observed in this study.\u003c/p\u003e \u003cp\u003eCurrent management options for correcting thrombocytopenia remain limited. Platelet transfusion, a common intervention for severe thrombocytopenia, is constrained by supply shortages, infection risks, and transient efficacy[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Despite approval for this condition, platelet growth factors (rhTPO, interleukin-11) are often limited clinically by parenteral administration and associated adverse effects (fluid retention, allergic reactions)[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Consequently, an unmet clinical need persists for more convenient, well-tolerated, and effective agents. TPO-RAs, originally approved for hematologic disorders, have emerged as a promising alternative and are under investigation for CIT.\u003c/p\u003e \u003cp\u003eRomiplostim, a peptide-based TPO-RA, has been evaluated for treating CIT in solid tumor patients. Previous retrospective studies have indicated its efficacy in elevating platelet counts[\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], with the findings of prospective trials likewise demonstrating its superiority over placebo in normalizing platelet levels[\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. However, concerns regarding romiplostim-associated bone marrow fibrosis have limited its clinical adoption, spurring the development of small-molecule, non-peptide TPO-RAs. A phase II trial showed eltrombopag may improve platelet counts in chronic myeloid leukemia[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], and another phase II trial confirmed its efficacy for thrombocytopenia in hematological malignancies versus placebo[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. An international phase III trial demonstrated that avatrombopag significantly increased the nadir PLT in solid tumor patients with CIT compared with control (51.5\u0026times;10⁹/L vs. 29.1\u0026times;10⁹/L).[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Additionally, a phase II study of hetrombopag for CIT revealed a superior response rate versus placebo (85.7% vs. 48.4%) during the correction phase in patients with advanced solid tumors[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], this finding was supported by preliminary results from an expanded phase III trial[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. However, there remains a paucity of positive-controlled studies evaluating the efficacy of TPO-RAs. Our study represented the first RCT to directly compare hetrombopag with rhTPO, demonstrating the non-inferiority of hetrombopag to rhTPO for correction of thrombocytopenia (87.9% vs. 81.8%). Furthermore, post hoc analysis showed a higher response rate in the hetrombopag group compared with the rhTPO group in ADC-induced thrombocytopenia (95.7% vs. 85.7%). In contrast, no apparent advantage of hetrombopag over rhTPO was observed in the CBR population (70.0% vs. 75.0%), likely due to the limited sample size and the pan-hematopoietic bone marrow suppression effects of CIT in this cohort.\u003c/p\u003e \u003cp\u003eHematological suppression and elevated transaminases, well-recognized adverse events of anti-tumor therapy, occurred at comparable rates in the hetrombopag and rhTPO groups, further confirming that such toxicities are not uniquely attributable to hetrombopag. A total of six participants experienced minor bleeding events in this study, which were associated with thrombocytopenia and clinically manifested as mild epistaxis or cutaneous petechiae. In addition, thrombotic risk may be influenced by patient age, comorbidities, and concomitant medications. Research on romiplostim indicated a thrombosis incidence of around 10%[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Subsequent investigations on other TPO-RAs demonstrated a significant decrease in thrombotic events, with a rate of 5% reported for eltrombopag[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and no events observed in a hetrombopag trial[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. A meta-analysis further confirmed that TPO-RAs are not associated with an increased risk of thrombotic events[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], which aligns with the safety profile observed in the present study.\u003c/p\u003e \u003cp\u003eOur findings should be interpreted with several limitations in mind. First, the two-cycle study duration and moderate sample size restrict robust assessment of sustained efficacy and long-term safety profiles. While follow-up data provided valuable reference, further validation in large-scale prospective trials with extended follow-up is warranted. Additionally, the absence of stratification by anti-tumor regimens prior to randomization may have resulted in imbalances in key prognostic factors across the study arms. To mitigate this limitation, a dedicated single-arm, multicenter trial evaluating hetrombopag for the prevention of T-DM1-associated thrombocytopenia is currently ongoing at our center (NCT07198672), designed to validate and strengthen the translational significance of our findings.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAs the first prospective trial to evaluate hetrombopag for preventing CTIT in breast cancer patients, this multicenter, exploratory study demonstrated that hetrombopag may be a promising and well-tolerated option for the secondary prevention and management of CTIT. Moreover, encouraging efficacy was observed in patients receiving ADCs, which prompts the need for large-scale, prospective studies with extended cycles and longer follow-up to confirm these findings.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all the patients who participated in this study and their families, as well as the investigators and staff at each study site. For this investigator-initiated trial, the authors acknowledge Henan Cancer Hospital for providing research facilities and equipment. The study drug (hetrombopag) was supplied by Jiangsu Hengrui Pharmaceuticals Co., Ltd. This study was funded by the XINRUI Project for Tumor Translational Medicine Research (hx2416, M.Y.).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData supporting the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no financial or non-financial conflicts of interest in relation to the work described in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e- Approval of the research protocol by an Institutional Reviewer Board: The study protocol was approved by the Ethics Committee of Henan Cancer Hospital (approval number: 2022-214-012) and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;- Informed Consent: Written informed consent was obtained from all participants before enrollment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;- Registry and the Registration No. of the study/trial: This clinical trial was registered at clinicaltrial.gov (NCT05394285).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHuihui Sun and Huimin Lv contributed equally to this work. Min Yan, Huihui Sun, and Huimin Lv conceived and designed the study. Huihui Sun, Huimin Lv, Wenyan Chen, Yanxia Zhao, Mengwei Zhang, and Limin Niu collected and interpreted the data. Huihui Sun and Huimin Lv drafted the original draft. Min Yan supervised the study and critically revised the manuscript. All authors participated in the enrollment and management of patients. All authors had full access to the data, reviewed and edited the manuscript, and had final responsibility for the decision to submit for publication\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eYan D, Yang J, Gao Y, Zhang P, Zhang C, Cheng Y, Zhang X, Fan C, Wang K, Zhu S\u003cem\u003e\u0026nbsp;et al\u003c/em\u003e: \u003cstrong\u003eCombination of Thrombopoietin Receptor Agonist and Recombinant Human Thrombopoietin for Treating Cancer Therapy Induced Thrombopenia\u003c/strong\u003e. \u003cem\u003eBlood\u0026nbsp;\u003c/em\u003e2022, \u003cstrong\u003e140\u003c/strong\u003e(Supplement 1):8420-8421.\u003c/li\u003e\n \u003cli\u003eMei J, Jiao F, Li Y, Cui J, Yang H, Wang L: \u003cstrong\u003eApplication of thrombopoietic agents in cancer therapy-induced thrombocytopenia: A comprehensive review\u003c/strong\u003e. \u003cem\u003eBlood reviews\u0026nbsp;\u003c/em\u003e2025, \u003cstrong\u003e70\u003c/strong\u003e:101257.\u003c/li\u003e\n 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thrombocytopenia\u003c/strong\u003e. \u003cem\u003ePloS one\u0026nbsp;\u003c/em\u003e2022, \u003cstrong\u003e17\u003c/strong\u003e(6):e0257673.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Cancer therapy-induced thrombocytopenia, secondary prevention, breast cancer, hetrombopag, recombinant human thrombopoietin","lastPublishedDoi":"10.21203/rs.3.rs-8976504/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8976504/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Cancer therapy-induced thrombocytopenia (CTIT) is a common complication of anti-tumor therapy, leading to treatment delays or interruptions, increased bleeding risk and compromised outcomes. In the present study, we aimed to evaluate the efficacy and safety of hetrombopag, an oral thrombopoietin receptor agonist, for managing and preventing CTIT in patients with breast cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e In this multi-center, randomized phase II clinical trial (NCT05394285), breast cancer patients with platelet counts \u0026lt;50×10⁹/L during anti-tumor treatment (Cycle 1) were enrolled. Those patients were randomly assigned (1:1)to receive either hetrombopag or subcutaneous recombinant human thrombopoietin (rhTPO) until their platelet counts \u0026gt;100×10⁹/L, which was defined as the thrombocytopenia treatment phase (TTP). During the secondary prevention phase (SPP), all cases as self-control received hetrombopag for 14 days starting on day 1 of the subsequent anti-tumor treatment cycle (Cycle 2). The primary endpoint was the response rate of the SPP. Secondary endpoints comprised the response rate of TTP (key secondary endpoint), other platelet-related parameters, and safety outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Between September 2022 and May 2025, 67 patients with breast cancer were enrolled. After excluding one patient who withdrew informed consent, 66 patients were randomized. During the trial, 6 patients discontinued participation in the SPP, the remaining 60 patients constituted the per-protocol set (PPS). The majority of patients in the PPS (n=47) received antibody-drug conjugates (ADCs) treatment. For the primary endpoint, the response rate was 85.0% (51/60) in the PPS, and 89.4% (42/47) among patients receiving ADCs. Regarding the key secondary endpoint during the TTP, the response rates were 87.9% (29/33) in patients receiving hetrombopag and 81.8% (27/33) in those receiving rhTPO. No treatment-emergent severe adverse events were observed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eHetrombopag represents a promising and well-tolerated strategy for the secondary prevention and management of CTIT in breast cancer patients, particularly in patients received ADCs.\u003c/p\u003e","manuscriptTitle":"Secondary prevention of cancer therapy-induced thrombocytopenia with hetrombopag in breast cancer: a multicenter, randomized, exploratory phase II trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-19 07:57:29","doi":"10.21203/rs.3.rs-8976504/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"323117793420475885056974768260607977184","date":"2026-05-07T05:25:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-18T01:14:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"178132113274731457739366635815741564801","date":"2026-04-10T07:50:35+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-08T14:59:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-27T10:05:34+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-27T09:32:17+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Medicine","date":"2026-02-26T09:59:37+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b2b992b0-dc87-49f3-bf3a-b718e9a680ce","owner":[],"postedDate":"April 19th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"323117793420475885056974768260607977184","date":"2026-05-07T05:25:40+00:00","index":31,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-19T07:57:30+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-19 07:57:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8976504","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8976504","identity":"rs-8976504","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}