Hetrombopag for the treatment of chemotherapy-induced thrombocytopenia in advanced solid tumors: A multicenter, randomized, double-blind, placebo-controlled phase III trial

Abstract Introduction: Chemotherapy-induced thrombocytopenia (CIT) is a common complication resulting from the myelosuppressive effects of cytotoxic regimens. It frequently necessitates dose reductions, treatment delays, or platelet transfusions, which could compromise the efficacy of anticancer therapy. However, no widely approved therapies are currently available to address this clinical gap. This phase III trial was designed to evaluate the efficacy and safety of hetrombopag, a potent oral thrombopoietin receptor agonist, in patients with CIT. Methods: This randomized, double-blind, placebo-controlled phase III study (ClinicalTrials.gov: NCT05864014) enrolled patients with malignancies experiencing ≥7-day chemotherapy delay due to thrombocytopenia (platelet count <75×10⁹/L) following platinum-based combination regimens. Eligible patients were randomly assigned 1:1:1 to Arm I (hetrombopag), Arm II (hetrombopag administered only prior to the initiation of the first chemotherapy cycle [C1], with subsequent switch to placebo) or the Control Arm (placebo). Stratification factors included baseline platelet count (≥50 vs <50×10⁹/L) and immune checkpoint inhibitor use. The starting dose of investigational medicinal product was 7.5 mg/day which could be titrated to a maximum of 15 mg/day. The primary endpoint was the proportion of treatment responders, defined as patients who: (1) achieved platelet recovery (≥100×10⁹/L) within 14 days; (2) completed C1 and maintained a platelet count ≥75×10⁹/L at C1 Day 21 (+4 days) without the use of platelet rescue therapy. Results: Between April 27, 2023, and March 3, 2025, a total of 337 patients underwent screening, of whom 213 were randomized to Arm I (n = 70), Arm II (n = 72), or the Control Arm (n = 71). The median age of enrolled patients was 61.0 years, and 79.3% of patients had a baseline platelet count of ≥50×10⁹/L. The most common tumor types were gastric cancer (36.2%) and colorectal cancer (46.9%). Most patients (88.1%) were undergoing front-line or adjuvant therapy at enrollment. The third-generation platinum-based regimen was administered to 88.3% of patients, while 20.9% received chemo-immunotherapy and 18.5% chemo-targeted regimens. For the primary endpoint, treatment response rates were 75.7% (53/70) in the Arm I, 48.6% (35/72) in the Arm II, and 39.4% (28/71) in the Control Arm, respectively. A statistically significant improvement in response rate was observed in Arm I compared with the Control Arm (+36.2 percentage points; 95% CI: 21.0 to 51.3; p<0.0001), whereas no clinically meaningful difference was observed between Arm II and the Control Arm (difference +9.0 percentage points; 95% CI -7.2 to 25.1; p=0.2757). Patients in Arm I sustained median platelet counts >100×10⁹/L at all post-chemotherapy visits; and the median platelet counts were 104.0×10⁹/L (Arms I), 67.5×10⁹/L (Arms II), and 66.0×10⁹/L (Control Arm), respectively at Cycle 2 Day 21 (C2D21). The median delay in initiating C2 was 1.5 days in Arm I, compared with 13.0 days in Arm II and 12.0 days in the Control Arm. Notably, increased patients in Arm I could complete two cycles (C1 and C2) without platelet-related treatment modifications or rescue therapy while maintaining a platelet count ≥75×10⁹/L at C2D21 (Arm I 62.9% [44/70] vs. Arm II 9.7% [7/72] vs. Control Arm: 5.6% [4/71]). Treatment-emergent adverse events occurred in 90.0% (Arm I), 91.5% (Arm II), and 92.9% (Control Arm) of patients, predominantly grade 1-2. Critically, no treatment-related adverse events of special interest including prespecified liver function abnormalities, thrombotic events, or World Health Organization (WHO) grade ≥2 bleeding were observed in hetrombopag-treated arms (Arms I and II). Conclusions: In patients with CIT from solid tumors, continuous hetrombopag administration throughout chemotherapy cycles maintained stable platelet counts and thereby facilitated on-schedule full-dose chemotherapy with a favorable safety profile, addressing an unmet clinical need and offering a viable oral strategy for CIT management.