Cytotoxic chemotherapies have long been the cornerstone of cancer treatment (1). However, their effectiveness is constrained by a narrow therapeutic index, resulting in significant off-target toxicity due to non-specific drug distribution (2, 3). To overcome these limitations and improve clinical outcomes, molecularly targeted therapies—particularly antibody-drug conjugates (ADCs)—have emerged as a promising alternative.

ADCs combine the target specificity of monoclonal antibodies with the cytotoxic potency of chemotherapeutic agents, linked via a chemical linker. This design allows for the selective delivery of cytotoxic agents to tumor-specific antigens, thereby enhancing therapeutic efficacy while reducing systemic toxicity—advantages that conventional chemotherapy cannot offer (4). Several ADCs have received approval from the United States Food and Drug Administration (FDA) for the treatment of cancer (5, 6).

Among these, sacituzumab govitecan (SG) has demonstrated notable efficacy in breast, lung, urothelial, gastric, and other solid tumors (7–10). SG targets trophoblast cell-surface antigen 2 (Trop-2), a protein frequently overexpressed in aggressive tumors and associated with poor prognosis (10). It delivers SN-38, a potent topoisomerase I inhibitor, directly to Trop-2–expressing cancer cells, thereby minimizing damage to normal tissues (11, 12). SG was the first Trop-2–targeting ADC to receive regulatory approval. In April 2020, the FDA granted accelerated approval for SG in patients with metastatic triple-negative breast cancer who had received at least two prior systemic therapies, based on phase I/II trials demonstrating a high overall response rate (ORR) and durable clinical benefit (5, 13). A second accelerated approval followed in April 2021 for patients with locally advanced or metastatic urothelial carcinoma who had progressed after platinum-based chemotherapy and PD-1/PD-L1 inhibitor therapy (14). Despite these important milestones, SG’s clinical profile remains under evaluation. Some studies have reported higher incidences of grade ≥3 treatment-emergent adverse events (TEAEs) compared to conventional chemotherapy (15). Therefore, a thorough assessment of SG’s efficacy and safety is warranted. This study presents a meta-analysis of clinical trials evaluating SG across various solid tumors. Key outcomes include ORR, disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs), with the aim of providing evidence-based guidance to inform clinical decision-making.

ADCs are currently under investigation for their efficacy and safety in the treatment of solid tumors, both as monotherapy and in combination with other therapeutic agents. Among these, SG has shown particular promise, especially in BC and UC, where it has attracted considerable clinical interest (7, 9, 15, 19). Although SG has been evaluated across a broad spectrum of solid malignancies, several recent trials have reported variable outcomes, with some indicating limited therapeutic benefit (8, 9). These heterogeneous findings underscore the need to delineate the tumor types most likely to derive substantial benefit from SG. To address this, we conducted a comprehensive meta-analysis to evaluate the efficacy and safety of SG across multiple solid tumor types.

Our analysis, which included five RCTs comparing SG to standard chemotherapy across various malignancies, demonstrated significant improvements in OS, PFS and DCR. Subgroup analyses revealed that patients with BC derived the greatest clinical benefit, exhibiting both superior short-term response rates and enhanced long-term survival outcomes. In a previous meta-analysis, Qureshi et al. assessed the efficacy of SG in patients with HR+/HER2- advanced BC. Two studies were eligible for inclusion, and the results showed a significant improvement in PFS and DOR, although no significant difference in OS was observed between the SG and control groups (12). To further explore the therapeutic potential of SG across different malignancies, Sultana et al. evaluated its clinical efficacy in a range of solid tumors, including BC, UC, NSCLC, SCLC, colorectal cancer, pancreatic ductal adenocarcinoma, esophageal cancer, castration-resistant prostate cancer, endometrial cancer, and other epithelial malignancies. The pooled median PFS and OS were 4.9 months (95% CI: 4.0–5.8 months) and 9.6 months (95% CI: 7.6–11.6 months), respectively (27). However, only two of the ten studies included in their analysis were RCTs; the remainder comprised cohort studies and one real-world evidence report. While our meta-analysis incorporated only five studies, all were phase 3 RCTs with large sample size, enhancing the robustness and generalizability of our findings. This provides a higher level of evidence and may offer more definitive guidance for clinical decision-making regarding the use of SG in solid tumors.

Given the limited number of RCTs, relevant single-arm studies were also included to supplement the analysis. These studies further supported the observed trends, showing more favorable outcomes with SG in BC and UC compared to other tumor types. However, the inherent limitations of single-arm trials—such as the absence of a control group, small sample sizes, and susceptibility to various confounding factors—reduce their scientific rigor and confirmatory value relative to RCTs.

Although ADCs are generally perceived as less toxic than traditional chemotherapy, our meta-analysis revealed a higher incidence of AEs associated with SG. The most frequently reported AEs included neutropenia, leukopenia, diarrhea, and anemia. Subgroup analyses suggested differential toxicity profiles among tumor types. In particular, patients with BC appeared more prone to developing diarrhea, whereas those with UC exhibited a higher risk of neutropenia and lymphopenia, warranting heightened clinical vigilance in these populations. Notably, the TROPiCS-04 trial (9) reported 25 deaths in the SG treatment group, 16 of which were infection-related and occurred in the setting of neutropenia. Fourteen of these deaths occurred within the first month of treatment. All 16 patients had multiple risk factors that would typically warrant primary prophylaxis with granulocyte colony-stimulating factor (G-CSF), including age ≥65 years, prior anticancer therapies, and the presence of multiple comorbidities. Despite this, only two of these patients received primary G-CSF prophylaxis, while nine received it as treatment after neutropenia had developed. These findings underscore the critical importance of early neutrophil monitoring and proactive management of neutropenia during SG therapy, particularly in patients with identifiable risk factors. Efforts have also been made to identify high-risk populations for treatment-related AEs. Given the central role of uridine diphosphate-glucuronosyltransferase family 1 member A1 (UGT1A1) in the metabolism of SN-38, the active metabolite of SG, this enzyme has been the focus of considerable investigation. Several studies have reported that patients homozygous for the UGT1A128 allele experience a higher incidence of severe neutropenia compared to non-carriers (10, 13). The ASCENT trial further suggested the relevance of genotype-directed dosing, as treatment-related AEs were more frequent in patients with the UGT1A128/*28 genotype compared to heterozygous or wild-type individuals (7), indicating that UGT1A1 genotyping may help predict SG-related toxicities. However, a meta-analysis evaluating the association between SG toxicity and UGT1A1 genotype across 11 clinical studies involving various solid tumors found no significant difference in AEs between genotypes. This result may be attributable to the lack of genotype data in more than 50% of the included studies (28). Therefore, larger, well-designed, genotype-informed studies are necessary to clarify the clinical utility of UGT1A1 testing in predicting SG-related toxicities.

Given the limitations of SG monotherapy in certain tumor types, combination strategies are currently under investigation. These include regimens integrating SG with immune checkpoint inhibitors, other ADCs (28), and radiotherapy (29). The results of these ongoing large-scale trials are eagerly anticipated and may provide new avenues to enhance therapeutic efficacy and broaden the clinical applicability of SG.

This systematic review demonstrates that SG provides superior OS, PFS, and DCR compared to standard chemotherapy in patients with solid tumors. To address the limited availability of RCT data, relevant single-arm studies were also included to enhance clinical insight. The findings suggest that patients with BC and UC derive the most substantial benefit from SG treatment. However, the methodological limitations of single-arm trials—such as lack of a control group and potential bias—must be carefully considered when interpreting these results. Moreover, SG is associated with a higher incidence of TEAEs, highlighting the importance of vigilant toxicity monitoring and management. Further research, particularly well-designed, large-scale RCTs, is essential to more definitively establish the clinical efficacy and safety profile of SG across diverse tumor types.