Sacituzumab govitecan: a new hope for patients with pretreated extensive small-cell lung cancer (SCLC)—insights from the TROPiCS-03 trial

Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers and is associated with a poor prognosis (1). While immunotherapies and targeted therapies have transformed the treatment of non-small-cell lung cancer (NSCLC) (2,3), little progress has been made in the treatment of extensive SCLC over the past three decades, with platinum-etoposide regimens still remaining the cornerstone of treatment (4,5). Over the past few years, the addition of immune checkpoint inhibitors (ICIs) to first-line platinum-etoposide chemotherapy showed a modest but significant improvement in overall survival (OS) (6,7).

Despite SCLC’s initial strong response to chemotherapy, most patients experience relapse within six months. Second-line treatment is determined by the treatment-free interval (TFI) and the response to first-line platinum-based chemotherapy (4,5). Platinum-etoposide rechallenge is recommended for platinum-sensitive SCLC (TFI ≥3 months), as it yields a high objective response rate (ORR) of 49% and is associated with better clinical outcomes compared to alternative chemotherapy regimens (8). In contrast, for platinum-refractory (progression during platinum chemotherapy) or platinum-resistant disease (TFI <3 months), outcomes are poor, with second-line chemotherapy achieving a very low ORR of approximately 15% (5). Topotecan, a topoisomerase I inhibitor, remains one of the standard treatments in this setting, having demonstrated improved OS compared to best supportive care (9). However, its clinical use is often limited due to frequent and severe hematological toxicities, along with a modest clinical benefit (10). The anthracycline-based regimen cyclophosphamide-adriamycin-vincristine (CAV) showed similar efficacy to topotecan in a phase III randomized trial (11). In 2020, lurbinectedin demonstrated an ORR of 22.2% in second-line treatment of platinum-resistant SCLC (12), but its combination with doxorubicin failed to improve OS compared to topotecan (13). More recently, tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 and the cluster of differentiation 3 (CD3), demonstrated promising antitumor activity in phase I (14) and phase II (15) trials in patients with previously treated SCLC, leading to its Food and Drug Administration (FDA) approval. Nevertheless, several promising second-line strategies, including rovalpituzumab-tesirine (16) and nivolumab-ipilimumab (17), did not translate in phase III clinical trials significant improvement. This highlights the continued unmet need for more effective therapeutic options.

Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) targeting trophoblast cell surface antigen 2 (Trop-2). It comprises a humanized monoclonal antibody linked to 7-ethyl-10-hydroxy-camptothecin (SN-38), the active metabolite of the topoisomerase I inhibitor irinotecan. SG is currently used in the routine management of breast cancer but was recently assessed against docetaxel for pretreated advanced NSCLC, with disappointing results from the phase III EVOKE-01 trial (18). Trop-2 is expressed by SCLC cells, though typically at moderate or low levels (19). However, SG has a strong binding affinity, a high drug-to-antibody ratio, a pronounced bystander effect, and potent SN-38 activity (20). These features allow SG to target tumors even when Trop-2 expression is low. In a sub-analysis of the TROPHY-U-01 trial, SG showed significant antitumor activity in platinum-refractory urothelial cancer regardless of Trop-2 levels, supporting its use in tumors with low Trop-2 expression, such as SCLC (21).

The recently published phase II TROPiCS-03 trial investigated the efficacy and safety profile of SG as a second-line treatment in patients with previously treated extensive SCLC (22). This single-arm, open-label clinical trial demonstrated a highly promising ORR of 41.9% [95% confidence interval (CI): 27.0–57.9%]. Notably, in the subgroup of patients with platinum-resistant disease, the ORR remained noteworthy at 35% (95% CI: 15.4–59.2%). The median duration of response (DOR) was 4.70 months (95% CI: 3.52–6.70), while the disease control rate (DCR) reached an impressive 83.7% (95% CI: 69.3–93.2%). In terms of survival outcomes, the median progression-free survival (PFS) was 4.40 months (95% CI: 3.81–6.11) in the overall cohort. Stratified by platinum sensitivity, the median PFS was 4.98 months (95% CI: 4.07–7.43) in the platinum-sensitive group and 3.81 months (95% CI: 1.38–7.56) in the platinum-resistant group. The median OS was particularly encouraging, reaching 13.60 months (95% CI: 6.57–14.78) in the overall cohort. Among subgroups, the median OS was 14.70 months (95% CI: 7.72–NR) in platinum-sensitive patients and 6.57 months (95% CI: 4.73–17.71) in platinum-resistant patients. This highly compelling efficacy is comparable to the most promising drug in this indication to date, tarlatamab, and appears to surpass the efficacy of lurbinectedin and other historically used treatments (Table 1).

Certain limitations and nuances should be emphasized. First, the study’s selection criteria excluded patients with active central nervous system (CNS) metastasis, leading to the exclusion of 14/79 screened for eligibility. This limits the reported clinical efficacy, given the high incidence of CNS metastasis in SCLC patients. It is crucial that future phase III trials incorporate these patients to address the significant unmet need in this population, especially since the ASCENT trial demonstrated SG’s efficacy in brain metastases (23). Additionally, the impressive 41.9% ORR contrasts with a previous phase I study that reported an ORR of 17% with SG in extensive-stage SCLC (19). This discrepancy may in part be explained by differences in patient populations: the phase I trial included heavily pretreated patients, with 58% having received ≥2 prior lines of therapy, and only 9% having received prior ICI, compared to 100% in the TROPiCS-03 trial. Future ancillary studies may identify biomarkers that could help select the best candidates for SG treatment in SCLC patients. Indeed, exploratory biomarker analyses are ongoing within the TROPiCS-03 study, including the assessment of Trop-2 expression levels and the evaluation of tumor sensitivity to the topoisomerase inhibitor payload. These investigations aim to better understand the mechanisms of response and resistance to SG and to identify potential biomarkers that could optimize patient selection in SCLC. Safety concerns also arose, as 74.4% of patients experienced grade >2 adverse events, with neutropenia (44.2%) and diarrhea (9.3%) being the most common. This relatively high rate of grade >2 adverse events exceeds the 59.4% reported with tarlatamab in a comparable patient population (15), and is also higher than the 25.6% observed with the other anti-Trop-2 ADC, datopotamab deruxtecan, in previously treated NSCLC patients (24). These adverse events led to treatment interruptions in 69.8% of patients and dose reductions in 37.2%. Additionally, three patients (7%) died from sepsis, with one case linked to treatment-induced febrile neutropenia. While the safety profile requires further exploration, it may limit the broader application of SG in the frail population of extensive-stage SCLC patients.

Despite these limitations, and considering the trial design (phase II, open-label) and the small sample size (43 patients), SG demonstrates significant potential as a treatment for platinum-resistant SCLC, a refractory disease with a significant unmet medical need. SG is not the only ADC showing encouraging results; other molecules, such as ifinatamab deruxtecan, have also shown highly promising efficacy in early clinical trials (25). While no significant therapeutic advances have been made for pretreated SCLC over the recent decades, the advent of ADCs, along with tarlatamab, offers renewed hope for the treatment of extensive-stage SCLC. Randomized phase III trials are eagerly awaited. However, caution is warranted; many drugs have shown promising results in phase I/II trials for pretreated extensive SCLC but ultimately resulted in resounding failures in randomized phase III trials (13,16,17).

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Lung Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-216/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-216/coif). B.A. reports research grant from MSD avenir, and consulting fees or honoraria from Novartis, AstraZeneca, BMS, MSD, Astellas, and Sanofi. J.P.S. reports consultant or advisory role fees from Roche, MSD, BMS, Lilly, AstraZeneca, Daiichi-Sankyo, Mylan, Novartis, Pfizer, PFO, LeoPharma, and Gilead and Grant for MSD Avenir. J.C. reports personal fees from AZ, Daiichi-Sankyo, J&J/Janssen, MSD, Pfizer, Regeneron, Roche, Sanofi, and Takeda for participating to boards of experts for the development of cancer drugs. P.G. reports an academic grant from Sanofi and travel accommodation from Eisai. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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