Sacituzumab govitecan: another emerging treatment option for patients with relapsed small cell lung cancer

After years of stagnancy, the treatment paradigm for small cell lung cancer (SCLC) has shifted rapidly in recent years. In frontline, extensive-stage SCLC (ES-SCLC), the CASPIAN and IMpower133 studies established new standard-of-care (SOC) options of platinum-etoposide plus programmed cell death ligand 1 (PD-L1) immunotherapies based on modest overall survival (OS) benefit over chemotherapy alone (1,2). In treating relapsed ES-SCLC, after decades of topotecan as the only SOC option, both lurbinectedin and the delta-like-ligand 3 (DLL3) bi-specific T-cell engager tarlatamab have been approved in the United States (3,4). With respect to the latter, a recent update from the DeLLphi-304 trial reported tarlatamab has an OS benefit over the physician’s choice SOC in the relapsed setting (4-6).

Unlike non-SCLC (NSCLC), SCLC is not a disease driven by genomic alterations or oncogenes that can be treated with small molecule targeted therapies. Rather, it is characterized by almost universal loss of tumor suppressor genes TP53 and RB1—alterations not yet amenable to drug development (7). While genomically homogeneous, SCLC has rich transcriptional and proteomic diversity, which led to the establishment of four molecular subtypes—three based on dominant transcription factors (ASCL1, NEUROD1, and POU2F3) and a fourth subtype characterized by an inflammatory gene signature (8-10). Of note, YAP1 as a subtype-defining transcription factor was originally proposed, however, later patient-level protein expression data did not find YAP1 meaningfully present in SCLC, as YAP1 was expressed at low levels, primarily in combined SCLC and not exclusive of other subtypes (11,12). In addition, given the limitation of tissue availability in SCLC diagnoses, several groups have devised methylation-based molecular subtyping of SCLC based on liquid biopsies (13,14). Despite the advances, ES-SCLC remains an incurable, aggressive cancer with limited treatment options.

TROPiCS-03 (NCT03964727) study is a multicenter, open-label, phase 2 basket study of sacituzumab govitecan (SG) in solid tumors that included patients with ES-SCLC (15). SG is a trophoblast cell surface antigen 2 (TROP2)-directed antibody-drug conjugate (ADC) consisting of a humanized monoclonal antibody linked to SN-38, the active metabolite of the topoisomerase I inhibitor irinotecan. All patients within the ES-SCLC cohort in this study received current SOC first-line chemoimmunotherapy with disease progression. Active central nervous system (CNS) metastases or carcinomatous meningitis were excluded. However, patients with treated brain metastases with stable CNS disease for over 4 weeks before the first dose would be eligible (11.6% of patients in this cohort had brain metastasis). Among 43 patients, the overall response rate (ORR) assessed by investigators was 41.9% [95% confidence interval (CI): 27.0–57.9%], including 18 confirmed partial responses. The median duration of response (DOR), progression-free survival (PFS), and OS were 4.73 months (95% CI: 3.52–6.70), 4.40 months (95% CI: 3.81–6.11), and 13.60 months (95% CI: 6.57–14.78), respectively. Similar efficacy outcomes were observed in the blinded independent central review. Among patients with platinum-resistant disease [defined by chemotherapy-free interval (CTFI), less than 90 days, n=20], the investigator-assessed ORR was 35.0% (95% CI: 15.4–59.2%), while in those with platinum-sensitive disease (n=23), the ORR was slightly higher at 47.8% (95% CI: 26.8–69.4%). Most common treatment-emerging adverse events (TEAE) were diarrhea (76.7%), fatigue (60.5%), and neutropenia (55.8%). Overall, 26 patients (60.5%) experienced a grade greater than or equal to 3 treatment-related TEAE. Twenty-two patients (51.2%) experienced serious TEAEs, most common being febrile neutropenia (7.0%). Sixteen patients (37.2%) had dose reduction related to TEAEs, but there was no SG discontinuation due to TEAE.

The caveats of cross-trial comparisons notwithstanding, a few notable findings in this trial are worth highlighting. First, this is a true second-line study where all patients received first-line treatment with both chemotherapy and immunotherapy, which is different compared to other trials with tarlatamab and lurbinectedin in relapsed ES-SCLC settings (3,4). As the authors pointed out, the ORR observed with SG (41.9%) compares favorably to topotecan as historical control and is in line with that achieved with lurbinectedin and tarlatamab (15). Definitive comparative efficacy of SG can only be established through head-to-head randomized trials which are currently lacking. Common grade 3 TEAEs from SG are neutropenia and diarrhea, likely from the activity of topoisomerase 1 inhibitor payload, which are consistent with its known safety profile from breast cancer studies and manageable with established supportive measures. In comparison, tarlatamab also has around 60% of grade 3 TEAEs, albeit unique in its presentation of cytokine release syndrome and neurotoxicity that require close monitoring and additional healthcare staff education. As SG has been approved and used for some time for advanced breast cancer treatment, the side effect profile is manageable and well-known to oncologists, and it is a viable potential treatment option for relapsed ES-SCLC if it is sufficiently effective. Importantly, SG appears to be active regardless of platinum sensitivity status, as defined by CFTI greater than or less than 90 days in pre-specified sub-analyses. This could be a potential advantage over therapies like lurbinectedin, which appear more active in patients with longer CTFI (16). Lastly, the study did not report any potential biomarker analyses, although the authors pointed out exploratory biomarkers, including TROP2 expression levels and sensitivity of topoisomerase inhibitor payload, are ongoing.

The TROPiCs-3 trial is indicative of a broader treatment paradigm shift in SCLC—that is to target the surface antigens to deliver therapeutic agents. In addition to SG and the aforementioned tarlatamab, there are multiple other agents in development for SCLC target cell surface proteins. These include ADC or T-cell engager therapies targeting DLL3 (e.g., tarlatamab, obrixtamig, MK-6070), TROP2 [e.g., SG, datopotamab deruxtecan (Dato-Dxd)], B7-H3 (e.g., ifinatamab-deruxtecan, HS-20093, YL201), SEZ6 (e.g., ABBV-706). Several clinical trials with therapeutics targeting these cell surface antigens are ongoing (Figure 1) (4,17).

Figure 1 Cell surface antibody-targeting therapeutics in clinical trials.

Thus, while SG compares favorably in terms of ORR to established SOC options in the relapsed setting, such as lurbinectedin and tarlatamab, an increasingly crowded development landscape is likely to lead to a revision in the benchmark ORRs and clinical outcomes necessary to advance the standard of care. Further, as more treatment options become available to patients with relapsed ES-SCLC, identifying biomarkers for optimal treatment selection and sequence are of greater importance. As all-comers agents, the treatment landscape may only support a single ADC with topoisomerase inhibitor payload, but with better insight into those patients most likely to uniquely benefit from B7-H3, TROP2, etc. as their target, there could be a role for personalized application (or rational combinations, e.g., with T-cell engagers) of these agents.

Other clinical caveats may also prove critical in distinguishing among the crowded field of ADCs and other surface targeting agents, including activity among those with short CTFIs and the role of brain metastases. To the latter point, intracranial response is another area of importance for patients with SCLC, and there is a paucity of data on how available systemic agents may impact intracranial response. DeLLphi-300 phase I study of tarlatamab, which allowed patients with treated brain metastases to enroll, suggested potential intracranial efficacy given continued tumor shrinkage in brain metastases previously treated with radiation, and recent small real-world cohort demonstrated intracranial response to tarlatamab in patients with actively untreated brain metastases (18). It is unclear yet if lurbinectedin, SG, or other novel cell-surface targeting ADC therapies have significant intracranial activity. Clinical trials inclusive of patients with untreated brain metastases could provide a valuable opportunity to test this.

Predictive biomarkers for ADCs remain elusive. Taking trastuzumab deruxtecan (T-dxd) as the poster-child of ADCs, its efficacy has been seen across human epidermal growth factor receptor 2 (HER2) expression including HER2 immunohistochemistry (IHC) 1+ or even 0 (19). TROP2 IHC has not been found to be predictive of SG efficacy, however tumors with low TROP2 expression did have numerically lower PFS and OS (20). A more recent study using quantitative scoring of normalized membrane ratio of TROP2 demonstrated its potential as predictive biomarker for another TROP2 ADC Dato-Dxd (21). Intratumoral heterogeneity of all four molecular subtypes have been found in SCLC tumors and likely contribute to target heterogeneity and resistance to therapy (11). Data suggest higher expression levels of DLL3 and SEZ6 for example in neuroendocrine subtypes of SCLC (driven by ASCL1 and NEUROD1), CD276 (B7-H3) seems to be expressed across all subtypes including non-neuroendocrine subtypes, and TACSTD2 (TROP2) seems to have lowest relative expression (22,23). The mixed data, however, are not surprising that the target expression alone would not predict response to an ADC given its complex mechanism of action. Linker characteristics, membrane permeability, bystander effect, payload sensitivity, tumor microenvironment are additional factors likely play a role in its efficacy. A recent study showed T-dxd efficacy in HER2-low/negative breast cancer relies not on ADC internalization, but rather on extracellular payload release, inducing cytotoxicity and immunogenic cell death (24). We have also shown that increased SLFN11 expression predicts topoisomerase 1 inhibitor payload sensitivity in SG and T-dxd (25). Notably, the majority of ADCs being tested in SCLC use a topoisomerase I inhibitor payload, raising concern for cross-resistance among these therapies.

The results of TROPiCs-3 provide yet another reason for optimism among SCLC investigators and patients after so many years of disappointment. We will soon see how SG fares in a randomized, phase 3 study (NCT06801834), but simultaneously must anticipate a rapidly evolving first-line and relapsed SOC that will invariably lead to challenging cross-trial comparisons and must be complemented by better predictive biomarkers if we are to optimize selection from this growing repertoire of treatment options for patients with SCLC.

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-2025-514/prf

Funding: This study was supported by the NIH/NCI awards (Nos. R01-CA207295, U01-CA256780, and P50-CA070907), CPRIT Early Clinical Investigator Award, the Sabin Family Fellowship, the Neuroendocrine Tumor Research Foundation, the Rexanna Foundation for Fighting Lung Cancer, and generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Lung Cancer Moonshot Program (to C.M.G.). This study was also supported by the Lung Cancer Research Foundation (to B.Z. and C.M.G.).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-514/coif). B.Z. received consulting fees from Abderat therapeutics and Oncohost; and speaking fee from IDEOlogy health. C.M.G. received consulting fees from Abdera, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, G1, Jazz, Monte Rosa, OncoHost, and Roche/Genentech; and honoraria or speaking fees from ACHL, AstraZeneca, BeiGene, Daiichi Sankyo, IDEOlogy, IDR, MJH, OncLive, PeerView, PER, Targeted Healthcare, Catalyst, Kisoji, and STCube. The authors have no other 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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