The role of sacituzumab govitecan in hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer

Antibody-drug conjugates (ADCs) represent a major new subclass of antibody related therapeutics in oncology. ADCs combine the cancer-targeting abilities of monoclonal antibodies with the delivery of highly cytotoxic drugs into tumor as a targeted chemotherapy (1). There are currently 3 ADCs approved for the treatment of breast cancer (BC); 2 of them: trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) for human epidermal growth factor receptor 2 (HER2) positive BC; and most recently sacituzumab govitecan (SG) for triple negative breast cancer (TNBC) (2,3).

SG is a new ADC directed against the trophoblast cell-surface antigen 2 (Trop-2) (4). Trop-2 is a transmembrane calcium signal transducer highly expressed in solid tumors, especially hormone receptor (HR)⁺/HER2^– and TNBC. Upon ligation, the ADC is internalized via endocytosis which allows for the targeted delivery of its payload SN-38 into the tumor cells. This process allows SG to kill tumor cells expressing Trop-2 and also the adjacent tumor cells (5,6). Zhu et al. suggested that the expression level of Trop-2 differs among cell lines, independent of their subtype, and is highly variable on treatment with kinase inhibitors, tamoxifen, radiation and chemotherapy agents including irinotecan. BC with acquired resistance to tamoxifen exhibit higher levels of Trop-2, possibly via transcription factor EB (TFEB) (7).

Based on this mechanism, it would be expected that the targeted antigen needs to be overexpressed to permit antitumor activity, nonetheless, further observations challenged this paradigm, suggesting a more complex picture for ADC predictive biomarkers (8). In fact, in the case of T-Dxd, HER2 mutations could be more reliable than HER2 expression itself, possibly because of increased binding and internalization of ADCs conferred by HER2 mutations (9).

In 2020, SG received accelerated approval in TNBC after promising results were presented by Bardia et al. (10). More recently, Rugo et al. reported the results of the TROPiCS-02 phase III study assessing SG as compared to single-agent chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with endocrine-resistant, HR⁺/HER2⁻ locally recurrent inoperable or metastatic BC, and previously treated with 2–4 systemic chemotherapy regimens.

A total of 543 patients were enrolled and randomly assigned to the SG group (272 patients) or chemotherapy group (271 patients); 26 patients were randomized but not treated. The primary end point of progression free survival (PFS) was met with a 34% reduction in risk of progression or death in favor of the SG group [hazard ratio (HR) =0.66; 95% CI: 0.53–0.83; P=0.003]. PFS was 5.5 months for the SG group and 4.0 months for the single-agent chemotherapy. However, the difference in overall survival (OS) was not significant; 13.9 months for SG and 12.3 months for chemotherapy (HR for death, 0.84; 95% CI: 0.67–1.06; P=0.14); so due to the hierarchical statistical design, objective response and quality of life end points were not formally tested. The incidence of key grade ≥3 treatment-related adverse events (SG vs. chemotherapy) were neutropenia (51% vs. 38%), diarrhea (9% vs. 1%), anemia (6% vs. 3%) and fatigue (6% vs. 2%) (11). More recently, Rugo et al. presented the planned second interim analysis of OS from the TROPiCS-02 study in The European Society for Medical Oncology (ESMO) 2022. The results showed that SG significantly improved OS (14.4 vs. 11.2; P=0.020) when compared to chemotherapy (12). We await the reporting on the types of treatments administered post progression.

These data demonstrated that SG is an acceptable treatment option for patients with heavily pretreated, endocrine-resistant HR⁺/HER2⁻ advanced BC. Because of this, the Food and Drug Administration granted a priority review to SG for this type of BC in October 2022 (13).

Strengths of TROPiCS-02 include the relevance of the research question, addressing an area of unmet need in the management of metastatic HR⁺/HER2⁻ BC. Another important strength is that the trial included a contemporary cohort of patients who nearly all had prior therapy with CDK 4/6 inhibitors, making the interpretation of the results very applicable to the management of our current patients. Although OS was not statistically significant between the groups, this represented the first planned interim analysis, and further follow-up was required.

The results of TROPiCS-02 need to be considered along with the results from the recently reported DESTINY-Breast 04, a clinical trial that evaluated T-DXd in pre-treated HER2-low metastatic BC, given that TROPiCS-02 population overlaps with the one in DESTINY-Breast 04. However, DESTINY-Breast 04 included less heavily pre-treated patients with a median number of 1 line of prior chemotherapy in the metastatic setting, as compared with 3 in TROPiCS-02. Nonetheless both trials provide strong evidence supporting that ADCs significantly improve outcomes in patients with metastatic HR⁺ BC in populations that overlap but are not identical, namely DESTINY-Breast 04 included only patients with HER2 low disease. However, a large number of patients we see in clinic will fit criteria for both trials. A key question for patients that fit criteria for both ADCs is which agent to use first and how to sequence them. Although the target for both antibodies is different (Trop-2 for SG and HER2 for T-DXd), both payloads are topoisomerase I inhibitors. Additional research is necessary to understand the best sequence for using these ADCs, hopefully from a randomized clinical trial that compares them head to head. In understanding this sequence, it will be critical to collect data on the efficacy of these ADCs after progression to a prior ADC.

Additional questions from TROPiCS-02 include whether and by how much the efficacy of SG may depend on the bystander effect. It is possible that SG can exert this given that SN-38 is a membrane-permeable free molecule that gets released in the tumor microenvironment, however additional data supporting this hypothesis is required. Given the efficacy of SG independent from the TROP2 expression, further studies on the mechanism of action (and resistance) to this drug are needed and would be helpful to inform patient selection. Currently, there are different clinical trials evaluating the use of SG in HR⁺ BC. One of them (NCT04639986) will study the efficacy of SG in HR⁺/HER2⁻ metastatic BC in the Asian population. Two other ongoing trials, SASCIA (NCT04595565) and COGNITION-GUIDE (NCT05332561), will evaluate SG after neoadjuvant therapy, in non-metastatic BC (14-16). These studies will provide further insights on the efficacy and biomarkers of response to SG in this type of BC.

This could also represent a promising path for the future development of ADCs focusing on the creation of combinations to exploit the tumor microenvironment (3). Nowadays, different assays on the characterization of other types of anti-trop monoclonal antibodies are also under development for the detection of TROP2 in a wide variety of BC types (17,18) and may help refine the predictive value for drugs like SG.

Other points to consider about the TROPiCS-02 trial include that in the chemotherapy group, the distribution was not homogeneous among the different treatment options, as 48% received eribulin, 23% vinorelbine, 21% gemcitabine, and only 8% capecitabine. Given the known superiority of eribulin when compared with other agents in third line and beyond (19), the heterogeneity of the control group in TROPiCS-02 prevents us from being able to draw conclusions about the comparative efficacy between SG and eribulin, which remains an important question. In addition, at the data cutoff date, only 7% of patients from the SG and 1.5% from the chemotherapy group remained on the study, as most of the patients discontinued study treatment because of disease progression (77% and 73% respectively). Despite the efficacy seen with SG, unfortunately the chances of progression are still very similar and high in both groups.

TROPiCS-02 provides key data on the efficacy of SG in HR⁺ BC, and adds to the known efficacy profile of SG in TNBC. It is encouraging to see the efficacy of a new class of anti-cancer agents—the ADCs, and in particular with SG in TROPiCS-02, within different subgroups of BC.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5266/coif). JPL has received research funding from Kazia therapeutics and consulting fees from Minerva Biotechnologies. 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.

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/.

References

1. Breast Cancer Group, Branch of Oncologist, Chinese Medical Doctor Association. International Medical Exchange Society. Chinese expert consensus of antibody-drug conjugate toxicity management for breast cancer. Zhonghua Zhong Liu Za Zhi 2022;44:913-27. [PubMed]
2. de Lartigue J. Next-Generation Antibody-Drug Conjugates Make Their Mark in Breast Cancer. OncLive 2022;23.
3. de Nonneville A, Goncalves A, Mamessier E, et al. Sacituzumab govitecan in triple-negative breast cancer. Ann Transl Med 2022;10:647. [Crossref] [PubMed]
4. Furlanetto J, Marmé F, Loibl S. Sacituzumab govitecan: past, present and future of a new antibody-drug conjugate and future horizon. Future Oncol 2022;18:3199-215. [Crossref] [PubMed]
5. Vidula N, Yau C, Rugo HS. Trop2 gene expression (Trop2e) in primary breast cancer (BC): Correlations with clinical and tumor characteristics. J Clin Oncol 2017;35:abstr 1075.
6. Aslan M, Hsu EC, Garcia-Marques FJ, et al. Oncogene-mediated metabolic gene signature predicts breast cancer outcome. NPJ Breast Cancer 2021;7:141. [Crossref] [PubMed]
7. Zhu J, Wu W, Togashi Y, et al. Alteration of Trop-2 expression in breast cancer cells by clinically used therapeutic agents and acquired tamoxifen resistance. Breast Cancer 2022;29:1076-87. [Crossref] [PubMed]
8. Tarantino P, Carmagnani Pestana R, Corti C, et al. Antibody-drug conjugates: Smart chemotherapy delivery across tumor histologies. CA Cancer J Clin 2022;72:165-82. [Crossref] [PubMed]
9. Li BT, Michelini F, Misale S, et al. HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers. Cancer Discov 2020;10:674-87. [Crossref] [PubMed]
10. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. N Engl J Med 2019;380:741-51. [Crossref] [PubMed]
11. Rugo HS, Bardia A, Marmé F, et al. Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol 2022;40:3365-76. [Crossref] [PubMed]
12. Rugo HS, Bardia A, Marmé F, et al. LBA76 Overall survival (OS) results from the phase III TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician's choice (TPC) in patients (pts) with HR+/HER2- metastatic breast cancer (mBC). Ann Oncol 2022;33:abstr S1386.
13. Gilead Sciences. U.S. FDA Accepts for Priority Review the Supplemental Biologics License Application for Gilead’s Trodelvy® for Pre-Treated HR+/HER2- Metastatic Breast Cancer. 2022. Available online: https://www.gilead.com/news-and-press/press-room/press-releases/2022/10/us-fda-accepts-for-priority-review-the-supplemental-biologics-license-application-for-gileads-trodelvy-for-pretreated-hrher2-metastatic-breast
14. Asian Study of Sacituzumab Govitecan (IMMU-132) in HR+/HER2- MBC. Available online: https://ClinicalTrials.gov/show/NCT04639986
15. Genomics Guided Targeted Post-neoadjuvant Therapy in Patients With Early Breast Cancer (COGNITION-GUIDE). Available online: https://ClinicalTrials.gov/show/NCT05332561
16. Sacituzumab Govitecan in Primary HER2-negative Breast Cancer. Available online: https://ClinicalTrials.gov/show/NCT04595565
17. Sayama Y, Kaneko MK, Kato Y. Development and characterization of TrMab 6, a novel anti TROP2 monoclonal antibody for antigen detection in breast cancer. Mol Med Rep 2021;23:92. [Crossref] [PubMed]
18. Sayama Y, Kaneko MK, Takei J, et al. Establishment of a novel anti-TROP2 monoclonal antibody TrMab-29 for immunohistochemical analysis. Biochem Biophys Rep 2021;25:100902. [Crossref] [PubMed]
19. Cortes J, O'Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 2011;377:914-23. [Crossref] [PubMed]