Trodelvy® (sacituzumab govitecan-hziy)

Resistance

This document is in response to your request for information regarding resistance to Trodelvy® (sacituzumab govitecan-hziy [SG]).

Some data may be outside of the US FDA-approved Prescribing Information. In providing this data, Gilead Sciences, Inc. is not making any representation as to its clinical relevance or to the use of any Gilead product(s). For information about the approved conditions of use of any Gilead drug product, please consult the FDA approved prescribing information.

The full indication, important safety information, and boxed warnings are available at:
www.gilead.com/-/media/files/pdfs/medicines/oncology/trodelvy/trodelvy_pi.

Summary

Relevant Product Labeling1

There is no information regarding resistance to SG available in the SG US FDA-approved Prescribing Information.

SG is a trophoblast cell-surface antigen-2 (Trop-2)-directed antibody-drug conjugate (ADC). Sacituzumab is a humanized antibody that recognizes Trop-2. The small molecule, active metabolite of irinotecan (SN-38), is a topoisomerase I inhibitor, which is covalently attached to the antibody by a linker. Pharmacology data suggest that SG binds to Trop-2-expressing cancer cells and is internalized with the subsequent release of SN-38 via hydrolysis of the linker. SN-38 interacts with topoisomerase I and prevents re-ligation of topoisomerase I-induced single strand breaks. The resulting DNA damage leads to apoptosis and cell death. SG decreased tumor growth in mouse xenograft models of triple-negative breast cancer (TNBC).

Clinical Data

A study of genomic and transcriptomic analysis of tumor tissue from 3 patients with metastatic TNBC (mTNBC) who received SG demonstrated that resistance to SG was associated with parallel genomic alterations in both antibody and payload targets. An association was found between lowered Trop-2 expression and decreased cellular sensitivity to SG.2

Pre-Clinical Data

A study in mice evaluated the use of an adenosine triphosphate binding cassette subfamily G member 2 (ABCG2) inhibitor (YHO-13351) to overcome resistance to SN‑38 and to improve the efficacy of SG.3

• Administration of SG with YHO-13351 in mice with SN-38–resistant NCI‑N87-S120 tumors resulted in a 64% improvement in survival compared with no treatment (P=0.0278).

Background

SG is an ADC made from a humanized anti-Trop-2 monoclonal antibody (hRS7) conjugated with SN-38, a topoisomerase I inhibitor, the active metabolite of irinotecan via a hydrolysable linker (CL2A).2 Although SG has been studied in multiple tumor types, there are limited data available on resistance to SG, and the specific underlying mechanisms associated with this resistance have yet to be formally established.

A genomic and transcriptional analysis of mTNBC tumor tissue that revealed genomic alterations of TOP1 (encodes the SN-38 drug target topoisomerase I) and TACSTD2 (encodes Trop-2), a potential mechanism of acquired resistance, is summarized below.2 Preclinical animal data in cells with high expression levels of ABCG2 (the overexpression of which is another potential mechanism of acquired resistance) are also summarized below.3  

Clinical Data2

Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to SG in mTNBC

Study design

A genomic and transcriptomic analysis of tumor tissue from patients with mTNBC who were treated with SG was conducted to determine mechanisms of SG resistance. Three patients (MGH-18, MGH-19, and MGH-20) with available pretreatment and multisite post-progression specimens were included in this analysis. All patients had previously received SG after they experienced disease progression with ≥2 prior therapies for mTNBC. Trop-2 gene expression and genomic copy number were analyzed in pre- and post-treatment specimens. Whole‑exome sequencing for MGH-18 was performed on the pre-SG treatment and 9 post‑progression rapid autopsy tumor lesions.

Results

MGH-20 demonstrated evidence of disease progression at the first radiologic assessment, which led to drug discontinuation; MGH-19 exhibited stable disease for 5 months as per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; MGH-18 had a partial response, followed by multisite progressive disease. MGH-20 had no Trop-2 protein expression observed with immunohistochemistry, and RNA sequencing of tumor specimens showed nearly undetectable Trop-2 RNA expression. Both MGH-18 and MGH-19 had detectable Trop-2 RNA expression in all analyzed specimens.

Table 1. Trop-2 Expression and Response to SG2

The focus of this analysis was MGH-18, a 42-year-old female patient who was diagnosed with metastatic disease that spread to other organs within weeks of completion of standard preoperative chemotherapy for TNBC. The patient then underwent a mastectomy and received 2 investigational combinations in sequence but did not experience an objective response. Treatment with SG was initiated, and a partial response (45% tumor regression) as per RECIST 1.1 was observed for >8 months. After 8 months, restaging scans exposed disease progression at multiple sites, and the patient died.

Whole-exome sequencing discovered a truncal TP53 (K132R) mutation, which is commonly observed in triple-negative breast cancer (TNBC), in the pre‑sacituzumab govitecan-hziy primary tumor and all 9 post-progression lesions. Two major phylogenetic branches (TOP1 and TACSTD2) exhibited distinct mutations that were found at high frequencies in multiple, mutually exclusive metastatic lesions. E418K, a TOP1 missense mutation, was frequently present within abdominal lesions in the liver and periaortic lymph nodes. This mutation is established to induce resistance to clinical topoisomerase I inhibitors. This mutation was accompanied by a frameshift TOP1 mutation. T256R, a missense mutation of TACSTD2/Trop-2, was frequently present in thoracic metastatic lesions, including chest wall and hilar lymph node.

Complementary DNA that encoded either the wild-type or mutant Trop-2 were synthesized and reconstituted into multiple Trop-2‑negative–based models to determine the significance of the TACSTD2/Trop-2 mutation. It was found that TACSTD2/Trop‑2T256R encoded a stable protein that could be expressed in both TNBC (BT549) cells and non-transformed (NIH 3T3) cells, with both types of cells lacking endogenous Trop-2 expression. In TNBC cells that were reconstituted with the Trop-2 mutant, binding of hRS7 (the antibody component of SG), was reduced by >80% compared with wild-type Trop-2; similar results were observed in 3T3 cells.

Reconstitution of wild-type Trop-2 into Trop-2-negative TNBC and 3T3 cells resulted in significant increases in sensitivity to SG. There was no effect on SN-38 sensitivity in either TNBC or 3T3 cells when wild-type or mutant Trop-2 was reconstituted. Trop-2T256R had resistance to SG via altered plasma membrane localization and reduced cell-surface binding to the anti-Trop-2 antibody, hRS7. Mutant Trop-2 as compared with wild-type Trop‑2 was associated with decreased cellular sensitivity to SG, which indicated the role of Trop-2 as a response determinant in SG resistance.

This analysis highlighted the parallel genetic mechanisms of acquired resistance under selective pressure from SG.

Pre-Clinical Data3

Combining ABCG2 Inhibitors with SG, to Investigate Resistance to SN-38 in Pre-Clinical Models of Breast and Gastric Cancers

Study design

A study was performed in mice to evaluate the use of a known ABCG2 inhibitor (YHO‑13351) to overcome SN-38 resistance and to improve the efficacy of SG. NCI-N87, a human gastric cancer cell line was utilized to establish NCI‑N87‑S120, a cell line resistant to SN-38. Mice with NCI-N87-S120 were divided into six study groups: SG + YHO-13351, irinotecan + YHO-13351, SG monotherapy, irinotecan monotherapy, YHO-13351 monotherapy, or no treatment. Mice with NCI‑N87 served as a control to evaluate the efficacy of SG and irinotecan in NCI‑N87-S120 tumors. These mice were divided into three study groups: SG monotherapy, irinotecan monotherapy, or no treatment. Irinotecan 40 mg/kg was administered IV every other day for 5 doses. SG 0.5 mg was administered IV twice weekly for 4 weeks. YHO-13351 was coadministered at the start of irinotecan or SG therapy and 4 hours after therapy. Mice in the SG group received a third dose of YHO‑13351 twenty-four hours after therapy. YHO-13351 control mice received YHO‑13351 on the same schedule as when combined with irinotecan. Mice were euthanized and were classified as treatment failures when tumor size was >1 cm3.

Additional in vitro testing was performed with additional ABCG2 agents and additional lines of SN-38-resistant tumor cell lines. The detailed description of the in vitro tests performed, and their results can be located in the cited literature.

Results

In mice with NCI-N87 tumors, both SG and irinotecan treatment resulted in a >2-fold increase in survival compared with no treatment (P<0.0001). No significant increase in survival was observed in mice with NCI-N87-S120 tumors. Compared with no treatment, administration of SG with YHO-13351 in mice with SN-38–resistant NCI‑N87-S120 tumors resulted in a 64% improvement in survival (P=0.0278).

References

1. TRODELVY®, Gilead Sciences Inc. Trodelvy (sacituzumab govitecan-hziy) for injection, for intravenous use. U.S. Prescibing Information. Foster City, CA. Revised: 06/2022. 2022.
2. Coates JT, Sun S, Leshchiner I, et al. Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to Sacituzumab Govitecan in Triple-Negative Breast Cancer. Cancer Discov. 2021;11(10):2436-2445.
3. Chang CH, Wang Y, Zalath M, Liu D, Cardillo TM, Goldenberg DM. Combining ABCG2 Inhibitors with IMMU-132, an Anti-Trop-2 Antibody Conjugate of SN-38, Overcomes Resistance to SN-38 in Breast and Gastric Cancers. Mol Cancer Ther. 2016;15(8):1910-1919.

Product Label

For the full indication, important safety information, and Boxed Warning(s), please refer to the Trodelvy US Prescribing Information available at:
www.gilead.com/-/media/files/pdfs/medicines/oncology/trodelvy/trodelvy_pi.

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