Genomic and Transcriptomic Predictors of Sequential SG Sensitivity After T-DXd in ER+/HER2-Low Metastatic Breast Cancer

Whole Genome and Transcriptome Tumor Sequencing to Identify Predictors of Sensitivity to Sequential Sacituzumab Govitecan (SG) Following Trastuzumab Deruxtecan (T-DXd) Treatment in ER+/HER-2 Low Metastatic Breast Cancer

Advanced hormone positive (HR+), HER2 negative breast cancer continues to pose a challenge when patients have progressed on CDK4/6 inhibitor and endocrine therapy leaving limited treatment options. Antibody-drug conjugates (ADCs) such as sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd) have changed practice due to significant improvement in progression free survival (PFS) and overall survival (OS) seen in this disease setting. There is a genuine interest to use SG sequentially after T-DXd, however there is no current prospectively curated evidence to support this strategy. Though the epitope is different, the payload are both topoisomerase I inhibitors. Thus, evidence is needed of both clinical efficacy and identification of mechanisms of sensitivity and resistance to sequential ADCs in HER-2 low MBC.

It is hypothesized that performing whole genome and whole transcriptome sequencing in fresh tumour biopsies post progression of T-DXd and prior to SG in ER+/HER2 low metastatic breast cancer (MBC) will provide mechanistic insights into identifying biomarkers, and thus patients, sensitive to sequential SG.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Sacituzumab Govitecan

Detailed Description

This is a prospective single-centre Canadian study (BC Cancer Vancouver) enrolling ER+/HER2 low MBC with disease progression after at least one line of endocrine therapy in combination with a CDK 4/6 inhibitor and at least one line of chemotherapy which must include T-DXd as the immediate prior line of treatment in the advanced stage setting.

Patients will receive SG at an initial dose of 10 mg per kilogram intravenously on day 1 and 8 of 21 day cycles. Treatment will continue until evidence of progressive disease, significant toxicity in which patient and or physician wishes to discontinue treatment and/or patient or physician desire to discontinue treatment for any reason.

Tumor specimens will collected from biopsies between the time of informed consent and prior to first administration of SG. The pathology will be reviewed and nucleic acids extracted. Constitutional DNA representing normal cells will be extracted from peripheral blood. PCR-free DNA libraries and either strand-specific or ribo-depleted RNA libraries will be constructed. Following which whole genome sequencing and transcriptome sequencing will be performed.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Stephen Chia, MD; Phone Number: 2785 604-877-6000; Email: schia@bccancer.bc.ca

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z4E6
      • Recruiting
      • BC Cancer - Vancouver Center
      • Contact: Stephen Chia, MD; Phone Number: 2785 604-877-6000; Email: schia@bccancer.bc.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

Patients must meet all of the following inclusion criteria to be eligible for participation in this study:

1. Willing and able to provide signed informed consent approved by UBC/BC Cancer REB
2. Female or male patients, regardless of race and ethnic group, who are ≥18 years old at the time of informed consent
3. Patients with locally advanced or metastatic ER+/HER2 low (defined as IHC 1+ or 2+ but FISH or CISH negative by ratio as per ASCO/CAP guidelines) breast cancer. Patients with imaging confirmed inoperable locally advanced breast cancer for which treatment is palliative in intent are also permitted.
4. Prior treatment must have included prior endocrine based treatment in the metastatic setting in conjunction with a CDK4/6 inhibitor.
5. Prior treatment must include at least 1 line of chemotherapy which must include trastuzumab deruxtecan (T-DXd) as the immediate prior line of therapy prior to study enrollment
6. The tumour must be accessible to be able to safely perform image guided biopsies for WGS and WTS.
7. Negative serum pregnancy test at baseline for pre-menopausal patients (within 14 days prior to randomization) and agreement to use medically approved precautions to prevent pregnancy during the study and for 12 weeks following the last dose of SG
8. Patients can have measurable or non measurable (but assessable) disease by CT or MRI as per RECIST Version 1.1 criteria as evaluated locally. Tumor lesions situated in a previously irradiated area are considered measurable if unequivocal progression has been documented in such lesions since radiation.
9. ECOG PS 0-2
10. Life expectancy ≥ 3 months

11. Acceptable bone marrow and organ function defined by the following laboratory values:

    1. Absolute neutrophil count ≥1.0 x 109/L
    2. Platelets ≥100 x 109/L
    3. Hemoglobin ≥9.0 g/dL
    4. INR ≤1.5
    5. Serum creatinine clearance >50 mL/min
    6. In absence of liver metastases, direct bilirubin ≤1.5 x ULN, ALT and AST should be below ≤2.5 x ULN. If the patient has liver metastases, ALT and AST should be < 5.0 x ULN.
12. Controlled brain metastasis (as per clinical determination) is allowed in the study at least 4 weeks before treatment. (Controlled brain metastasis is defined as no longer symptomatic from brain metastasis or no longer requiring higher doses of corticosteroids (> 10 mg Dexamethasone per day) for CNS management. Anticonvulsants and stable corticosteroids dose can be included in the study).

Exclusion Criteria

Patients who meet any of the following exclusion criteria are not eligible to be enrolled in this study:

1. Patient is currently participating in any other type of medical research judged not to be scientifically or medically compatible with this study.
2. Patient has a known hypersensitivity to SG, irinotecan or its active metabolite SN-38.
3. Patients not available for follow up
4. Patients who are not willing to consider systemic treatment options
5. Tumor not accessible or not safe to perform biopsies
6. Patient has not had resolution of all acute toxic effects of prior anti-cancer therapy to CTCAE v. 5.0 grade ≤1 (except toxicities not considered a safety risk for the patient at investigators discretion: e.g. grade 2 peripheral neuropathy from prior chemotherapy that is stable).
7. Have an active second malignancy. Patients with a history of malignancy that has been completely treated, with no evidence of active cancer for 3 years prior to enrollment, or patients with surgically cured tumors with low risk of recurrence (e.g. non-melanoma skin cancer, histologically confirmed complete excision of carcinoma in situ, or similar) are allowed to enroll.
8. Have known active central nervous system (CNS) metastases. Patients with previously treated brain metastases may participate provided they have stable CNS disease (defined as no longer symptomatic from brain metastasis or no longer requires higher doses of corticosteroids (> 10 mg Dexamethasone per day) for CNS symptom management. Anticonvulsants and stable corticosteroids dose can be included in the study). Screening for brain metastasis not required for enrollment.
9. Pregnancy and breast feeding
10. Patient without an adequate hematologic, renal and hepatic function as per above inclusion criteria
11. Patient has a pre-existing condition with uncontrolled diarrhea, chronic inflammatory bowel disease or GI perforation within 6 months prior to enrollment.
12. Have active serious infection requiring antibiotics.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sacituzumab Govitecan; Patients will receive SG at an initial dose of 10 mg per kilogram intravenously on day 1 and 8 of 21 day cycles.	Drug: Sacituzumab Govitecan; Administer Sacituzumab Govitecan (SG) at 10 mg/kg as an intravenous (IV) infusion on Days 1 and 8 of a 21-day cycle. SG should not be administered as an IV push or bolus.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Altered Tumor Genes by PFS Duration on SG Post T-DXd	Number and identification of altered/mutated genes in the tumors in the subgroup of patients with a longer PFS on SG post T-DXd compared to the tumors in the subgroup of patients with a shorter PFS on SG post T-DXd.	Up to an average of 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS)	Progression free survival (PFS) of SG post T-DXd in ER+/HER2 low MBC as measured by RECIST criteria	Up to an average of 6 months
Response rate (RR)	Response rate (RR) of SG post T-DXd as measured by RECIST 1.1 criteria	Up to an average of 6 months
Grade 2-4 toxicities	Number of Participants with the CTCAE version 5 grade 2-4 toxicities reported in SG post T-DXd in ER+/HER2 low MBC	Up to an average of 3 months
Overall survival	Overall survival of SG post T-DXd	Up to an average of 12 months
Trop-2 expression and HER-2 expression	Trop-2 expression and HER-2 expression by IHC in the metastatic biopsy and correlation with PFS and RR	Up to an average of 12 months
Dose intensity	Dose intensity (with and without growth factor support) of SG delivered post T-DXd in ER+/HER2 low MBC	Up to an average of 3 months

Collaborators and Investigators

• Sponsor: British Columbia Cancer Agency
• Collaborators: Gilead Sciences

Publications and helpful links

General Publications

• Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
• Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690. Epub 2022 Jun 5.
• Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, Brufsky A, Sardesai SD, Kalinsky K, Zelnak AB, Weaver R, Traina T, Dalenc F, Aftimos P, Lynce F, Diab S, Cortes J, O'Shaughnessy J, Dieras V, Ferrario C, Schmid P, Carey LA, Gianni L, Piccart MJ, Loibl S, Goldenberg DM, Hong Q, Olivo MS, Itri LM, Rugo HS; ASCENT Clinical Trial Investigators. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021 Apr 22;384(16):1529-1541. doi: 10.1056/NEJMoa2028485.

Helpful Links

• Jones, S.J., Laskin, J., Li, Y.Y. et al. Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors. Genome Biol 11, R82 (2010).
• Pleasance E, Titmuss E, Williamson L et al. Pan-cancer analysis of advanced patient tumors reveals interactions between therapy and genomic landscapes.

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2025
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: October 18, 2024
• First Submitted That Met QC Criteria: October 28, 2024
• First Posted (Actual): October 30, 2024

Study Record Updates

• Last Update Posted (Estimated): June 25, 2025
• Last Update Submitted That Met QC Criteria: June 19, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Immunologic Factors; Physiological Effects of Drugs; Immunoconjugates; Sacituzumab govitecan
• Other Study ID Numbers: SG6822

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No