Investigating Datopotamab Deruxtecan Plus Durvalumab Versus Datopotamab Deruxtecan in Patients With PDL1-negative Metastatic Triple-negative Breast Cancer

The aim of this study is to demonstrate the superiority of Datopotamab deruxtecan (Dato-DXd) plus Durvalumab (Durvalumab) relative to Dato-DXd alone in patients with PDL1-negative advanced or metastatic triple negative breast cancer (TNBC). This is also the primary endpoint of this study and effectivenss measured by progression-free survival. Dato-DXd is an antibody drug conjugate (ADC) that targets tumour-associated calcium signal transducer 2, TROP2, a transmembrane protein that is highly expressed in various epithelial tumors including breast cancer. Durvalumab is an immune checkpoint inhibitor and is expected to stimulate the patient's anti-tumour immune response by binding to PD-L1 and shifting the balance toward an anti-tumour response. The preclinical and clinical evidence have suggested synergistic activity between antibody drug conjugate and immune checkpoint inhibitor. This study will recruit 140 patients, aged 18 and over and consenting patients will be randomly placed into one of two treatment groups. One group will receive Datopotamab deruxtecan in combination with Durvalumab and the other groups will receive Datopotamab deruxtecan alone. Treatment will continue unless there is evidence of unacceptable toxicity, disease progression, or if the patient requests to stop the treatment or death. Safety and tolerability as well as progression free survival, overall survival, clinical benefit rate, duration of response and duration of clinical benefit and quality of life will be assessed. PD-L1 is part of a complex system of receptors and ligands that are involved in controlling T-cell activation. The PD-1 receptor (cluster of differentiation \[CD\]279) is expressed on the surface of activated T cells. It has 2 known ligands: programmed cell death ligand-1 (PD-L1; B7-H1; CD274) and programmed cell death ligand-2 (PD-L2; B7-DC; CD273). PD-L1/PD-L2 belong to a family of immune checkpoint proteins that act as coinhibitory factors, which can halt or limit the development of T cell response. When PD-L1 binds to PD-1, an inhibitory signal is transmitted into the T cell, which reduces cytokine production and suppresses T cell proliferation. Tumour cells exploit this immune checkpoint pathway as a mechanism to evade detection and inhibit immune response. Sites will perform local PD-L1 testing to confirm the PD-L1 status of potentially eligible patients. PD-L1 negativity in this trial will be defined as 22C3 Combined Positive Score (CPS) of less than 10. Durvalumab is a human mAb of the immunoglobulin G (IgG) 1 kappa subclass that blocks the interaction of PD-L1 (but not PD-L2) with PD-1 on T cells and CD80 (B7.1) on immune cells. The proposed mechanism of action for durvalumab is interference in the interaction of PD-L1 with PD-1 and CD80 (B7.1). The blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including those that may result in tumor elimination. In vitro studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on primary human T cells, resulting in restored interferon-gamma (IFN-γ)-induced proliferation. In vivo studies have shown that durvalumab inhibits tumor growth in xenograft models via a T cell-dependent mechanism. Based on these data, durvalumab is expected to stimulate the patient's antitumor immune response by binding to PD-L1 and shifting the balance toward an antitumor response. Durvalumab has been engineered to reduce antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Dato-DXd is an antibody drug conjugate that targets tumour-associated calcium signal transducer 2, TROP2, a transmembrane protein that is highly expressed in various epithelial tumours including breast cancer. TROP2 has several binding partners, including claudin 1, claudin 7, cyclin D1, protein kinase C, phosphatidylinositol 4,5-bisphosphate, and insulin-like growth factor 1. By binding to these targets, TROP2 affects tight junctions at the epithelial barrier and increases tumour proliferation, podosome formation, and Raf and NF-kappa activation and suppresses IGF-1R signaling \[21,22\]. Its expression correlates with aggressive tumour behaviour and has been used as a prognostic marker in several types of cancer. DNA topoisomerase I is an enzyme that acts by causing a transient break in 1 strand of DNA. This enables the unwinding of positive or negative supercoiled DNA through a hindered rotary system, thus allowing the separation of the double-helix strands. This activity is prominent during cell replication. Inhibition of DNA topoisomerase I can lead to cell apoptosis following multiple breaks in the cell DNA. DNA topoisomerase I has therefore been identified as a potential target for cancer treatment. In order to overcome the challenges of delivering cytostatics specifically into cancer cells, ADCs have been developed. ADCs are composed of an antibody, a linker, and a cytotoxic agent. ADCs are payload delivery systems that can target cells that express the preferred marker. The ADC specifically binds and is internalized into the target cells, and enzymatic processes release the drug into the cytoplasm. Dato-DXd binds to TROP2, is internalized, and undergoes enzymatic processing. Thereafter the DNA Dato-DXd binds to TROP2, and after further enzymatic processing, the DNA topoisomerase I inhibitor DXdis released, inhibits cell replication, and promotes cell apoptosis. The anti-TROP2 component, is a humanized IgG1 kappa monoclonal antibody. The released drug is a DNA topoisomerase I inhibitor derivative of exatecan. The monoclonal antibody is covalently conjugated to a drug-linker, which is composed of a cleavable maleimide tetrapeptide linker and the released drug. The tetrapeptide linker is designed to be stable in plasma to reduce systemic exposure to the released drug. In vitro studies indicate that Dato-DXd exhibits TROP2 expression-dependent cell growth inhibitory activity, and in vivo studies using a tumor-bearing mouse model indicate that administration of Dato-DXd results in the regression of TROP2-positive tumors. The biodistribution and antitumor activity of the ADC are expected to depend on the expression level of the target antigen in tumor tissue.Dato-DXd has been evaluated in multiple solid tumors ,including NSCLC, and TNBC, HR+/HER2- BC, and urothelial cancer have high expression of TROP2, 1,2 and the DNA topoisomerase I inhibitor, irinotecan, shows clinical efficacy in these indications 9,10. Dato-DXd has shown preliminary efficacy in the ongoing clinical studies. The screening period for the trial is 28 days. Following randomisation, patients must commence on trial treatment within 3 days. There are specific protocol mandated pre-randomisation eligibility criteria that needs to be fulfilled, which includes the below: 1. Assessing eligibility thoroughly using the protocol inclusion and exclusion criteria and obtaining informed consent. 2. Conducting local PD-L1 assessment and confirming PD-L1 negativity by 22C3 Combined Positive Score (CPS) of less than 10. 3. A representative formalin-fixed, paraffin embedded (FFPE) tumour specimen with the supporting report is required to enable the definitive diagnosis of TNBC, with adequate viable tumour cells in a tissue block. 4. Obtaining medical history and demographics. 5. Confirming ECOG performance status. 6. Completing limited physical exam (including clinical breast examination), vital sins and weight with height. 7. Haematology and Biochemistry bloods. 8. Urinalysis. 9. Pregnancy test. 10. Thyroid function test. 11. Coagulation and Virology test. 12. Yearly ophthalmologic assessment if done as routine standard of care. 13. CT tumour assessment (using RECIST v1.1). 14. Brain scan. 15. Collection of adverse events and concomitant medications. 16. Completion of QOL questionnaires. 17. Collection if research blood samples. Once the above assessments have satisfactorily completed, the sponsor team, CECM DIAMOND coordinating team will check the screening eCRF data against the protocol and confirm eligibility. Once this has been completed, site staff can then proceed to randomising the patient on the Interactive Response Technology (IRT) system. Both the site and pharmacy staff and the CECM coordination team will receive a confirmation of randomisation via email. Patients will be randomised in 1:1 rations to receive one of the two following treatment arms: 1. Dato-DXd (Dose 6mg/kg, IV) plus Durvalumab (1120 mg, IV) on Day 1 Q3W. 2. Dato-DXd (Dose 6mg/kg) on Day 1 Q3W. Randomisation will be stratified as a three-part stratification by the following: 1. Is de novo; or 2. has treatment-free interval of \< = 12 months or 3. has a treatment-free interval of \> 12 months Throughout the duration of the trial treatment, the below assessments will be performed (+/- 3 days) and associated data collected and reported on the eCRF: 1. ECOG performance status. 2. Limited physical exam (including clinical breast examination), vital sins and weight with height. 3. Haematology and Biochemistry bloods. 4. Pregnancy test. 5. Thyroid function test. 6. CT tumour assessment (using RECIST v1.1) every 9 weeks until disease progression. 6\. Yearly ophthalmologic assessment if done as routine standard of care. 7. Adverse events and concomitant medications. 8. QOL questionnaires. 9. Patient review for safety occurring only on day 14 from cycle 1 to 3, where information on adverse events on concomitant medications will be collected. During the safety visit, which occurs 90 days after the last dose (+/- 7 days), the below assessments will be performed and associated data collected and reported on the eCRF: 1. ECOG performance status. 2. Limited physical exam (including clinical breast examination), vital sins and weight with height. 3. Haematology and Biochemistry bloods. 4. Pregnancy test. 5. Thyroid function test. 6. Ophthalmologic assessment if done as routine standard of care. 7. Adverse events and concomitant medications. 8. QOL questionnaires. Upon disease progression, the below assessments will be performed and associated data collected and reported on the eCRF: 1. CT tumour assessment (using RECIST v1.1). 2. Adverse events and concomitant medications. 3. Optional fresh tumour biopsy. 4. Research blood samples. When a patient discontinues study treatment, they will be followed up for subsequent anti-cancer therapies, disease and survival status until death, loss to follow-up or withdrawal of consent (whichever comes first) All patients will be followed up for survival until 2 year post last patient treatment discontinuation. Each patient will be followed up at least every 6 months in the follow up period. If patient requests to be withdrawn from follow-up; this request must be documented in the source documents and signed by the investigator. If the patient withdraws from study treatment but not from follow-up, the study staff may use patient medical records to obtain information about subsequent anti-cancer therapies.