The DIAMOND study is being carried out to evaluate if Datopotamab deruxtecan (Dato-DX) in combination with Durvalumab is more effective than Dato-DXd alone in treating PDL1-negative advanced or metastatic triple negative breast cancer (TNBC). Globally, breast cancer is the most common malignancy in women and the second most common cancer overall. The term TNBC is used to define tumours that do not express oestrogen receptors, progesterone receptors and HER2 receptors. TNBC comprises 10 -15% of all breast cancers. It remains the subtype with poorest outcome and there is a significant need to develop new therapies for this group of patients especially. Moreover, the PDL1-negative tumour has demonstrated no benefit from standard 1st line treatment of chemotherapy plus immune checkpoint inhibitors.
Willing and able to provide written informed consent.
Ability to comply with the protocol.
Female ≥ 18 years of age.
Negative for ER with <10% of tumour cells positive for ER on IHC or IHC score (Allred) of ≤3.
Prior chemotherapy, immunotherapy (including durvalumab) or treatment with PARP inhibitors for advanced or metastatic breast cancer.
Prior treatment with immune checkpoint inhibitors (eg atezolizumab, pembrolizumab) or DNA topoisomerase I or TROP2- or HER2-targeting ADCs and TROP2 targeted therapy in the (neo)adjuvant setting within 6 months from the end of treatment and randomisation into this study.
Patients with prior allogeneic stem cell or solid organ transplantation.
Patients must not have a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent), or had oral or IV steroids for 14 days prior to the first dose of study drug; the use of intranasal, inhaled corticosteroids topical steroids, or local steroid injections, physiologic replacement doses of glucocorticoids (i.e. for adrenal insufficiency) and mineralocorticoids (e.g. fludrocortisone) or steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication is allowed.
Parallel
Datopotamab Deruxtecan (Dato-DXd)
DrugPatients will receive Dato-DXd 6.0mg/kg, which will be administered by infusion on day 1 of each 21-day cycle.
Durvalumab
DrugPatients will receive Durva 1120mg, which will be administered by infusion on day 1 of each 21-day cycle.
PFS is defined as the time from the date of randomisation to the date of first documented confirmed tumour progression (using RECIST 1.1) or death from any cause, whichever occurs first in all patients.
PFS is defined as the time from randomisation to disease progression or relapse (as assessed by the site radiologist and/or investigator, using RECIST, Version 1.1) or death on study from any cause (defined as death within 30 days of the last study treatment), whichever occurs first. For patients who have not died or experienced disease progression at the end of study, PFS will be censored on the last date the patient was known to be progression free.
OS is defined as the time from date of randomisation to the date of death due to any cause in all patients.
Overall survival is defined as the time from randomisation to death from any cause. All deaths will be included, whether they occur on study or following treatment discontinuation. For patients who have not died, overall survival will be censored at the date of last contact.
DoR is defined as the time from first documentation of CR or PR to confirmed disease progression using RECIST 1.1, or death on study from any cause, whichever occurs first, in patients with objective response.
CBR is defined as the percentage of patients who have achieved at least one CR or PR or met the SD criteria at least once after randomisation for a minimum interval of 24 weeks continuously (using RECIST 1.1).
Clinical Benefit rate is defined as number of patients with complete or partial response or stable disease maintained ≥24 weeks (as assessed by the site radiologist and/or investigator, using RECIST1.1) divided by the number of patients in the analysis. Patients without a post-baseline tumour assessment will be considered to have no clinical benefit. An estimate of the clinical benefit rate and 95% CIs (Blyth-Still-Casella; 21-22) will be calculated for each treatment arm. CIs for the difference in clinical benefit rate (Satner and Snell 1980; Berger and Boos 1994; 23-24) will be calculated. The relative risk (treatment:control) will be reported along with the associated 95% confidence interval. Statistical inference will be evaluated using Chi-square statistic; the Fisher's exact test may be used if the expected counts in some cells are small.
DoCB is calculated as time (in months) from randomisation to progression or death from any cause in patients with a clinical benefit.
For patients with an objective response, duration of objective response is defined as the time from initial complete or partial response to disease progression or death on study from any cause (defined as death within 30 days of the last study treatment), whichever occurs first. For patients with a clinical benefit (objective response or stable disease maintained ≥24 weeks), duration of clinical benefit is defined as the time from randomisation to disease progression or death on study from any cause (defined as death within 30 days of the last study treatment), whichever occurs first. Methods for handling censoring and for analysis are the same as those described for PFS.
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Queen Mary University of London
Lead sponsor
AstraZeneca
Collaborator
