Trial Outcomes & Findings for Trastuzumab Deruxtecan in First-line HER2-positive Locally Advanced/MBC Patients Resistant to Trastuzumab+Pertuzumab (NCT NCT05744375)

Trastuzumab Deruxtecan in First-line HER2-positive Locally Advanced/MBC Patients Resistant to Trastuzumab+Pertuzumab

Objective Response Rate (ORR) is defined as the rate of complete response (CR) plus partial response (PR) based on the investigator's assessment using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1., out of the patients who received at least 1 dose of treatment (efficacy population). Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an \>=30% decrease in the sum of the longest diameter of target lesions. The ORR will be reported, including a 95% Confidence Interval (CI) using the Clopper-Pearson method. A sensitivity analysis will be performed using the Intent to treat population (ITT) population.

Progression-Free Survival (PFS) is defined as the time from the date of enrollment to the date of disease progression, based on the investigator's assessment using RECIST version 1.1., or death from any cause, whichever occurs first. PFS data will be censored on the date of the last tumor assessment on study for patients who do not have objective tumor progression and who have not died due to any cause while on study. Additionally, patients who start a new anti-cancer therapy prior to documented progression disease (PD) will be censored at the date of the last tumor assessment prior to the start of the new therapy. PD is defined using RECIST, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. PFS analysis will be performed in the safety population. PFS will be assessed using the Kaplan-Meier method. The median event time and 95% CI will be estimated if reached.

Overall Survival (OS) is defined as the time from the date of enrollment to the date of death from any cause. OS data will be censored on the last date the patient is known to be alive. OS analysis will be performed in the safety population. OS will be assessed using the Kaplan-Meier method. The median event time and 95% CI will be estimated if reached.

Time to treatment response (TTR) is defined as the time from the date of enrollment to the date of first documentation of objective tumor response (CR or PR). TTR analysis will be performed in the efficacy population in patients with an Objective Response (OR). TTR will be assessed using the Kaplan-Meier method. The median event time and 95% CI will be estimated.

Duration of response (DoR) is defined as the time from the date of first documentation of objective tumor response (CR or PR) to the date of first documented progressive disease based on the investigator's assessment using RECIST version 1.1., or death from any cause, whichever occurs first. DoR will be censored on the date of the last tumor assessment on study for patients who do not have objective tumor progression and who have not died due to any cause while on study. Additionally, patients who start a new anti-cancer therapy prior to documented PD will be censored at the date of the last tumor assessment prior to the start of the new therapy. DoR analysis will be performed in the efficacy population in patients with an OR. DoR will be estimated using Kaplan-Meier methods. The median event time and 95% CI will be estimated if reached.

Safety assessments will be performed at baseline and during the study: Vital signs assessments (blood pressure, pulse and body temperature), measurement of left ventricular ejection fraction, triplicate 12-lead electrocardiogram, laboratory assessments (hemoglobin, White Blood Cell, Absolute Neutrophil Count, Lymphocytes, platelet count, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, total bilirubin, serum creatinine, creatinine clearance, sodium, potassium, total calcium, blood urea nitrogen (or urea), albumin, Troponin Test, Coagulation testing (International Normalized Ratio, activated partial thromboplastin time), pregnancy test , ophthalmologic assessments (visual acuity testing, slit lamp examination, fundoscopy), Viral serology. AEs will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The toxicity of study treatments will be evaluated in the safety population.

Change from baseline in the GHS and each scale of the EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30) will be presented at each scheduled time point for the GHS score and each of the functionals and symptoms scales from the QLQ-C30 questionnaires. Longitudinal analysis of scores will be performed using linear mixed models. QLQ-C30 is composed of both multi-item scales and single-item measures. These include 5 functional scales, 3 symptom scales, a global health status/QoL scale, and 6 single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high/healthy level of functioning, a high score for the global health status/QoL represents a high QoL, but a high score for a symptom scale/item represents a high level of symptomatology/problems.

Time to deterioration (TTD) in QoL is defined as the time from the date of enrollment to the date of first detection of a deterioration event. A deterioration event is defined as an increase of ≥ minimally important difference (MID) from baseline for the EORTC QLQ-C30 symptom scales and a decrease of ≥ MID from baseline for the EORTC QLQ-C30 functional scales and GHS scale. It will be assessed using the Kaplan-Meier. Method. The median event time and 95% CI for the median will be estimated if reached. TTD will be censored at the date of the last QoL assessment prior to the start of a new therapy.

PFS2 is defined as the time from the date of enrollment to the date of disease progression to the second line of therapy. PFS2 data will be censored on the last date in which the patient was known not to have tumor progression or death due to any cause within the second line of therapy. Additionally, patients who start a third line therapy prior to progression to the second line will be censored at the date of the start of the third line therapy. PFS2 will be performed in the safety population. PFS2 will be assessed using the Kaplan-Meier method. The median event time and 95% CI will be estimated if reached.

PFS3 is defined as the time from the date of enrollment to the date of disease progression to the third line of therapy. PFS2 data will be censored on the last date in which the patient was known not to have tumor progression or death due to any cause within the second line of therapy. Additionally, patients who start a third line therapy prior to progression to the second line will be censored at the date of the start of the third line therapy. PFS3 will be performed in the safety population. PFS3 will be assessed using the Kaplan-Meier method. The median event time and 95% CI will be estimated if reached.