Rationale:
In patients with metastatic breast cancer, fragments of tumor DNA called "circulating tumor DNA" or "ctDNA" can be detected in the blood. When the level of ctDNA increases, it often means that treatment is no longer effective and that the disease is likely to progress. Previous studies have shown that quickly changing hormone therapy as soon as a specific genetic anomaly (ESR1 mutation) is detected in the blood can improve outcomes for breast cancer patients. This monitoring also allows for earlier action against cells that are resistant to treatment. However, this mutation is only present in about 4 out of 10 women, which limits the use of this method to only some patients.
Unlike previous approaches that targeted only the ESR1 mutation, the TAILORswitch study will assess a change in treatment following an increase in ctDNA, even in the absence of mutation, and before any other signs of disease progression. This change will include a new oral hormone therapy (camizestrant) combined with a targeted treatment that has shown benefits in cases of resistance (abemaciclib). This approach aims to intervene earlier in order to prevent disease progression.
In summary, TAILORswitch explores a new way to personalize treatment, using more sensitive blood monitoring tools to improve quality of life and patient outcomes.
Objectives:
The primary objective of this trial is to demonstrate the efficacy of switching to camizestrant-abemaciclib combination therapy in patients with hormone-dependent metastatic breast cancer (ER+ HER2-) receiving targeted therapy combined with hormone therapy as first-line treatment, in cases where ctDNA levels increase without other signs of disease progression (clinical or radiological).
Secondary objectives include:
* The efficacy, safety, and tolerability of the treatment switch * The safety and feasibility of reducing the number of imaging exams in patients undergoing ctDNA monitoring every 3 months (optional substudy).
Trial Design:
TAILORswitch is a multi-step phase 3 randomized trial. Step 1 involves recruiting 370 patients with advanced or metastatic hormone-dependent breast cancer who are receiving CDK4/6 inhibitor and aromatase inhibitor therapy as their first treatment.
Optional: some patients included in Step 1 will be offered to participate in a sub-study to evaluate imaging follow-up de-escalation. These patients will be allocated in of the following groups:
* Group A: maintenance of standard imaging every 3 to 4 months. * Group B: reduction to imaging once per year at most, with a return to the standard frequency in case of clinical, radiological, biological, or ctDNA-based signs of progression.
Step 2 involves patients who are initially eligible and show an increase in ctDNA levels without radiological progression. These patients will be allocated to one of the following groups:
* Group experimental: switch to the combination of camizestrant + abemaciclib until progression. * Group control: continuation of standard treatment (AI + CDK4/6i) until progression.
The recruitment period is 30 months, with the aim of including 156 patients in Step 2. Each participant will be followed for 30 months after inclusion.
First written informed consent (ICF#1) prior to any trial specific procedures. When the participant is physically unable to give his written consent, an impartial witness, independent from the investigator and the sponsor, can confirm in signing the participant's consent;
Men or women ≥ 18 years of age;
Eastern Cooperative Oncology Group performance status of 0 or 1;
ER+ HER2- advanced (metastatic or locally advanced inoperable) breast adenocarcinoma (ER-positivity threshold: ≥10% tumor cells; HER2-negative tumour is defined as an immunohistochemical (IHC) score of 0 or 1+, or an IHC score of 2+ with negative in situ hybridization (ISH) (HER2/CEP17 ratio <2 or, for single probe assessment, HER2 copy number <4, according to the most recent available results), not amenable to resection or radiation therapy with curative intent;
Systemic antineoplastic therapy (except adjuvant therapies) received prior to AI and CDK4/6i;
Known leptomeningeal metastasis and/or brain metastasis;
Known contraindication to camizestrant and abemaciclib, per investigator assessment;
Prior exposure to camizestrant, other SERD or investigational endocrine therapy agents;
Parallel
Tumor assessment
Procedure/SurgeryTumor assessment by RECIST 1.1 performed every 2 months the first 6 months then every 3 months during the participant visit at the hospital.
Completion of Quality-of-life questionnaires
Other interventionCompletion of Quality-of-life questionnaires: EORTC QLQ-C30 and BR42
ECG
Procedure/Surgery12-lead ECG if allocated to arm D
Visual Acuity assessment
Procedure/SurgeryVisual acuity assessment if allocated to arm D and if indicated
Progression free survival
Progression free survival is defined as the time from randomization in step #2 until the date of objective disease progression per RECIST 1.1 as assessed by local investigator or death due to any cause, whichever occurs first.
Related to Step #1: assess the feasibility of imaging de-escalation
1. The number of imaging assessments per participants and per year will be reported in both arms (no imaging de-escalation: arm A or no imaging de-escalation: arm B). 2. Percentage of participants who followed the planned schedule of no more than one imaging assessment per year among participants enrolled in arm B.
Related to Step #1: To assess the safety of imaging de-escalation
1. Rates of randomized participants in Step #1 (arm A \& B) who experience a disease progression: * with no ctDNA detected prior to disease progression, * with visceral crisis (per investigator assessment), * with altered general condition (ECOG PS ≥2), * treated with chemotherapy as 2nd line of treatment, reported by randomization arm. 2. Rates of randomized participants in Step #1 (arm A \& B) - experiencing a venous thrombo-embolic event, adherent to the allocated imaging schedule, reported by randomization arm
Related to Step #2: Progression free survival by subgoups according to stratification factors
The median PFS as defined in the primary endpoint will be estimated using Kaplan-Meier method with its 95% CI for each sub-group of stratification.
Related to Step #2: Progression free survival 2
PFS2 is defined as the time from randomisation in step#2 to the earliest progression after the 1st progression, or death from any cause. PFS2 will be estimated using the Kaplan-Meier method in arms C and D and compared using the log-rank test.
Click on the lead sponsor to view all of their trials.
UNICANCER
Lead sponsor
AstraZeneca
Collaborator
Natera, Inc.
Collaborator
Institut du Cancer de Montpellier - Val d'Aurelle
Collaborator
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