Rising ctDNA to Tailor Endocrine Therapy Switch in Patients With ER+/HER2- Metastatic Breast Cancer.

Traditional ctDNA detection has relied on identifying one or more point mutations using targeted methods such as digital droplet polymerase chain reaction (ddPCR) or small next generation sequencing (NGS) panels covering a limited set of genes. These approaches typically offer a sensitivity of no more than 1-0.1% (roughly one mutated DNA molecule among 100 to 1,000). Large studies across multiple tumor types have shown a consistent kinetic pattern: at treatment initiation, ctDNA is detectable in about 80-90% of participants with metastatic disease. In responders, ctDNA levels drop quickly and often become undetectable within weeks or months. As progression approaches, ctDNA re-emerges several weeks or months before clinical progression.

In participants receiving first line therapy for ER+ HER2- metastatic breast cancer, a quantitative increase in ctDNA (rising ctDNA) serves as a dual-purpose biomarker: (i) predictive indicating that the current treatment is no longer effective and (ii) prognostic since ctDNA detection is a known prognostic factor for overall survival (OS). In other words, participants with rising ctDNA are about to experience a disease progression and they also correspond to a subgroup with worse outcome.

PADA-1 was the first trial to investigate a "watch and switch" design. It showed that switching from an aromatase inhibitor (AI) to fulvestrant while maintaining the same CDK4/6 inhibitor (CDK4/6i) showed a significant clinical benefit in metastatic breast cancers (mBC) participants harboring an ESR1 mutation (ESR1mut) detectable in their blood, compared to those remaining on AI plus CDK4/6i (Bidard, Lancet Oncol 2022). A global phase 3 trial, SERENA-6, with a similar design but offering ESR1mut mBC participants to switch AI to camizestrant (a novel oral selective estrogen receptor down regulator [SERD]) rather than fulvestrant (with an unchanged CDK4/6i) has also shown improved participants' outcomes and quality of life.

CtDNA-based monitoring is seen as promising for participants, as it allows (i) transitioning softly from one endocrine therapy regimen to another; (ii) avoiding a tumor progression event, which can have a detrimental impact on the participant quality of life; (iii) the potential for higher efficacy against resistant clones when targeted early.

PADA-1 and SERENA-6 support the use of serial monitoring of ESR1mut in ctDNA of participants treated with AI and CDK4/6i, in order to detect and tackle ESR1mut early. The clinical benefit associated with the ctDNA monitoring strategy is attractive yet only 40% of monitored participants will eventually develop a rising ESR1mut.

The overall concept of TAILORswitch is to demonstrate that the benefit of ctDNA monitoring goes beyond the clinical scenario explored by PADA-1 and SERENA-6. Indeed, the approach explored in this academic and non-registrational trial, is supported by:

(i) The broad clinical activity of camizestrant, an oral ngSERD which demonstrated its efficacy in all participants with endocrine-resistant ER+/HER2- mBC (with and without ESR1mut).

(ii) Technical evolutions of ctDNA detection assays ctDNA detection techniques can intercept molecular progression at very low variant allelic frequency, before ESR1mut could be reliably detected. For details, refer to synopsis section D and protocol section 1.2.2.

(iii) Recent results of post-Monarch & Ember-3 phase 3 trials, showing that CDK4/6i switch from ribociclib or palbociclib to abemaciclib could also bring a clinical benefit to participants, independently of ESR1mut status. While post-Monarch & Ember-3 were conducted in the second line setting after disease progression, TAILORswitch will include this switch of CDK4/6i before tumor progression.

(iv) The potential of ctDNA monitoring to de-escalate serial tumor imaging (in Step 1, before randomization #1), which could make the strategy even more attractive by decreasing the need of serial imaging in participants treated by standard of care AI + CDK4/6i (secondary objective).

Inclusion criteria

Related to Step #1

• 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;
• Eligible to (per investigator assessment) or currently receiving for up to 3 years, AI (+/- LH-RH agonist) and CDK4/6i (palbociclib or ribociclib) as first line therapy with adequate cardiac, renal, hematological and hepatic functions per investigator assessment;
• Evaluable disease (RECIST v1.1) before the start of AI+CDK4/6i and, in participants currently receiving AI and CDK4/6i, no evidence of clinical or radiological progression since AI+CDK4/6i initiation;
• Must have an adequate archival tumor tissue sample available (with a cellularity > 30%) for centralized WGS analysis to design the ctDNA test. Requirements:
• Pre/perimenopausal women and fertile men must agree to use adequate contraception methods during the study:

• Female participants must be using highly effective standard-of-care non-hormonal contraceptive measures from the time of screening until 3 weeks after exiting from Step #1 (a highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly); or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: (a) Post-menopausal, defined as women with: (i) Cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; (ii) Cessation of regular menses for at least 6 consecutive months with no alternative pathological or physiological cause AND with serum estradiol and follicle stimulating hormone level within the laboratory's reference range for post-menopausal females; (iii) Previous bilateral surgical oophorectomy.
• Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception until at least one week after the last treatment administration.
• Women of childbearing potential must have a negative serum or urine pregnancy test done within 28 days before inclusion;
• Minimum life expectancy of at least 6 months;
• Participants must be willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan and other study procedures including follow-up;
• Participants must be affiliated with a social security scheme or a beneficiary of such a scheme (or equivalent);

Additional criteria to be part of the imaging de-escalation sub-study in Step #1:

• Additional written informed consent (ICF#2). 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;
• Participants must have received at least 6 months (from 22 weeks authorized) of treatment with AI + CDK4/6 inhibitor, with no evidence of ctDNA rising in STEP #1 (at the current visit or, if current results are pending, at the previous visit), and no disease progression on imaging at the current visit as per RECIST v1.1.
• ctDNA detected at study entry and no rising ctDNA;
• No history of venous thrombo-embolic event, interstitial lung disease or any pre-existing condition that may impair participant's respiratory function (per investigator assessment);
• Willingness and ability to comply with scheduled visits;

Related to Step #2:

• Additional written informed consent (ICF#3). 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;
• Rising ctDNA (as defined in the protocol) detected during Step #1 (centrally determined);
• Having received at least 6 months of AI + CDK4/6i;
• Adequate bone marrow reserve and organ function as follows:

• Hemoglobin ≥9.0g/dL (90 g/L).
• Absolute neutrophil count ≥1000/mm3 (1.0×10^9/L) or documented institutional normal range for starting abemaciclib.
• Total bilirubin ≤1.5×ULN or ≤3×ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia).
• ALT and AST ≤3×ULN; for participants with hepatic metastases, ALT and AST ≤5×ULN.
• Alkaline phosphatase ≤2.5×ULN (≤ 5.0×ULN if bone or liver metastases present).
• Serum creatinine ≤ 1.5×ULN or calculated creatinine clearance ≥ 30 mL/min as determined by Cockcroft-Gault (using actual body weight).
• Female participants must have a negative highly sensitive serum pregnancy test during the screening period if they are of childbearing potential and agree to use highly effective contraceptive methods to prevent pregnancy during the study and for 4 weeks following the last dose of camizestrant (if applicable) and/or for 3 weeks after the last dose of CDK4/6inhibitor or must have evidence of nonchildbearing potential. In addition, female participants must refrain from egg cell donation and breastfeeding during this same period.

• Non-sterilized male partners of a participant who is a woman of childbearing potential must use a male condom plus spermicide from the time of screening throughout the total duration of the study until 4 weeks after last dose of camizestrant.
• Non-sterilised male participants (including males sterilised by a method other than bilateral orchidectomy, eg, vasectomy) who intend to be sexually active with a Female Of ChildBearing Potential (FOCBP) must be using an acceptable method of contraception, such as male condom plus spermicide (condom alone in countries where spermicides are not approved), from enrolment throughout the study until at least 1 week to avoid conception during treatment. Male participants must not donate or bank sperm during this same period.
• Female partners (of child-bearing potential) of male participants enrolled in this study must also use a highly effective method of contraception from the time of study enrolment of their male partner, throughout their participation in the study, and until at least 1 week after their male partners last dose of camizestrant.

Exclusion criteria

Related to step #1:

• 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;
• History of another malignancy, except (i) those treated with curative intent and with no known active disease ≥3 years; (ii) adequately treated non-melanoma cutaneous and in-situ cervix cancer;
• History of bone marrow transplantation;
• Patients relapsing while on or during the year after the discontinuation of adjuvant CDK4/6 inhibitor.
• Pregnant women or women who are breast-feeding or participants not willing to apply highly effective contraception as defined in the protocol;
• Participants unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons;
• Participation in another clinical study whose procedures interfere with those of the study (within 28 days prior to participant enrolment and for the duration of the study);
• Persons deprived of their liberty or under protective custody or guardianship;

Related to step #2:

• Participants with synchronous disease progression per local assessment (tumor imaging performed within 28 days prior to entry in Step #2 RECIST v1.1);
• Participants with a contraindication to abemaciclib, as assessed by the investigator;
• Participants presenting any cardiovascular conditions (as described in the protocol)
• Participants treated within the last 2 weeks before randomization with medications that are sensitive substrates (e.g. omeprazole) or substrates with narrow therapeutic index of CYP2C9 and/or CYP2C19 (e.g. warfarin and phenytoin). Strong CYP3A4/5 inducers should be stopped at least 2 weeks before randomization (3 weeks for St John's Wort).
• Participant who was treated within the timeframe indicated in the CSP with drugs that are known to prolong the QT interval.
• Participant taking medications known to prolong the QT interval and associated with a known risk of Torsades de Pointes
• Participant with a known active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), HBV (known positive HBsAg result), and HCV. Participants with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA
• Participants known to be positive for HIV can be enrolled if they fulfil the criteria recommended by Food and Drug Administration (FDA) and ASCO guidelines (FDA Guidance, Uldrick et al 2017): CD4+ T-cell (CD4+) counts ≥350 cells/µL, AND No history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections within the past 12 months (prophylactic antimicrobials allowed if no DDI or overlapping toxicities), AND On established anti-retroviral therapy (ART) for at least 4 weeks and have an HIV viral load less than 400 copies/mL before enrolment. Effective ART is defined as a drug, dosage and schedule associated with reduction and control of the viral load