Based on the results of the phase Ib/II study, the investigators hypothesize that combining a RET inhibitor lenvatinib with endocrine therapy letrozole improves objective response and progression-free survival compared to fulvestrant alone in the second line setting in patients who have progressed on first line endocrine therapy incorporating a CDK4/6 inhibitor.

Letrozole and fulvestrant are anti-hormonal drugs that have been proven to have activity and are considered standard therapies for hormone receptor positive breast cancer. The purpose of this study is to determine if the combination therapy of letrozole (an anti-hormonal drug) and lenvatinib (a targeted therapy), when compared to another anti-hormonal drug fulvestrant, is effective in patients with hormone receptor positive breast cancer.

Preliminary studies have shown that approximately 50-60% of hormone receptor positive breast cancers over-express RET, and may therefore respond to treatment by a drug that blocks the RET pathway. An earlier study conducted at the National University Cancer Institute, Singapore (NCIS) on the combination of letrozole and Lenvatinib has shown promising results. Among patients in whom hormonal therapy and a CDK4/6 inhibitor no longer worked, about one-quarter of patients had meaningful disease control. The study also showed that patients tolerated the combination of Lenvatinib and letrozole well with manageable side effects.

Based on the promising findings from the earlier study, this study seeks to compare the effectiveness of lenvatinib plus letrozole with another standard anti-hormone treatment drug called fulvestrant.

In addition, investigators are studying how body reacts to the treatment as well as studying gene and protein changes in the tumour in response to treatment, which may in the future, help us tailor drug treatment for individual patients according to the patient's and/or the tumour's genetic or protein make-up.

Breast cancer is the commonest cancer among females in Singapore and worldwide. Approximately 60-70% of breast cancers are hormone receptor positive and thus potentially sensitive to endocrine therapy. However, both primary and acquired resistance to endocrine therapy exists, and better combinations are constantly being explored to delay endocrine resistance and improve treatment outcome. Several known mechanisms of endocrine resistance have been proposed, and include deregulation of various components of the ER pathway itself, alterations in cell cycle and cell survival signaling molecules, and the activation of escape pathways that can provide tumors with alternative proliferative and survival stimuli.

Endocrine blockade in breast cancer can be achieved by reducing the levels of estrogens through ovarian ablation (medical, surgical, or through radiation) in pre-menopausal women or with the administration of aromatase inhibitors (AI) in post-menopausal women. Direct inhibition of estrogen receptors can be achieved by administering selective estrogen receptor modulators, such as tamoxifen, or a pure estrogen receptor antagonist such as fulvestrant. Sequential single agent endocrine therapy used to be the standard of care in advanced hormone receptor positive, HER2 negative breast cancer patients without visceral crisis and low tumor burden. However, the development of CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) since 2014 has resulted in endocrine therapy + CDK4/6 inhibitor becoming a new standard of care in the first- or second-line setting for these patients, even in those with visceral disease (though not visceral crisis) and substantial tumor burden. The addition of CDK4/6 inhibitors has resulted in consistent improvement in progression-free survival 2-4, and a recent meta-analyses has also confirmed improvement in overall survival outcomes.

There is limited literature on the median progression-free survival (PFS) of single agent fulvestrant in patients who have failed first-line AI + CDK4/6 inhibitors. However, in several contemporary phase II/III randomized trials of second-line endocrine therapy in patients who failed prior AI (majority or all had no prior CDK4/6 inhibitors), e.g., FAKTION, SANDIPIPER, BELLE2 trials, median PFS in the control arm of single agent fulvestrant is fairly consistent at 4.5 to 5.6 months. Median PFS of fulvestrant post-progression from first-line AI + CDK4/6 inhibitors is expected to be shorter than 4.5 to 5.6 months as these patients are likely to be more endocrine-resistant. In a subgroup analysis of patients who failed prior CDK4/6 inhibitors (n=20) and who received single agent fulvestrant as second-line endocrine therapy in the phase III randomized SOLAR-1 trial, median PFS was 1.8 months and 1-year PFS was <10%.

RET is an estrogen response gene, and preclinical studies have demonstrated cross talk between RET and ER. Significant interactions between RET and ERa pathways have been described, with increased response to estrogen stimulation observed in the presence of functional RET. RET is associated with resistance to tamoxifen and aromatase inhibitors, and increased RET expression has been demonstrated in hormone resistant cell lines and primary tumors. Combined anti-estrogen and anti-RET therapy in luminal breast cancer had a greater effect on cell growth than either therapy alone. The two classes of drugs have different mechanisms of action; a RET tyrosine kinase inhibitor (TKI) reduced growth through induction of apoptosis, while anti-ERa reduced cell proliferation, forming the biologic basis for dual treatment. Dual therapy with tamoxifen and vandetinib, a RET inhibitor, resulted in greater reduction in tumor growth rate in MCF7 xenografts in mice. RET has been reported to be over-expressed in up to 75% of ER+ breast cancers (n=20), compared to only 10% of ER-negative breast cancers (n=10) in a small study.

Preclinical experiments from laboratory showed lenvatinib to have activity in ER positive breast cancer cell lines, regardless of levels of RET expression. Lenvatinib was at least additive with tamoxifen in all 6 ER positive breast cancer cell lines tested, with the combination resulting in =50% cell kill compared to single agent tamoxifen in BT474, CAMA1, and T47D cell lines supporting the potential role of lenvatinib in combination with endocrine therapy in the treatment of ER positive breast cancers.

A phase Ib with dose expansion study was carried out at the National University Cancer Institute, Singapore with the use of lenvatinib together with letrozole in the treatment of patients with estrogen receptor positive, HER2 negative breast cancer. This study was initiated in patients for neoadjuvant therapy, but expanded to include patients with metastatic breast cancer. In total, 47 patients were enrolled, among whom the first 4 patients received neoadjuvant therapy for locally advanced disease, and the remaining 43 patients received treatment in the metastatic setting. Recommended phase 2 dose of lenvatinib was established at 14mg daily in combination with letrozole 2.5mg daily. Thirty-one patients were enrolled in the dose expansion cohort at recommended phase 2 dose (RP2D).

At interim analyses, patients enrolled had a median of 4 prior lines of therapy (range 0-11), with 78.9% of patients having prior exposure to CDK4/6 inhibitor therapy. In the intention-to-treat population, an overall response rate (ORR) of 36.8% was observed, with 28.9% patients remaining progression-free (PPF) at 1 year. Among patients with partial response or stable disease, median duration of response was 16.1 months (range 5.4 to 21.7 months). Amongst these patients, 78.9% (n=30) had prior CDK4/6 inhibitor treatment, and 12 patients received CDK4/6 inhibitors as immediate prior line of therapy. In the subset of patients with prior CDK4/6 inhibitor exposure, similar encouraging results were observed, with a ORR of 26.7, 23.3% PPF at 1 year, and duration of response of 13.2 months (range 3.8 to 21.3 months).

Additionally, on-target effect, downregulation of RET expression among tumors were found to have positive RET expression at baseline. Main toxicities observed included hypertension (all grade 59%, grade3 8%), hypothyroidism (all grade 46%, grade 3 0%), and fatigue (all grade 43%, grade 3 5%), all of which were well controlled with optimal medical therapy. No grade 4-5 toxicities were observed. The promising results from the phase Ib study forms the basis of this randomized phase II study.

Inclusion Criteria:

Patients may be included in the study only if patient meet all of the following criteria:

• Female, age =>18 years.

• Histologic or cytologic diagnosis of breast carcinoma.

• Estrogen receptor positive (defined as =>1% on immunohistochemical staining)

• Progressed on first-line palliative endocrine therapy plus CDK4/6 inhibitor as immediate prior line of endocrine therapy. Prior palliative letrozole is allowed.

• Only one prior line of endocrine therapy in the metastatic setting.

• No more than 1 prior line of chemotherapy in the metastatic setting.

• Measurable disease by RECIST criteria.

• ECOG 0-1.

• Estimated life expectancy of at least 12 weeks.

• Adequate organ function including the following:

  - Bone marrow: Absolute neutrophil (segmented and bands) count (ANC) =>1.5 x 109/L Platelets =>100 x 109/L

  - Hepatic: Bilirubin <= 1.5 x upper limit of normal (ULN), ALT or AST<= 2.5x ULN, (or <=5 X with liver metastases)

  - Renal: Creatinine <= 1.5x ULN

• Normal thyroid function on thyroid screen (fT4 and TSH). Patients who have thyroid dysfunction are eligible if thyroid function is optimally controlled.

• Post-menopausal women. Post-menopausal status is defined either by Age => 60 years and one year or more of amenorrhea Age <= 60 years and one year or more of amenorrhea (in the absence of ovarian suppression) and with estradiol and FSH levels consistent with menopause, Pre-menopausal women who are treated with medical ovarian suppression with post-menopausal levels of estradiol (institutional limits) at time of study entry and who will continue to be suppressed with 4-weekly LHRH agonist during study treatment may be enrolled. If these patients were previously on 12-weekly long-acting LHRH agonist, this has to be switched to 4-weekly LHRH agonist while the patient is on study treatment.

• Signed informed consent from patient or legal representative.

Exclusion Criteria:

Patients will be excluded from the study for any of the following reasons:

• HER2 positive tumors.
• Treatment within the last 30 days with any investigational drug.
• Prior therapy with fulvestrant.
• Concurrent administration of any other tumor therapy, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy.
• Major surgery within 28 days of study drug administration.
• Active infection that in the opinion of the investigator would compromise the patient's ability to tolerate therapy.
• Pregnancy.
• Breast feeding.
• Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator.
• Non-healing wound.
• Poorly controlled diabetes mellitus.
• Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
• Uncontrolled or symptomatic brain metastases, and/or brain metastases requiring steroids
• History of significant neurological or mental disorder, including seizures or dementia.
• Uncontrolled blood pressure (defined as persistent systolic BP >140 mmHg or diastolic BP>90mmHg) in spite of optimized regimen of antihypertensive medication
• Presence of proteinuria defined as 24h urine collection of grade 2 and above (protein >1.0g/24h)
• Significant cardiovascular impairment: history of congestive heart failure greater that New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of first dose of study drug, or cardiac arrhythmia requiring medical treatment at screening.
• Bleeding or thrombotic disorders or gastrointestinal bleeding event or active hemoptysis or use of anticoagulants such as warfarin or similar agents requiring therapeutic INR monitoring, or subjects at risk of severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage / necrosis following Lenvatinib therapy.
• Patients with baseline QTc interval >480ms that persists despite correction of electrolyte abnormalities and/or discontinuation of concomitant medications that are known to prolong QTc interval.

Breast cancer study - 99.9% breast cancer patients are female. Male breast cancer is extremely rare and investigators do not intend to include this rare population