Lenvatinib+Letrozole Versus Fulvestrant in Metastatic ER+/HER2- Breast Cancer, Post Progression on Al + CDK4/6 Inhibitor

NCT05181033 | Recruiting Phase 2

• 1 other identifier: BR01/02/21
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Breast Cancer

Keywords

Metastatic Estrogen Receptor (ER) positive; HER2 negative; breast cancer; first-line aromatase inhibitor; CDK4/6 inhibitor

Outcome Measures

Primary Outcomes (1)

• Progression-free survival (PFS) of patients treated on lenvatinib and letrozole compared to single agent fulvestrant

  The PFS will be described using the Kaplan-Meier method and compared via logrank test. A total of 10 patients will be enrolled in the lead in portion of the study. If median PFS of the 10 patients is ≥4.5 months (upper limit of the 95% CI of median PFS to single agent fulvestrant in the retrospective study from NCIS), investigators will proceed to phase II randomized trial. If median PFS of the 10 patients is \<3 months, study will not proceed to phase II randomized portion. If the median PFS of the 10 patients is between \>3 months and \<4.5 months, the study scientific committee will review and decide whether to proceed to the next part of trial. Interim analysis will be performed after 6 patients have been enrolled and the patient has been on study treatment for ≥6 months. If the PFS of all 6 patients is ≥4.5 months, investigators will move into the phase II randomized portion without the need to complete recruitment of all 10 patients into the lead-in phase II portion.

  30 months

Secondary Outcomes (3)

• Overall objective response rate (ORR) measured by RECIST 1.1 criteria of patients treated with lenvatinib and letrozole compared to single agent fulvestrant

  30 months

• Clinical benefit rate (CBR) measured by RECIST 1.1 criteria of patients treated with lenvatinib and letrozole compared to single agent fulvestrant

  30 months

• Overall survival (OS) of patients treated with lenvatinib and letrozole compared to single agent fulvestrant

  30 months

Study Arms (2)

Control arm

ACTIVE COMPARATOR

intramuscular (IM) fulvestrant 500mg on day 1 and day 15 during cycle 1, then day 1 only from cycle 2 onwards of every 4-weekly cycle

Drug: Fulvestrant

Experimental arm

EXPERIMENTAL

oral (PO) letrozole 2.5mg daily plus lenvatinib 14mg daily

Drug: Lenvatinib + Letrozole

Interventions

Lenvatinib + Letrozole DRUG

Patient will receive letrozole 2.5mg daily plus lenvatinib 14mg daily until disease progression/unacceptable toxicity. Patient review, safety evaluations, thyroid function monitoring and urine dipstick will be done. Toxicities will be graded using NCI CTCAE toxicity grading vs 4.0. Patient should be discontinued if drug cannot be resumed within 28 days due to toxicities. Drugs should be withheld when subject has imminent risk to develop hypertensive crisis/has significant risk factors for severe complications of uncontrolled hypertension. Drugs can be resumed once patient received same hypertensive medications for at least 48 hours and the BP is controlled. Lenvatinib should be withheld for at least 1 week prior to elective surgery, at least 2 weeks after major surgery, until adequate wound healing. For risk of ONJ, oral dental examination and preventive dentistry should be considered prior to lenvatinib intake. There is no dose modifications for letrozole.

Also known as: Lenvima

Experimental arm

Fulvestrant DRUG

Patients will be treated with Fulvestrant 500mg injections that are administered into the muscles (intramuscularly). This is injected at 2-weekly interval for the first 3 doses, followed by 4-weekly interval dosing.

Also known as: Faslodex

Control arm

Eligibility Criteria

• Age: 18 Years - 99 Years
• Gender Eligibility Details: 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
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National University Hospital, Singapore: lead
• Eisai Co., Ltd.: collaborator

Study Sites (1)

Nationa University Hospital

Singapore, Singapore

RECRUITING

Related Publications (14)

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  PMID: 20887199 BACKGROUND

• Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Dieras V, Slamon DJ. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016 Nov 17;375(20):1925-1936. doi: 10.1056/NEJMoa1607303.

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• Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N, Hurvitz SA, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Babu KG, Wheatley-Price P, De Laurentiis M, Im YH, Kuemmel S, El-Saghir N, Liu MC, Carlson G, Hughes G, Diaz-Padilla I, Germa C, Hirawat S, Lu YS. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018 Jul;19(7):904-915. doi: 10.1016/S1470-2045(18)30292-4. Epub 2018 May 24.

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• Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, Park IH, Tredan O, Chen SC, Manso L, Freedman OC, Garnica Jaliffe G, Forrester T, Frenzel M, Barriga S, Smith IC, Bourayou N, Di Leo A. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol. 2017 Nov 10;35(32):3638-3646. doi: 10.1200/JCO.2017.75.6155. Epub 2017 Oct 2.

  PMID: 28968163 BACKGROUND

• Li J, Huo X, Zhao F, Ren D, Ahmad R, Yuan X, Du F, Zhao J. Association of Cyclin-Dependent Kinases 4 and 6 Inhibitors With Survival in Patients With Hormone Receptor-Positive Metastatic Breast Cancer: A Systematic Review and Meta-analysis. JAMA Netw Open. 2020 Oct 1;3(10):e2020312. doi: 10.1001/jamanetworkopen.2020.20312.

  PMID: 33048129 BACKGROUND

• Jones RH, Casbard A, Carucci M, Cox C, Butler R, Alchami F, Madden TA, Bale C, Bezecny P, Joffe J, Moon S, Twelves C, Venkitaraman R, Waters S, Foxley A, Howell SJ. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2020 Mar;21(3):345-357. doi: 10.1016/S1470-2045(19)30817-4. Epub 2020 Feb 5.

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• Dent S, Cortes J, Im YH, Dieras V, Harbeck N, Krop IE, Wilson TR, Cui N, Schimmoller F, Hsu JY, He J, De Laurentiis M, Sousa S, Drullinsky P, Jacot W. Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial. Ann Oncol. 2021 Feb;32(2):197-207. doi: 10.1016/j.annonc.2020.10.596. Epub 2020 Nov 10.

  PMID: 33186740 BACKGROUND

• Baselga J, Im SA, Iwata H, Cortes J, De Laurentiis M, Jiang Z, Arteaga CL, Jonat W, Clemons M, Ito Y, Awada A, Chia S, Jagiello-Gruszfeld A, Pistilli B, Tseng LM, Hurvitz S, Masuda N, Takahashi M, Vuylsteke P, Hachemi S, Dharan B, Di Tomaso E, Urban P, Massacesi C, Campone M. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Jul;18(7):904-916. doi: 10.1016/S1470-2045(17)30376-5. Epub 2017 May 30.

  PMID: 28576675 BACKGROUND

• Andre F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer IA, Kaufman B, Yamashita T, Lu YS, Inoue K, Takahashi M, Papai Z, Longin AS, Mills D, Wilke C, Hirawat S, Juric D; SOLAR-1 Study Group. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2019 May 16;380(20):1929-1940. doi: 10.1056/NEJMoa1813904.

  PMID: 31091374 BACKGROUND

• Boulay A, Breuleux M, Stephan C, Fux C, Brisken C, Fiche M, Wartmann M, Stumm M, Lane HA, Hynes NE. The Ret receptor tyrosine kinase pathway functionally interacts with the ERalpha pathway in breast cancer. Cancer Res. 2008 May 15;68(10):3743-51. doi: 10.1158/0008-5472.CAN-07-5100.

  PMID: 18483257 BACKGROUND

• Plaza-Menacho I, Morandi A, Robertson D, Pancholi S, Drury S, Dowsett M, Martin LA, Isacke CM. Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance. Oncogene. 2010 Aug 19;29(33):4648-57. doi: 10.1038/onc.2010.209. Epub 2010 Jun 7.

  PMID: 20531297 BACKGROUND

• Morandi A, Martin LA, Gao Q, Pancholi S, Mackay A, Robertson D, Zvelebil M, Dowsett M, Plaza-Menacho I, Isacke CM. GDNF-RET signaling in ER-positive breast cancers is a key determinant of response and resistance to aromatase inhibitors. Cancer Res. 2013 Jun 15;73(12):3783-95. doi: 10.1158/0008-5472.CAN-12-4265. Epub 2013 May 6.

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MeSH Terms

Conditions

Breast Neoplasms

Interventions

lenvatinib; Letrozole; Fulvestrant

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Soo Chin Lee

  National University Hospital, Singapore

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Soo Chin Lee

CONTACT

6772 4629; soo_chin_lee@nuhs.edu.sg

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a multi-centre study comprising two phases: a lead-in phase II (Part A) followed by a randomized phase II portion (Part B). Part A: Lead in phase II study A total of up to 10 patients will be enrolled. Patients will be treated with letrozole 2.5mg daily plus lenvatinib 14mg daily until disease progression or unacceptable toxicity. ' Part B: Randomised phase II study Patients will be randomized in a 1:1 fashion to one of 2 arms: * Control arm: intramuscular (IM) fulvestrant 500mg on day 1 and day 15 during cycle 1, then day 1 only from cycle 2 onwards of every 4-weekly cycle * Experimental arm: oral (PO) letrozole 2.5mg daily plus lenvatinib 14mg daily A total of 110 patients with ER positive breast cancer and measurable primary tumor will be enrolled over a period of 24-30 months.

Study Record Dates

• First Submitted: November 30, 2021
• First Posted: January 6, 2022
• Study Start: December 27, 2021
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): August 1, 2027
• Last Updated: July 25, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

SG (1)