Phase II Lenvatinib and Pembrolizumab in Endocrine Resistant Breast Cancer With Letrozole

Male/female participants who are at least 21 years of age on the day of signing informed consent, with histologically or cytologically confirmed diagnosis of metastatic or locally advanced carcinoma of the breast not amenable to treatment with curative intent, will be enrolled in this study.

Disease progression after treatment with at least 1 line of palliative endocrine therapy in the metastatic setting.

There is no limit to the number of lines of prior palliative endocrine therapy.Prior targeted therapy in the locally advanced (recurrent or progressed) or metastatic setting, such as CDK4/6 inhibitors, mTOR inhibitors, PI3K inhibitors, is allowed with no limit to the number of lines of targeted therapy (prior lenvatinib is not allowed).

Maximum of 1 line of palliative chemotherapy is allowed.

A chemotherapy line in advanced disease is an anticancer regimen(s) that contains at least 1 cytotoxic chemotherapy agent and was discontinued due to progression. If a cytotoxic chemotherapy regimen was discontinued for a reason other than disease progression then this regimen does not count as a "prior line of chemotherapy".Antibody-drug conjugate will be considered as cytotoxic chemotherapy in the assessment of the lines of treatment. ER positive and/or PgR positive breast cancer (based on most recent tumor biopsy or archived tumor specimen) according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, assessed locally and defined as at least 1% of tumor cells stained positive.

HER2-negative tumor assessed locally and defined as meeting one of the following sets of criteria:

HER2 IHC score of 0 or 1+HER2 IHC score of 2+ accompanied by a negative fluorescence, chromogenic, or silver in situ hybridization test indicating the absence of HER2 gene amplification HER2/CEP17 ratio of < 2.0 based on the most recent tumor biopsy (or archived tumor sample).

For women: postmenopausal or premenopausal/perimenopausal status, defined as follows: Postmenopausal, as defined by at least one of the following criteria:

Age ≥ 60 yearsAge < 60 years and ≥ 12 months of amenorrhea plus follicle-stimulating hormone (FSH) and plasma estradiol levels within postmenopausal range by local laboratory assessment, in the absence of oral contraceptive pills, hormone replacement therapy, or gonadotropin-releasing hormone agonist or antagonist Documented bilateral oophorectomy (≥14 days prior to first treatment on Day 1 of Cycle 1 and recovery from surgery to baseline) Premenopausal or perimenopausal, defined as not meeting the criteria for postmenopausal, and willing to undergo and maintain treatment with approved LHRH-agonist therapy for the duration of study treatment LHRH-agonist therapy may be initiated 14-28 days prior to commencement of letrozole, and continued 4-weekly. For men: willing to undergo and maintain treatment with approved LHRH-agonist therapy for the duration of study treatment; LHRH-agonist therapy may be initiated 14-28 days prior to commencement of letrozole, and continued 4-weekly.

A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

a. Not a woman of childbearing potential (WOCBP) as defined in protocol OR b. A WOCBP who agrees to follow the contraceptive guidance in protocol during the treatment period and for at least 120 days (corresponding to time needed to eliminate pembrolizumab and/or any active comparator/combination) plus 30 days (a menstruation cycle) after the last dose of study treatment.

A male participant must agree to use a contraception during the treatment period and for at least 120 days, corresponding to time needed to eliminate pembrolizumab plus an additional 90 days (a spermatogenesis cycle) after the last dose of study treatment and refrain from donating sperm during this period.The participant provides written informed consent for the trial. Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

Availability of tumor sample:

Patient should have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institutions guidelines. Patient must be willing to undergo a new tumor biopsy at screening. Bone metastases are not acceptable.A representative tumor sample obtained after progression on the patients most recent endocrine therapy must be submitted In the event that a post-progression sample is not available and a new biopsy cannot be obtained, enrolment may be considered after documented discussion with the Principal Investigator and the study team for a waiver. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention. Life expectancy of more than 12 weeks. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤150/90 mmHg at screening and no change in antihypertensive medications within 1 week prior to the Cycle 1 Day -14. Have adequate organ and haematological functions as defined in the protocol.