Abstract P2-08-29: Lenvatinib and Pembrolizumab in Endocrine Resistant Breast Cancer with Letrozole in the Advanced setting – a Phase II Study (LaPemERLA)

Abstract Background and Rationale: There is an unmet need to develop more effective immune-based therapies in the hormone receptor (HR)+HER2- breast cancer (BC) subtype, especially in the metastatic setting. We hypothesise that lenvatinib, a multi-kinase inhibitor with activity against vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4 and ret protooncogene, will enhance the immunogenicity in HR+ BC through normalisation of the tumor vasculature, suppression of myeloid-derived suppressor cells and regulatory T cells, increased T-cell infiltration of the tumor, and possibly increased apoptosis. Since the estrogen receptor (ER) pathway has been implicated in the immune escape of HR+ BCs, letrozole will be required to suppress the HR pathway concurrently. Study DesignPhase II open-label, non-randomized study will recruit up to 40 subjects with advanced ER and/or progesterone receptor positive HER2- BC which has progressed on standard endocrine therapy. The treatment will be defined in 6-weekly cycles. Lenvatinib and letrozole will be given orally daily from Day -14, while pembrolizumab will be administered intravenously during week 1 of each cycle from Cycle 1 Day 1 (C1D1), with daily lenvatinib and letrozole. Ovarian suppression will be required for premenopausal, perimenopausal and male patients. The study treatment will be continued for up to a maximum of 18 6-weekly cycles (approximately 2 years) per patient. Treatment may be discontinued upon disease progression, intolerable toxicities, or patient’s withdrawal request. Subjects will undergo at least 1 mandatory biopsy – pretreatment before Day -14 lenvatinib and letrozole run-in phase. Posttreatment biopsy at the following timepoints will be optional: 1) at or up to 3 days before C1D1, 2) within 3 weeks of receiving pembrolizumab in C1, 3) post-progression. Eligibility: Key inclusion criteria: age ≥21 years; histologically confirmed HR+/HER2- metastatic BC; disease progression after at least 1 line of palliative endocrine therapy (prior adjuvant/palliative letrozole is allowed); any number of lines or prior targeted therapy (except lenvatinib) is allowed; ≤1 line of palliative chemotherapy; measurable disease based on RECIST 1.1; availability of tumor sample and be a candidate for tumor biopsy. Key Exclusion Criteria: unstable intracranial disease; contraindications to lenvatinib or pembrolizumab. Objectives: Primary objective: to determine the efficacy of pembrolizumab, lenvatinib and letrozole in patients with advanced HR+HER2- BC in terms of the objective response rate (ORR). Secondary Objectives: To assess the anti-tumor activity of this combination treatment in advanced HR+HER2- BC (progression-free survival, duration of response, clinical benefit rate and overall survival) as well as safety. Exploratory Objectives: To identify biomarkers in peripheral blood/plasma, tumor and faecal specimens that are predictive of efficacy and toxicity to this triplet combination therapy; To investigate differences in tumour characteristics in biopsies taken post treatment with lenvatinib + letrozole, and post treatment with pembrolizumab in addition to lenvatinib + letrozole versus baseline. Statistical Method: A Simon’s 2-stage design will be used to allow early stopping if there is no strong evidence suggesting that the treatment regimen is active; testing for an ORR of 30% versus 10% with one-sided alpha of 5% and power of 90%. A total of 22 evaluable patients will be analyzed in the first stage and the trial will stop early if there are fewer than 3 responders. If 3 or more patients experience objective response, trial accrual will continue to the second stage. An additional 18 patients will be accrued for a total of 40 patients. This study is registered with clinicaltrials.gov (NCT05286437) Citation Format: Yoon-Sim Yap, Tira Jing Ying Tan, Hui Zhen Gay, Elizabeth Ann Lee, Sze Huey Tan, Timothy Kwang Yong Tay, Babar Nazir, Choon Hua Thng, Mabel Wong, Ryan Shea Ying Cong Tan, Zewen Zhang, Han Yi Lee, Joshua Zhi Chien Tan, Bernard Ji Guang Chua, Sophia Yien Ning Wong, Jack Junjie Chan, Jun Ma, Chung-Lie Oey, Veronique Kiak Mien Tan, Kah Suan Lim, Jason Yongsheng Chan. Lenvatinib and Pembrolizumab in Endocrine Resistant Breast Cancer with Letrozole in the Advanced setting – a Phase II Study (LaPemERLA) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-08-29.