Reverse HER2-negative Immune Resistant Breast Cancer

Phase 2

Recruiting

• Conditions: HER2 Negative Breast Cancer
• Interventions: Drug: Retinoic Acid; Drug: anti-PD-1 antibody and chemotherapy

• Registration Number: NCT06731140
• Lead Sponsor: Fudan University

Brief Summary

This is a Phase II, open-label study evaluating the efficacy and safety of combined treatment (retinoic acid) with immune checkpoint inhibitor in HER2-negative breast cancer patients who progressed during previous immune checkpoint inhibitors.

Detailed Description

This is a Phase II, open-label study evaluating the efficacy and safety of combined treatment (retinoic acid) with immune checkpoint inhibitors in metastatic HER2-negative breast cancer patients who progressed during or following previous immune checkpoint inhibitors. HER2-negative breast cancers include luminal breast cancers and triple-negative breast cancers.

Current clinical studies on immunotherapy for luminal breast cancer are limited, with inconsistent results across trials. The KEYNOTE-028 study reported an objective response rate (ORR) of only 12% for pembrolizumab in PD-L1-positive, previously treated advanced luminal breast cancer patients, demonstrating limited efficacy. The GIADA phase II trial revealed a pathological complete response (pCR) rate of 16.3% with neoadjuvant chemotherapy followed by immunotherapy in luminal breast cancer. Additionally, trials such as NCT02779751 and NCT03051659 also indicated limited clinical benefits from immunotherapy. However, the I-SPY2 platform showed that combinations like olaparib, paclitaxel, and immunotherapy or wP-AC chemotherapy with immunotherapy could improve pCR rates in high-risk patients. Despite advancements, immunotherapy benefits are limited in luminal breast cancer compared to other cancers, with advanced-stage patients more likely to develop resistance.

Recent clinical studies on advanced triple-negative breast cancer have shown that immunotherapy combined with chemotherapy demonstrates superior clinical efficacy compared to traditional chemotherapy alone. Phase III trials such as IMPassion130 and Keynote-522 have confirmed that PD-1/PD-L1 inhibitors used with chemotherapy significantly improve progression-free survival, overall survival, and pathological complete response rates. However, compared to other malignancies, triple-negative breast cancer patients still show relatively low overall response rates to immunotherapy: treatment-naïve patients achieve objective response rates of only 10-20% with immunotherapy monotherapy, though this improves to 56% when combined with chemotherapy, extending median progression-free survival to 7.2 months. Unfortunately, efficacy decreases significantly in later treatment lines, with objective response rates falling to just 10.6-15.9% after multiple previous treatments. Thus, strategies to overcome immunotherapy resistance or increase the sensitivity of immunotherapy efficacy are urgently needed for HER2-negative breast cancer patients.

The preclinical results of our center show that retinoic acid can enhance the anti-tumor immune response by promoting the peroxidation of macrophages, increasing the infiltration and function of cytotoxic CD8+ T cells, inhibiting the growth of tumors in mice. Based on the preclinical study, the investigators designed this study to enroll metastatic HER2-negative breast cancer patients who have progressed during or following immunotherapy, and to explore the efficacy of retinoic acid combined with immunotherapy at a clinical level, providing new strategies of combined treatment for HER2-negative breast cancer patients.

Study Timeline

• Study First Submitted: 2024-12-09
• Study First Submitted QC: 2024-12-09
• Study First Posted: 2024-12-12
• Study Start: 2025-02-12
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-08
• Last Update Posted: 2025-05-13
• Primary Completion: 2026-10
• Study Completion: 2027-10

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 10

Inclusion Criteria

• ECOG Performance Status of 0, 1, or 2
• Metastatic or locally advanced, histologically confirmed luminal breast cancer (defined as: ER positive when immunohistochemistry shows >1% positive tumor cells, PR positive when >1% tumor cells are positive, and HER2 negative when scored as 0-1+ or when HER2 2+ shows no amplification by FISH or CISH) or triple negative breast cancer (defined as: ER negative when immunohistochemistry shows <1% positive tumor cells, PR negative when <1% tumor cells are positive, and HER2 negative when scored as 0-1+ or when HER2 2+ shows no amplification by FISH or CISH).
• Radiologic/objective evidence of recurrence or disease progression after immunotherapy (combined with targeted therapy or chemo ) for metastatic breast cancer (MBC)
• Adequate hematologic and end-organ function, laboratory test results, obtained within 14 days prior to initiation of study treatment.

For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures as outlined for each specific treatment arm

• Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1)
• have the cognitive ability to understand the protocol and be willing to participate and to be followed up.

Exclusion Criteria

• Symptomatic, untreated, or actively progressing CNS metastases
• Active or history of autoimmune disease or immune deficiency
• Significant cardiovascular disease
• History of malignancy other than breast cancer within 5 years prior to screening, with the exception of those with a negligible risk of metastasis or death
• Treatment with chemotherapy, radiotherapy, immunotherapy or surgery (outpatient clinic surgery excluded) within 3 weeks prior to initiation of study treatment.
• Pregnancy or breastfeeding, or intention of becoming pregnant during the study
• History of allergies to the drug components of this trial
• History of eosinophilosis or mastocytosis
• Patients who have been using oral steroid hormones for a long time will need to stop for 4 weeks if they have used them occasionally in the past

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
retinoic acid with anti-PD-1 immunotherapy	Retinoic Acid	retinoic acid with anti-PD-1 immunotherapy
retinoic acid with anti-PD-1 immunotherapy	anti-PD-1 antibody and chemotherapy	retinoic acid with anti-PD-1 immunotherapy

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Baseline until disease progression or loss of clinical benefit, assessed up to 6 months
Immune changes in peripheral blood	Baseline until disease progression or loss of clinical benefit, assessed up to 6 months

Secondary Outcome Measures

Name	Time	Method
Biomarker analysis	Baseline until disease progression or loss of clinical benefit, assessed up to 6 months	Retinoic acid related genes, cell functions and microbes will be measured in pre-treatment and post-treatment samples (tumor tissue, blood and fecal samples) to predict therapy response.
Disease Control Rate (DCR)	Baseline through end of study, assessed up to 6 months
Progression Free Survival (PFS)	Randomization to death from any cause, through the end of study, assessed up to 6 months
Safety and treatment-related AEs	Randomization to death from any cause, through the end of study, assessed up to 12 months

Trial Locations

Locations (1)

Fudan University Shanghai Cancer Center; 🇨🇳 Shanghai, Shanghai, China