The Optimal Radioimmunotherapy Combinations for Advanced TNBC

Phase 2

Recruiting

• Conditions: Triple-Negative Breast Cancer (TNBC)
• Interventions: Radiation: radiotehrapy 0.5Gy twice-a-day × 2 days, repeat for 4 cycles (total 8Gy); Radiation: radiotherapy 5 Gy × 5 fractions, once a day; Radiation: radiotherapy 8 Gy × 5 fractions, once a day; Radiation: radiotherapy 8 Gy × 3 fractions, once every other day; Radiation: radiotherapy 10 Gy× 3 fractions, once every other day; Drug: Toripalimab; Drug: chemotherapy regimen selected by the investigator

• Registration Number: NCT06735131
• Lead Sponsor: Sun Yat-sen University

Brief Summary

This study aims to explore the best combination patterns of radiotherapy and immunotherapy for advanced triple-negative breast cancer (TNBC).

Detailed Description

Metastatic triple-negative breast cancer (mTNBC) is a particularly aggressive form of breast cancer that poses significant therapeutic challenges. Because mTNBC tumors do not express estrogen receptors (ER), progesterone receptors (PR), or HER2, patients with this subtype cannot receive benefits from endocrine therapy or HER2-targeted treatments, leaving chemotherapy as the main treatment option. However, the effectiveness of traditional chemotherapy drugs is limited and they often come with severe side effects. This leads to short durations of progression-free survival (PFS) and overall survival (OS), and the development of drug resistance, which can cause the cancer to recur and spread.

Recently, the advent of immune checkpoint inhibitors has offered new therapeutic prospects for mTNBC. Inhibitors of PD-1/PD-L1, such as Pembrolizumab, Atezolizumab, and Toripalimab, have demonstrated some effectiveness in clinical trials, especially in patients with PD-L1-positive tumors. Yet, the overall response to immunotherapy remains low, and there is a risk of immune-related adverse events (irAEs), which require vigilant monitoring.

To address the shortcomings of both chemotherapy and immunotherapy, researchers are investigating innovative treatment strategies. These include targeting additional immune checkpoint molecules within the tumor microenvironment, developing novel chemotherapy drugs, and integrating immunotherapy with other treatments like radiotherapy. Local radiotherapy can substantially stimulate the immune system, increasing the antigenicity of cancer cells and enhancing the ability of cytotoxic T lymphocytes to recognize and attack cancer cells.

Although combined radiotherapy and immunotherapy have shown promise in treating other types of cancer, the most effective combination patterns, optimal radiotherapy dosing schedules, and the most suitable patient groups for advanced breast cancer, particularly mTNBC, are not well defined. This study seeks to identify the best combinations of radiotherapy and immunotherapy for advanced breast cancer, with the aim of improving survival rates and setting new standards for treatment.

Study Timeline

• Study First Submitted: 2024-12-05
• Study First Submitted QC: 2024-12-13
• Study First Posted: 2024-12-16
• Study Start: 2024-12-20
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-08
• Last Update Posted: 2025-05-14
• Primary Completion: 2026-07
• Study Completion: 2027-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

1. Inoperable locally advanced/metastatic triple-negative breast cancer (defined as ER and PR <1%; and HER2 negative as IHC 0 or IHC 1+, or IHC 2+ but negative upon fluorescence in situ hybridization (FISH) testing).

2. No prior chemotherapy for advanced/metastatic disease.

3. ECOG PS score of 0 or 1.

4. Presence of 1 to 5 tumor lesions, with individual lesion size between 0.5 and 5 cm, not limited to 1 to 2 organs.

5. At least one lesion suitable for radiotherapy.

6. Suitable to receive one of the chemotherapy regimens chosen by the investigator: nab-paclitaxel or gemcitabine + carboplatin.

7. Patients with only bone metastases are allowed to enroll.

8. Patients who have previously received PD-1/PD-L1 therapy for early-stage disease are allowed to enroll.

9. Able to provide tumor tissue sections or agree to tumor biopsy during the screening period.

10. Adequate organ and bone marrow function, with specific requirements:

    1. Hematology: Neutrophil count (ANC) ≥1.5×10^9/L; Platelet count (PLT) ≥90×10^9/L; Hemoglobin (Hb) ≥90 g/L; No blood product transfusion (including red blood cell and platelet products, etc.) or growth factor (including colony-stimulating factors, interleukins, and erythropoietin, etc.) support treatment within 2 weeks prior to examination.
    2. Liver function: Serum total bilirubin (TBIL) ≤1.5×upper limit of normal (ULN); Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤2.5×ULN (for patients with liver metastases: ALT and AST ≤5×ULN).
    3. Renal function: Serum creatinine (Cr) ≤1.5×ULN or creatinine clearance >60 mL/min.

Exclusion Criteria

1. Received platinum-containing regimens during the adjuvant/neoadjuvant therapy phase, and the interval from the last treatment to recurrence/metastasis is less than 6 months.
2. Have received radiotherapy within 12 weeks prior to enrollment, unless the radiotherapy was for adjuvant purposes and there are lesions outside the previously irradiated field.
3. Extensive tumor metastasis with surrounding normal tissues that cannot tolerate radiotherapy damage.
4. Patients with central nervous system metastases.
5. Significant third-space fluid retention (e.g., ascites, pleural effusion, pericardial effusion).
6. Require long-term systemic corticosteroid treatment.
7. Have active autoimmune diseases.
8. Have concurrent severe infections.
9. Other patients deemed unsuitable for enrollment by the investigator.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 4: 10Gy × 3, every other day	chemotherapy regimen selected by the investigator	within 4 weeks before the initiation of cycle of toripalimab and chemotherapy
Arm 5: 0.5Gy twice-a-day × 2 days, repeat for 4 cycles (8 Gy in total)	radiotehrapy 0.5Gy twice-a-day × 2 days, repeat for 4 cycles (total 8Gy)	on the first 2 days of first 4 cycles of toripalimab and chemotherapy
Arm 5: 0.5Gy twice-a-day × 2 days, repeat for 4 cycles (8 Gy in total)	Toripalimab	on the first 2 days of first 4 cycles of toripalimab and chemotherapy
Arm 1: 5Gy × 5 , daily	radiotherapy 5 Gy × 5 fractions, once a day	within 4 weeks before the initiation of cycle of toripalimab and chemotherapy
Arm 1: 5Gy × 5 , daily	Toripalimab	within 4 weeks before the initiation of cycle of toripalimab and chemotherapy
Arm 1: 5Gy × 5 , daily	chemotherapy regimen selected by the investigator	within 4 weeks before the initiation of cycle of toripalimab and chemotherapy
Arm 2: 8Gy × 5 , daily	radiotherapy 8 Gy × 5 fractions, once a day	within 4 weeks before the initiation of cycle of toripalimab and chemotherapy
Arm 2: 8Gy × 5 , daily	Toripalimab	within 4 weeks before the initiation of cycle of toripalimab and chemotherapy
Arm 2: 8Gy × 5 , daily	chemotherapy regimen selected by the investigator	within 4 weeks before the initiation of cycle of toripalimab and chemotherapy
Arm 3: 8Gy × 3, every other day	radiotherapy 8 Gy × 3 fractions, once every other day	within 4 weeks before the initiation of cycle of toripalimab and chemotherapy
Arm 3: 8Gy × 3, every other day	Toripalimab	within 4 weeks before the initiation of cycle of toripalimab and chemotherapy
Arm 5: 0.5Gy twice-a-day × 2 days, repeat for 4 cycles (8 Gy in total)	chemotherapy regimen selected by the investigator	on the first 2 days of first 4 cycles of toripalimab and chemotherapy
Arm 3: 8Gy × 3, every other day	chemotherapy regimen selected by the investigator	within 4 weeks before the initiation of cycle of toripalimab and chemotherapy
Arm 4: 10Gy × 3, every other day	radiotherapy 10 Gy× 3 fractions, once every other day	within 4 weeks before the initiation of cycle of toripalimab and chemotherapy
Arm 4: 10Gy × 3, every other day	Toripalimab	within 4 weeks before the initiation of cycle of toripalimab and chemotherapy

Primary Outcome Measures

Name	Time	Method
Progression-free survival at 6 months (6m-PFS rate)	6 months	Progression-free survival at 6 months (6m-PFS rate) is defined as the percentage of patients who have not experienced disease progression or death due to any cause at the 6-month mark after starting treatment.

Secondary Outcome Measures

Name	Time	Method
Progression-free survival (PFS)	Up to 3 years	Progression-free survival (PFS) is defined as the time from treatment initiation to disease progression or death from any cause.
Overall survival (OS)	up to 3 years	Overall survival (OS) is defined as the time from treatment initiation to death from any cause.
Objective Response Rate	up to 3 years	Objective response rate (ORR) is defined as the percetage of patients achieving a complete response (CR) or partial response (PR) according to RECIST v.1.1.
Duration of response	up to 3 years	Duration of response (DOR) is defined as the duration from response initiation (when either CR or PR is first determined) to progression or death, whichever occurs first.
Number of participants with treatment-related adverse events	up to 3 years	Adverse events are assessed by CTCAE v5.0

Trial Locations

Locations (1)

Sun Yat-sen University Cancer Center; 🇨🇳 Guangzhou, Guangdong, China