Neoadjuvant Toripalimab Plus SBRT for Chemo-Resistant Triple-Negative Breast Cancer (NEOTRIO-2)

Neoadjuvant Toripalimab Combined With Preoperative Radiotherapy for Initial Chemotherapy-Nonresponding Triple-Negative Breast Cancer Patients (NEOTRIO-2)

The goal of this clinical trial is to test whether a "rescue" strategy can turn chemotherapy-resistant triple-negative breast cancer (TNBC) into a curable state. Patients whose tumors fail to shrink after 2 cycles of standard neoadjuvant chemotherapy will receive a short, high-precision course of stereotactic body radiotherapy (SBRT, 24 Gy in 3 daily fractions) to the breast primary tumor, followed by 4 cycles of toripalimab (an anti-PD-1 antibody) combined with albumin-bound paclitaxel plus carboplatin. The main questions are:

Can this SBRT-immuno-chemo triplet raise the pathologic complete response (pCR; no invasive cancer in breast or nodes at surgery)? Can it produce an objective radiologic response (ORR) in at least half of the patients, allowing more breast-conserving operations and fewer mastectomies? Secondary objectives include safety, changes in tumor-infiltrating lymphocytes (TILs), event-free survival, and exploratory biomarkers (whole-exome and RNA-seq, PBMC immunoprofiling) to discover signatures of benefit. Participants will undergo image-guided core biopsies before and after SBRT, provide serial blood samples, and have definitive surgery 3-5 weeks after the last cycle.

Study Overview

• Status: Recruiting
• Conditions: TNBC, Triple Negative Breast Cancer
• Intervention / Treatment: Radiation: SBRT; Drug: Toripalimab (anti-PD-1 antibody); Drug: Chemotherapy switch

Detailed Description

This is a single-arm, single-center, phase II exploratory trial designed for chemotherapy-refractory, early-stage triple-negative breast cancer (Stage II-III). After two cycles of standard neoadjuvant chemotherapy (taxane ± anthracycline ± platinum), patients with stable disease (SD) or progressive disease (PD) by RECIST 1.1 are eligible.

Intervention sequence:

Day 1-3: SBRT 8 Gy × 3 fractions to the intact breast primary (total 24 Gy) under daily image guidance.

Day 4: first dose of toripalimab 240 mg IV. Day 21 (±3 d): start cycle 2 of toripalimab 240 mg d1 + albumin-bound paclitaxel 125 mg/m² d1,8 + carboplatin AUC 6 d1, q21 d × 4 cycles (immunotherapy always given first on day 1).

Surgery: within 3-5 weeks after cycle 4; sentinel-node or axillary dissection per institutional standard. Adjuvant radiation (standard whole-breast/chest-wall plus nodal fields) is delivered post-operatively, but no further boost to the primary tumour bed is required.

Endpoints Primary: pCR rate (ypT0/is ypN0) in the intent-to-treat population. Secondary: ORR by RECIST 1.1 after 4 cycles, change in TILs (H&E-based, % stromal area), safety (CTCAE v5.0), event-free survival, overall survival, and rate of breast-conserving surgery. Exploratory: genomic scars, PD-L1, interferon signature, TCR clonality, ctDNA dynamics.

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ting Zhang, phD.; Phone Number: +86-571-87783521; Email: zezht@zju.edu.cn

Study Locations

• China
  • Hangzhou, China
    • Recruiting
    • The Department of Radiation Oncology，the Second Affiliated Hospital of Zhejiang University School of Medicine, hangzhou, zhejiang

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Female, age 18-75 years, newly diagnosed invasive breast cancer.
• Histologically confirmed triple-negative phenotype: ER < 1 %, PR < 1 % by IHC, HER2 negative (IHC 0/1+ or IHC 2+ with ISH negative).
• Clinical stage II-III (T2-4 or N1-3, M0).
• Completed 2 cycles of standard neoadjuvant chemotherapy (taxane ± anthracycline ± platinum) and assessed as non-responder: stable disease (SD) or progressive disease (PD) by RECIST 1.1.
• ECOG performance status 0 or 1.
• Radiation oncologist confirms suitability for SBRT and subsequent standard post-operative radiotherapy.
• Adequate organ function within 14 days before enrollment: WBC ≥ 2 000/µL, ANC ≥ 1 500/µL, platelets ≥ 100 000/µL, Hb ≥ 9 g/dL; Serum creatinine ≤ 2 mg/dL or GFR ≥ 40 mL/min; AST/ALT ≤ 2.5 × ULN, total bilirubin ≤ ULN (≤ 3 mg/dL if Gilbert syndrome); INR ≤ 1.5 (on anticoagulation allowed if therapeutic range)
• Negative HIV, HBV surface antigen, and HCV antibody (or HBV DNA / HCV RNA negative if false-positive).

Exclusion Criteria:

• Inflammatory breast cancer.
• Any other malignancy requiring treatment within the past 3 years (except adequately treated basal-cell skin carcinoma or cervical CIS).
• Active autoimmune disease, immunodeficiency, or systemic steroids > 10 mg/day prednisone equivalent within 2 years.
• Clinically significant cardiovascular disease (unstable angina, NYHA III/IV heart failure, recent MI).
• Prior radiotherapy to the breast or chest wall.
• Active infection requiring systemic therapy.
• Known intolerance or hypersensitivity to toripalimab, paclitaxel, or carboplatin.
• Pregnant or lactating women.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SBRT-Toripalimab-Chemo Rescue; All enrolled participants receive the same regimen: Stereotactic Body Radiation Therapy (SBRT): started within 1 week after confirmation of chemotherapy resistance.; Toripalimab (anti-PD-1 antibody): cycle 1 starts the day after SBRT ends.; Chemotherapy switch: every 21 days for 4 cycles.	Radiation: SBRT; 24 Gy in 3 daily fractions (8 Gy each) to the breast primary tumor, started within 1 week after confirmation of chemotherapy resistance.; Drug: Toripalimab (anti-PD-1 antibody); 240 mg intravenous infusion every 21 days for 4 cycles; Drug: Chemotherapy switch; Albumin-bound paclitaxel 125 mg/m² (days 1 & 8) plus carboplatin AUC 6 (day 1)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pCR rate	Pathological complete response (pCR), percentage of patients with no invasive residual tumor in breast and lymph nodes (ypT0/is ypN0) at surgery.	At definitive surgery, 3-5 weeks after completion of cycle 4 (week 15 from study entry)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR Rate	Proportion of patients achieving complete or partial tumor shrinkage by RECIST 1.1 on MRI.	After cycle 4, within 2 weeks before surgery (week 13).
Acute and late toxicities	Acute Radiation Skin Reaction;Immune-Related Adverse Events (irAEs)	From first SBRT fraction to 30 days post-SBRT (week 5); From first toripalimab dose to 90 days after last dose (week 28)

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Actual): January 4, 2026
• Primary Completion (Estimated): January 4, 2028
• Study Completion (Estimated): January 4, 2029

Study Registration Dates

• First Submitted: March 4, 2026
• First Submitted That Met QC Criteria: March 4, 2026
• First Posted (Actual): March 9, 2026

Study Record Updates

• Last Update Posted (Actual): March 9, 2026
• Last Update Submitted That Met QC Criteria: March 4, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: chemo-resistance; neoadjuvant SBRT
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Skin and Connective Tissue Diseases; Triple Negative Breast Neoplasms; toripalimab
• Other Study ID Numbers: Y2025-1398

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No