Addition of Platinum-based Chemotherapy to Tislelizumab in PD-L1high Metastatic Non-small Cell Lung Cancer With a High Tumor Burden (High Five)

AIO-TRK/YMO-0425 (High Five) is a phase III, open-label randomized-controlled, multicenter study to evaluate the progression-free survival by the addition of platinum-based chemotherapy to immunotherapy (IO) compared to IO monotherapy in patients with PD-L1high mNSCLC featuring a high tumor burden.

Study Overview

• Status: Not yet recruiting
• Conditions: Metastatic Non-small Cell Lung Cancer With a High Tumor Burden
• Intervention / Treatment: Drug: Tislelizumab; Drug: Pembrolizumab; Drug: Tislelizumab Combined With Chemotherapy

Detailed Description

This is a randomized, open-label, multicenter, phase III trial. Patients with squamous or non-squamous non-small-cell lung cancer (NSCLC) UICC 9th Stage IV, a high PD-L1 expression level (PD-L1 ≥ 50%) and a high tumor burden (baseline tumor size (BTS) ≥ 50 mm), eligible for 1st-line treatment with platinum and immunotherapy, will be enrolled in this trial. The patients will receive immuno-monotherapy (tislelizumab or pembrolizumab) or immunotherapy plus platinum-based doublet chemotherapy (squamous NSCLC: tislelizumab + carboplatin + (nab-) paclitaxel with tislelizumab maintenance; non-squamous NSCLC: tislelizumab + cis-/carboplatin + pemetrexed with tislelizumab maintenance) for a maximum of 24 months, with a subsequent follow-up phase until end of study (26 months after last patient in or until all patients have finished a 90-days safety follow-up) or preliminary termination or death. Standard of care tumor assessments will be performed and recorded according to RECIST version 1.1., at baseline/screening, throughout the treatment phase (initially after 6 weeks, thereafter each 12 ± 2 weeks), at end of treatment and during follow up.

• Study Type: Interventional
• Enrollment (Estimated): 230
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Gordana Bothe; Phone Number: +4930814534443; Email: gordana.bothe@aio-studien-ggmbh.de

Study Locations

• Germany
  • Frankfurt, Germany
    • University of Frankfurt
    • Contact: Sophie Ambrosius; Phone Number: +49 69 6301 5677; Email: s.ambrosius@med.uni-frankfurt.de
    • Principal Investigator: Sophie Ambrosius

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Written informed consent obtained from subject and ability for subject to comply with the requirements of the study
2. Histologically confirmed and treatment-naïve non-small cell lung cancer UICC 9th stage IV
3. PD-L1 ≥ 50%
4. High Tumor Burden defined as the longest diameter of the tumor or at least one metastasis ≥ 50mm and no eligibility for a curative treatment approach
5. Measurable disease according to RECIST v1.1
6. No actionable genomic alterations (AGA) qualifying for targeted first-line treatment
7. Eligible for platinum-based chemoimmunotherapy
8. Age ≥18 years
9. Patients with brain metastases may be included, except when whole brain radiation therapy (WBRT) is pending. In such case, patients may be included 7 or more days after completion of WBRT.

10. Female subjects of childbearing potential (FOCBP) should be using highly effective contraceptive measures and must have a negative urine or serum pregnancy test within 7 days prior to start of study treatment and must not be breast-feeding prior to start of trial. Non-child-bearing potential must be evidenced by fulfilling one of the following criteria at screening:

    • Postmenopausal, defined as at least 12 months with no menses without an alternative medical cause; a follicle stimulating hormone (FSH) level in the postmenopausal range for the institution may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
    • have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, at least 6 weeks prior to screening (Women with tubal ligation are still considered of child-bearing potential according to CTFG Guidance).
    • have a congenital or acquired condition that prevents childbearing Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.

Exclusion Criteria:

1. Presence of a condition, disease or abnormality that in the opinion of the Investigator would compromise the safety of the patient, the patient's ability to comply with the study procedures (e.g., dementia) or the quality of the data. Specifically, the presence of any preexisting autoimmune disease that prohibits dosing of IMP as per treatment modification guidelines in the current IB/SmPC
2. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study, or during the follow-up period of an interventional study
3. Concurrent malignancy other than NSCLC requiring active treatment
4. Has known hypersensitivity to the IMPs or to any component of the planned regimen, their metabolites, or formulation excipients, or any other contraindication to any component of the planned study regimen according to the tislelizumab IB and the relevant SmPCs

5. Current use of systemic corticosteroids that exceed 10 mg/day of prednisone or is equivalent medication within 3 days before the first dose of tislelizumab/pembrolizumab, except the following criterion:

   - steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)

6. Female subjects who are pregnant or breast-feeding or patients of reproductive potential who are not employing a highly effective method of birth control (failure rate of less than 1% per year)
7. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities
8. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Immune-monotherapy; Tislelizumab monotherapy 200 mg i.v. q3w or pembrolizumab monotherapy 200 mg i.v. q3w or	Drug: Tislelizumab; Tislelizumab monotherapy 200 mg i.v. q3w; Drug: Pembrolizumab; Pembrolizumab monotherapy 200 mg i.v. q3w
Experimental: Tislelizumab + platinum-based doublet chemotherapy; Non-squamous NSCLC: tislelizumab 200 mg i.v. + platinum-based chemotherapy (cisplatin 75 mg/m2 i.v. or carboplatin AUC 5-6 i.v.) + pemetrexed 500 mg/m2 i.v.; squamous NSCLC: tislelizumab 200 mg i.v. + carboplatin AUC 5-6 i.v. + (nab)paclitaxel (nab-paclitaxel 100 mg/m2 i.v., paclitaxel 175 or 200 mg/m2 i.v.	Drug: Tislelizumab Combined With Chemotherapy; Non-squamous NSCLC: tislelizumab 200 mg i.v. + platinum-based chemotherapy (cisplatin 75 mg/m2 i.v. or carboplatin AUC 5-6 i.v.) + pemetrexed 500 mg/m2 i.v.; squamous NSCLC: tislelizumab 200 mg i.v. + carboplatin AUC 5-6 i.v. + (nab)paclitaxel (nab-paclitaxel 100 mg/m2 i.v., paclitaxel 175 or 200 mg/m2 i.v.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	time from randomization to the date of first objective disease progression (according to RECIST V1.1) or death of any cause, whichever occurs first.	max. 50 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		max. 50 months
Objective response rate	rate of patients with complete response (CR) or partial response (PR) as best response	max. 50 months
Duration of response		max. 50 months
Disease control rate		max. 50 months
Quality of life (FACT-L)		max. 24 months

Collaborators and Investigators

• Sponsor: AIO-Studien-gGmbH
• Collaborators: BeOne Medicines

Study record dates

Study Major Dates

• Study Start (Estimated): October 30, 2026
• Primary Completion (Estimated): October 30, 2031
• Study Completion (Estimated): October 30, 2031

Study Registration Dates

• First Submitted: July 15, 2026
• First Submitted That Met QC Criteria: July 15, 2026
• First Posted (Actual): July 20, 2026

Study Record Updates

• Last Update Posted (Actual): July 20, 2026
• Last Update Submitted That Met QC Criteria: July 15, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: NSCLC; stage IV; Metastatic, Non-small Cell Lung Cancer, High Tumor Burden, Immunotherapy, Platinum-based Chemotherapy
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplastic Processes; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Pathological Conditions, Signs and Symptoms; Neoplasm Metastasis; Carcinoma, Non-Small-Cell Lung; Therapeutics; pembrolizumab; Drug Therapy; tislelizumab
• Other Study ID Numbers: AIO-TRK/YMO-0425; 2026-525497-18-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No