Hyperprogression in PD-L1 ≥ 50% NSCLC: a Biomarker Guided Phase 2 Trial

NCT07274384 | Not Yet Recruiting Phase 2

• 1 other identifier: 2025-521583-35-00
• Study Type: interventional
• Target: 74
• Locations: 0 countries
• Sites: N/A

Brief Summary

In metastatic NSCLC patients with PD-L1 expression ≥50%, a circulating immature (CD10-) LDNs level of ≥30.5% confers a high risk of hyperprogression (HPD) with first line single-agent immune-checkpoint inhibitors (SA-ICI). HPD is defined as a tumor growth rate (TGR) delta ≥50% between pre-treatment and post-treatment, and/or a TGR ratio ≥2. The combination of platinum-based chemotherapy (PCT) with ICI in this setting could prevent the occurrence of HPD and ultimately improve survival outcomes. This randomized, multicentric, open-label, phase 2 trial will include patients with stage IV NSCL, without targetable oncogene drivers, PD-L1 TPS≥50%, and measurable disease on two CT scans performed before randomization. Participants will be randomized 1:1 to SA-ICI or ICI+PCT. Radiological evaluation will be performed by CT-scan at 6-8 weeks and subsequently according to the local investigators' schedule. In the SA-ICI arm, ICI regimen will include cemiplimab. In the PCT+ICI arm, PCT regimens will include both carboplatin or cisplatin + pemetrexed (for non-squamous histology) or paclitaxel (for squamous histology) in combination with cemiplimab. PCT will be administered for three cycles. In case of stable disease or partial response according to RECIST v.1.1, cemiplimab will be performed as monotherapy from the third cycle until disease progression or unacceptable toxicity. If progression according to RECIST v.1.1 or HPD after three cycles of PCT+ICI, patients will be treated with standard second line therapy as local standard of care.

Conditions

NSCLC (Non-small Cell Lung Cancer); Hyperprogression

Keywords

lung; cancer; hyperprogression; chemotherapy; immunotherapy; carboplatin; cisplatin; pemetrexed; paclitaxel; cemiplimab; risk; immune-checkpoint inhibitors; ldns; CD10-; nsclc; PD-L1; randomized; open-label; Lung Immune Prognostic Index; recist; progression; monotherapy; hpd; non small cell lung cancer

Outcome Measures

Primary Outcomes (2)

• HPD rate

  HPD rate, defined as the proportion of patients with a delta of TGR ≥50% or a TGR ratio ≥2 at 7 weeks ± 5 days from randomization

  up to HPD, end of treatment for a maximum of 108 weeks whichever comes first

• ED rate

  ED rate: who died without undergoing a scan after treatment initiation.

  up to ED, end of treatment for a maximum of 108 weeks whichever comes first

Secondary Outcomes (4)

• Overall survival (OS)

  up to HPD, ED, end of treatment for a maximum of 108 weeks whichever comes first

• Progression free survival (PFS)

  up to HPD, ED, end of treatment for a maximum of 108 weeks whichever comes first

• Objective response rate (ORR)

  up to HPD, ED, end of treatment for a maximum of 108 weeks whichever comes first

• Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

  up to 90 days after the last dose of study treatment

Other Outcomes (3)

• Exploratory baseline and dynamic characterization of patients' tissue and circulating clinical and radiological features correlated with HPD occurrence, according to treatment arm

  through study completion, an avarage of 3 years

• Exploratory characterization of clinical, radiological, and biological patients' features correlated with HPD occurrence.

  through study completion, an avarage of 3 years

• HPD rate among patients not meeting inclusion criterion 7

  through study completion, an avarage of 3 years

Study Arms (2)

single-agent immune-checkpoint inhibitors

ACTIVE COMPARATOR

single-agent immune-checkpoint inhibitors (SA-ICI) (Cemiplimab)

Drug: Cemiplimab

PCT regimens + immune-checkpoint inhibitors

EXPERIMENTAL

PCT regimens will include both carboplatin or cisplatin plus pemetrexed (for non-squamous histology) or paclitaxel (for squamous histology) in combination with cemiplimab

Combination Product: chemotherapy plus cemiplimab

Interventions

chemotherapy plus cemiplimab COMBINATION_PRODUCT

Combination of platinum-based chemotherapy (PCT) with ICI. PCT regimens will include both carboplatin or cisplatin plus pemetrexed (for non-squamous histology) or paclitaxel (for squamous histology) in combination with cemiplimab. PCT will be administered for three cycles.

Also known as: cemiplimab, carboplatin, cisplatin, pemetrexed, paclitaxel

PCT regimens + immune-checkpoint inhibitors

Cemiplimab DRUG

single-agent immune-checkpoint inhibitors

Also known as: libtayo

single-agent immune-checkpoint inhibitors

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The participant (or legally acceptable representative) has provided documented informed consent to participation to the study and data protection consent form.
• Male or female aged 18 years or older.
• ECOG Performance Status of 0 - 2.
• Pathologically (histologically or cytologically) confirmed diagnosis of stage IV NSCLC (TNM 8th edition), who received no prior systemic treatment for recurrent or metastatic NSCLC. Mixed squamous/non-squamous tumors are eligible.
• PD-L1 TPS ≥ 50% (by local test).
• Absence of targetable oncogene alterations (EGFR, ALK, ROS1).
• Circulating CD10- LDNs \>30.5% at screening. LDNs will be defined as CD11b+CD15+ cells among live PBMC. Flow cytometry raw data will be centrally analyzed by the coordinating center.
• Measurable disease (RECIST 1.1) on two CT scans performed before randomization. The following criteria must be fulfilled:
• Participants must have at least one measurable lesion that has not been previously treated with radiotherapy.
• Chest and abdomen scans are mandatory
• Availability of measurable disease scans to be anonymized and sent for central independent confirmation by a radiologist of the coordinating center.
• A minimum 2-week interval and a maximum 12-week interval will be acceptable between the two pre-treatment CT scans.
• Availability to perform the baseline scan within a maximum 4-week interval before treatment start.
• Patient's willingness to undergo blood draws to provide plasma and blood samples for analysis according to study objectives.
• Adequate organ and marrow function as defined below:

You may not qualify if:

• Any infection requiring hospitalization or treatment with IV anti-infectives within 2 weeks of first dose of study medication
• Known uncontrolled infection with HIV, hepatitis B or hepatitis C infection, diagnosis of immunodeficiency, and/or tuberculosis (active or latent). No serological testing is required unless mandated by local health authority.
• Administration of live or live-attenuated vaccines within 30 days before the baseline LDNs assessment. Administration of killed vaccines is allowed. Receipt of COVID-19 vaccination within 1 week of planned start of study medication or for which the planned COVID-19 vaccinations would not be completed 1 week prior to start of study medication.
• History of interstitial lung disease (eg, idiopathic pulmonary fibrosis or organizing pneumonia), of active, noninfectious pneumonitis that required immune-suppressive doses of glucocorticoids to assist with management.
• Administration of radiotherapy within 7 days prior to the baseline LDNs assessment.
• Administration of colony-stimulating factors (e.g., G-CSF, GM-CSF) or recombinant erythropoietin within 28 days prior to the baseline LDNs assessment. Primary prophylaxis with G-CSF and pegylated G-CSF is not allowed. Secondary prophylaxis is not recommended and required case-by-case discussion with the coordinator center before G-CSF administration.
• Female patients who are pregnant, breast-feeding, male, or female patients of reproductive potential who are not employing an highly effective method of birth control.
• Any condition that, in the opinion of the investigator, would interfere with the evaluation of the study drug or interpretation of patient safety or study results.
• Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment (Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable).
• Allogenic tissue/solid organ transplant.

Sponsors & Collaborators

• Università Vita-Salute San Raffaele: lead
• Istituto Di Ricerche Farmacologiche Mario Negri: collaborator

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Neoplasms; Disease Progression

Interventions

Drug Therapy; cemiplimab; Carboplatin; Cisplatin; Pemetrexed; Paclitaxel

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Therapeutics; Coordination Complexes; Organic Chemicals; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: randomized, open-label

Study Record Dates

• First Submitted: September 17, 2025
• First Posted: December 10, 2025
• Study Start: January 1, 2026
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): June 1, 2030
• Last Updated: December 10, 2025

Record last verified: 2025-11