Hyperprogression upon cemiplimab alone or with chemotherapy in PD-L1 ≥ 50% NSCLC: a biomarker guided phase 2 trial – HYPERBOLIC study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universita' Vita-salute S. Raffaele

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2026-02-10

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

AIRC - Next Gen Clinician Scientist Grant

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To compare the efficacy of cemiplimab+PCT relative to cemiplimab alone in reducing HPD (hyperprogression) and early death (ED) rate. Patients who experimented early death (ED), defined as death within 12 weeks since ICI start with no scan performed from treatment start, will be also categorized as HPD

Secondary objectives 3

1. To compare the activity and efficacy of cemiplimab+PCT relative to cemiplimab alone. To compare the safety and tolerability of cemiplimab+PCT relative to cemiplimab alone.
2. To compare the safety and tolerability of cemiplimab+PCT relative to cemiplimab alone
3. To characterize how treatments with cemiplimab and cemiplimab+PCT modulate circulating or tissue features of HPD.

Conditions and MedDRA coding

non-small cell lung cancer (NSCLC)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 1. The participant (or legally acceptable representative) has provided documented informed consent to participation to the study and data protection consent form. 2. Male or female aged 18 years or older. 3. ECOG Performance Status of 0 – 2. 4. 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. 5. PD-L1 TPS ≥ 50% (by local test). 6. Absence of targetable oncogene alterations (EGFR, ALK, ROS1). 7. 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. 8. 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 scans are mandatory, while chest and abdomen CT scans are preferred. - 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. 9. Patient’s willingness to undergo blood draws to provide plasma and blood samples for analysis according to study objectives. 10. Adequate organ and marrow function as defined below: - Absolute neutrophil count > 1.5 x 109/L (1500/mm3) - Platelets ≥100 x 109/L (100 000/mm3) - Haemoglobin ≥9.0 g/dL (5.59 mmol/L) - Adequate renal function: Calculated creatinine clearance (according to Cockroft-Gault): ≥60ml/min for patient receiving cisplatin; ≥45ml/min for patient receiving carboplatin. - Serum bilirubin ≤1.5 x upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of evidence of hemolysis or hepatic pathology) who will be allowed in consultation with their physician. - AST and ALT ≤2.5 x ULN. 11. Absence of a known severe hypersensitivity (≥ Grade 3) to any of the study chemotherapy agents and/or cemiplimab and/or to any of their excipients

Exclusion criteria 1

1. 1. Any infection requiring hospitalization or treatment with IV anti-infectives within 2 weeks of first dose of study medication 2. 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. 3. 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. 4. 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. 5. Administration of radiotherapy within 7 days prior to the baseline LDNs assessment. 6. 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. 7. Ongoing or recent evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments. The following are not exclusionary: vitiligo, childhood asthma that has resolved, endocrinopathies (such as hypothyroidism or type 1 diabetes) that require only hormone replacement, or psoriasis that does not require systemic treatment. 8. 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. 9. 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. 10. 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). 11. Allogenic tissue/solid organ transplant.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. HPD and ED 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 or who died before with no scan performed from treatment start

Secondary endpoints 6

1. (related to activity-efficacy secondary objective) HPD rate, defined as the proportion of patients with a delta of TGR ≥50% and/or a TGR ratio ≥2 at 5 weeks ± 5 days from treatment start.
2. (related to activity-efficacy secondary objective) Objective Response Rate (ORR), defined as the percentage of patients with an objective response as determined by RECIST 1.1.
3. (related to activity-efficacy secondary objective) Progression free survival (PFS), defined as the time from randomization to the date of first progression or death from any cause, whichever comes first. Data from patients who have not had an event at the time of data analysis will be censored on the date on which they are last known to be alive and event free.
4. (related to activity-efficacy secondary objective) Overall survival (OS), defined as the time from randomization until the date of death from any cause. Data from patients who are still alive at the time of data analysis will be censored on the date on which they are last known to be alive.
5. (related to safety and tolerability secondary objective) Summary of adverse events (AE), with a focus on TRAEs coded based upon the Medical Dictionary for Regulatory Activities (MedDRA) and graded based upon CTCAE, ver. 5.0.
6. (related to exploratory objective) Characterization of clinical, radiological, and biological patients’ features correlated with HPD occurrence. - Dynamic assessment of circulating and tissue features of HPD according to treatment type (cemiplimab alone or cemiplimab + PCT) - HPD rate among patients not meeting inclusion criterion 7 (circulating CD10- LDNs >30.5% at screening).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universita' Vita-salute S. Raffaele

Sponsor organisation

Universita' Vita-salute S. Raffaele

Address

Via Olgettina 58

City

Milan

Postcode

20132

Country

Italy

Scientific contact point

Organisation

Universita' Vita-salute S. Raffaele

Contact name

Roberto Ferrara

Public contact point

Organisation

Universita' Vita-salute S. Raffaele

Contact name

Roberto Ferrara

Third parties 1

Locations

1 EU/EEA country · 27 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 23 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications