Three‑Cycle Cemiplimab Immunotherapy Versus Standard Radiotherapy for Recurrence‑Free Survival in Medically Inoperable Stage I Non‑Small Cell Lung Cancer

The primary objective is to estimate recurrence‑free survival following three cycles of cemiplimab immunotherapy in patients with medically inoperable stage I non‑small cell lung cancer, providing a direct measure of treatment efficacy in preventing disease return. Secondary objectives include:

• Estimation of event‑free survival to assess the interval without any disease‑related events.
• Evaluation of safety to monitor adverse events associated with the investigational regimen.
• Estimation of the objective response rate to determine the proportion of patients achieving a predefined tumor reduction.
• Estimation of the best observed response to capture the highest level of tumor shrinkage recorded.
• Estimation of the duration of response to quantify how long tumor control is maintained.
• Estimation of the location of disease recurrence to characterize patterns of relapse.
• Estimation of overall survival to evaluate the impact of treatment on patient lifespan.

The trial enrolled adult patients (≥18 years) of both sexes with Stage I non‑small cell lung cancer meeting specific disease and treatment criteria. Participants were required to have pathologically confirmed, newly diagnosed, treatment‑naïve disease ≤4 cm, measurable lesions per RECIST 1.1, and an ECOG performance status of 0–2. Eligibility required molecular profiling by next‑generation sequencing or, alternatively, a documented smoking history of ≥10 pack‑years. Additional requirements included PD‑L1 tumor proportion score ≥50 %, adequate organ function, and an indication for stereotactic ablative radiotherapy as determined by a multidisciplinary team. All subjects had to provide written informed consent and, for females of child‑bearing potential, a negative pregnancy test within 72 hours prior to the first dose. The sponsor did not provide the total number of participants enrolled.

The RADICAL‑IO trial is a phase 4 (phase II justification) investigation of three cycles of intravenous cemiplimab 350 mg administered every three weeks to participants with newly diagnosed, treatment‑naïve stage I non‑small cell lung cancer who meet predefined pathological, molecular, and PD‑L1 (≥50 %) criteria. After an initial screening visit to confirm eligibility—including pathology review, RECIST 1.1 measurability, ECOG performance status 0–2, organ‑function labs, pregnancy testing for women of child‑bearing potential, and next‑generation sequencing or a ≥10‑pack‑year smoking history—eligible subjects receive the first infusion (Day 1) followed by two additional infusions on Days 22 and 43. Safety assessments, laboratory tests, and imaging are performed at each infusion visit and at a 30‑day post‑treatment safety follow‑up. Subsequent follow‑up visits occur at regular intervals (e.g., every 12 weeks) to evaluate disease status per RECIST 1.1, capture adverse events, and record survival outcomes until the end‑of‑study visit, which concludes participant involvement. The overall participation period extends from screening through the final follow‑up, typically spanning up to 24 months depending on individual disease course. Early termination may occur for disease progression, occurrence of a grade ≥ 3 treatment‑related adverse event, withdrawal of consent, or death.

The investigational product is LIBTAYO 350 mg concentrate for solution for infusion, containing the monoclonal antibody cemiplimab. It is supplied as a concentrate for solution for infusion and is administered by intravenous infusion at a dose of 350 mg per treatment cycle. The dosing schedule comprises three consecutive cycles of immunotherapy, with each cycle consisting of a single infusion.

No additional investigational agents, placebo, or specified standard‑of‑care therapies are described in the protocol; therefore, no comparator treatments are detailed.

Drug administration is performed in a clinical setting by qualified personnel. Infusion parameters, including rate and duration, are recorded in the participant’s source documents. Compliance monitoring includes verification of dose preparation, infusion completion, and documentation of any infusion‑related adverse events. All dosing events are logged to ensure adherence to the three‑cycle schedule.

Efficacy will be evaluated primarily by the time interval from the first administration of cemiplimab to disease recurrence or progression, as defined by RECIST 1.1, fatal treatment‑related adverse events, or NSCLC‑related death. Secondary efficacy assessments include time to recurrence or progression per RECIST 1.1 or death from any cause, objective response rate and best objective response according to RECIST 1.1, time between documented response and subsequent recurrence, time to local, regional, and distant disease recurrence, overall survival, disease‑specific survival, and the rate of local radical therapy after recurrence. Grade ≥ 3 treatment‑related adverse events, particularly pneumonitis, will be recorded up to 90 days after the last cemiplimab cycle.

All radiologic evaluations will be performed using standardized imaging protocols and interpreted according to the RECIST 1.1 criteria. Time‑to‑event endpoints will be analyzed using appropriate survival analysis methods, such as Kaplan–Meier estimates and Cox proportional hazards modeling, to compare the observed outcomes with historical benchmarks. Objective response metrics will be derived from the proportion of participants achieving complete or partial responses as defined by RECIST 1.1.