RADICAL-IO: thRee Cycles of immunotherApy Without raDical Therapy In mediCALly InOperable Stage I Non-small Cell Lung Cancer (RADICAL-IO)

Traditionally, chemotherapy and/or immunotherapy are combined with surgery or radiotherapy to cure patients with lung cancer. However, some patients treated with immunotherapy appear to be cured before surgery or radiotherapy. In this study, we will select patients with a high chance to respond to immunotherapy. These patients will be treated with immunotherapy alone, thereby evaluating whether these patients can be cured without surgery or radiotherapy.

Study Overview

• Status: Not yet recruiting
• Conditions: Non Small Cell Lung Cancer; Immunotherapy
• Intervention / Treatment: Drug: Cemiplimab 350 mg IV

Detailed Description

Early-stage non-small cell lung cancer (NSCLC) patients with a pathological complete response (pCR) to neoadjuvant chemoimmunotherapy are potentially already cured before the local radical treatment is administered. However, treatment de-escalation in these patients is unfeasible since pCR detection before local radical treatment is unreliable. We propose to evaluate whether we can safely omit local radical therapy after immunotherapy in selected patients with stage Ia NSCLC with high probability of immunotherapy benefit.

Participants receive three cycles of 350 milligrams of cemiplimab intravenously every three weeks followed by a radiological and metabolic response evaluation with respectively CT and [18F]FDG-PET. Thereafter patients will enter the follow-up phase where response will be closely monitored with CT scans 3-monthly. Additionally, blood will be collected for ctDNA analysis at baseline, during treatment with cemiplimab and follow-up will be collected. According to standard of care, patients will undergo a [18F]FDG-PET scan if progressive disease is suspected. Participants with disease recurrence will be treated off-study at the discretion of the treating physician.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Dr. W.S.M.E. Theelen, MD PhD; Phone Number: 0031 020 512 9111.; Email: w.theelen@nki.nl
• Study Contact Backup: Name: Eline R Harding, MD; Phone Number: 0031 020 512 9111.; Email: e.harding@NKI.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Netherlands Cancer Institute - Antoni van Leeuwenhoek
    • Contact: Eline R Harding, MD; Phone Number: 0031 020 512 9111.; Email: e.harding@NKI.nl
    • Contact: Dr. W.S.M.E Theelen, MD PhD; Phone Number: 0031 020 512 9111.; Email: w.theelen@nki.nl
    • Sub-Investigator: Lydia Schonewille, MD
    • Principal Investigator: Egbert Smit, Prof. Dr. MD. PhD,
  • Leiden, Netherlands, 2333 ZA
    • Leids Universitair Medisch Centrum (LUMC)
    • Contact: Lydia Schonewille, MD; Phone Number: 0031 071 526 9111; Email: l.h.n.schonewille@lumc.nl

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Have pathologically proven newly diagnosed, treatment-naive stage IA (i.e. tumor diameter ≤ 3 cm) NSCLC according to the 9th AJCC/UICC staging classification (30).
2. Be willing and able to provide written informed consent/assent for the trial.
3. Be 18 years of age on day of signing informed consent.
4. Should have measurable disease according to RECIST 1.1.
5. Have a performance status of 0, 1 or 2 on the ECOG Performance Scale.
6. Molecular analysis using next-generation sequencing (NGS) should be performed to identify oncogenic driver alterations and/or STK11 or KEAP1 mutations. If NGS is not available, the patient must have a smoking history of at least 10 packyears.
7. PD-L1 TPS should be at least 50%.
8. Should have an indication for SABR determined by the multidisciplinary team meeting.
9. Demonstrate adequate organ function as defined in Table 1. All screening labs should be performed within 14 days of treatment initiation.
10. Female participant of childbearing potential should have a negative serum pregnancy test within 72 hours prior to receiving the 1st dose of study medication.

Exclusion Criteria:

1. Has a known driver mutation associated with lack of cemiplimab efficacy (e.g. EGFR, ALK, HER2, RET or ROS1). Patients with smoking-related targetable driver mutation (e.g. KRAS or BRAF non-V600E) are eligible for this study. If this is unavailable, a patient should have smoked ≥10 packyears to be eligible.
2. Has a known mutation in STK11 and/or KEAP1 predictive of poor response to PD-(L)1 inhibitors.
3. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the 1st dose of treatment.
4. Has received prior therapy with any antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways other than PD-(L)1 blockade, e.g. anti-CD137 or a CTLA-4 antibody.
5. Has a known additional malignancy that is progressing or requires active treatment.
6. Has evidence of symptomatic interstitial lung disease or an active, non-infectious pneumonitis.

7. Presence of cardiovascular disease, as defined by:

   1. New York Heart Association heart failure classifications of Class II, III or IV; or myocardial infarction, or acute coronary syndrome within 12 months of first dose of study medication or
   2. Transient ischemic attack or stroke within 1 year
8. Any condition that requires ongoing/continuous corticosteroid therapy (>10 mg prednisone/day or anti-inflammatory equivalent) within 1 week prior to the first dose of study medication. Participants who require a brief course of steroids (up to 2 days in the week before enrollment) or physiologic replacement are not excluded.

9. Ongoing or recent evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments.

   Note: 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.

10. Any infection requiring hospitalization or treatment with IV anti-infectives within 2 weeks of first dose of study medication.

11. Uncontrolled infection with known HIV, hepatitis B or hepatitis C infection, diagnosis of immunodeficiency, and/or tuberculosis (active or latent).

    1. Participants with known controlled HIV infection (undetectable viral load on HIV RNA PCR) and CD4 count above 350 either spontaneously or on a stable antiviral regimen are eligible. For these participants monitoring will be performed per local standards.
    2. Participants with HBsAg positive who have controlled infection (serum HBV DNA PCR that is below the limit of detection and receiving anti-viral therapy for hepatitis B) are eligible. Participants with controlled infections must undergo periodic monitoring of HBV DNA. Participants must remain on anti-viral therapy for at least 6 months beyond the last dose of investigational study medication.
    3. Participants with HBsAg negative but total HBcAb positive are permitted with the following requirements: If serum HBV DNA PCR is above the limit of detection at screening, initiate HBV antiviral therapy before study entry. If serum HBV DNA PCR is below the limit of detection, periodic monitoring of HBsAg must be performed.
    4. Participants who are HCV Ab+ who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to successful prior course of anti-HCV therapy) are eligible.
12. Receipt of a live vaccine within 4 weeks of start of study medication
13. 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
14. Known hypersensitivity to the active substances or to any of the excipients.
15. Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to first dose.
16. Is currently breastfeeding or intends to breastfeed during the study period.

17. WOCBP* or men** who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study and for at least 4 months after the last dose. Highly effective contraceptive measures include:

    1. Stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening;
    2. Intrauterine device; intrauterine hormone-releasing system;
    3. Bilateral tubal occlusion/ligation;
    4. Vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has obtained medical assessment of surgical success for the procedure); and/or
    5. Sexual abstinence †,‡

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
Active Comparator: Three cycles of cemiplimab	Drug: Cemiplimab 350 mg IV; three cycles of 350 milligrams of cemiplimab intravenously every three weeks; Other Names: Libtayo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence free survival (RFS) as per RECIST 1.1	Time from first cemiplimab administration to disease recurrence/progression as per RECIST 1.1, fatal TRAEs or NSCLC-related death.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimate event free survival	Time from first cemiplimab administration to disease recurrence/progression as per RECIST 1.1 or death of any cause	24 months
Evaluate safety	Grade >3 TRAEs classified by NCI-CTCAE v5 up until 90 days after the last cemiplimab cycle, in particular pneumonitis. Rate of local radical therapy after disease recurrence.	24 months
Estimate survival	Overall survival (time from first cemiplimab administration to death of any cause) and disease specific survival (time from first cemiplimab administration to NSCLC related death)	24 months
Estimate location of disease recurrence	Time from first cemiplimab administration to local, regional and distant disease recurrence/progression	24 months
Objective reponse rate (ORR)	Objective response rate as per RECIST 1.1	24 months
BoR	Best objective response rate as per RECIST 1.1	24 months
DoR	Time between objective response to disease recurrence as per RECIST 1.1	24 months

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Collaborators: Regeneron Pharmaceuticals; Leiden University Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2026
• Primary Completion (Estimated): December 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: September 3, 2026
• First Submitted That Met QC Criteria: September 3, 2026
• First Posted (Actual): September 8, 2026

Study Record Updates

• Last Update Posted (Actual): September 8, 2026
• Last Update Submitted That Met QC Criteria: September 3, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: Immunotherapy; early stage non small cell lung cancer
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; cemiplimab
• Other Study ID Numbers: M25RIO; 2025 (U.S. NIH Grant/Contract: Faculty of Social Sciences Scientific Grant at the University of Gdańsk); 2025-524305-32-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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