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

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.

Inclusion criteria

• 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).
• Be willing and able to provide written informed consent/assent for the trial.
• Be 18 years of age on day of signing informed consent.
• Should have measurable disease according to RECIST 1.1.
• Have a performance status of 0, 1 or 2 on the ECOG Performance Scale.
• 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.
• PD-L1 TPS should be at least 50%.
• Should have an indication for SABR determined by the multidisciplinary team meeting.
• Demonstrate adequate organ function as defined in Table 1. All screening labs should be performed within 14 days of treatment initiation.
• 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

• 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.
• Has a known mutation in STK11 and/or KEAP1 predictive of poor response to PD-(L)1 inhibitors.
• 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.
• 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.
• Has a known additional malignancy that is progressing or requires active treatment.
• Has evidence of symptomatic interstitial lung disease or an active, non-infectious pneumonitis.
• Presence of cardiovascular disease, as defined by:

• 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
• Transient ischemic attack or stroke within 1 year
• 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.
• 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.

• Any infection requiring hospitalization or treatment with IV anti-infectives within 2 weeks of first dose of study medication.
• Uncontrolled infection with known HIV, hepatitis B or hepatitis C infection, diagnosis of immunodeficiency, and/or tuberculosis (active or latent).

• 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.
• 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.
• 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.
• 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.
• Receipt of a live vaccine within 4 weeks of start of study medication
• 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
• Known hypersensitivity to the active substances or to any of the excipients.
• Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to first dose.
• Is currently breastfeeding or intends to breastfeed during the study period.
• 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:

• 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;
• Intrauterine device; intrauterine hormone-releasing system;
• Bilateral tubal occlusion/ligation;
• 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
• Sexual abstinence †,‡