Preoperative Radioimmunotherapy Versus Chemoimmunotherapy in NSCLC

Inclusion Criteria:

1. Patients with histologically or cytologically proven clinical stages IB (T2aN0), II,and III(N2) NSCLC (according to AJCC version 9) eligible for surgical resection withcurative intent. Patients with 2 synchronous NSCLC are allowed.

2. Measurable disease, as defined by RECIST v1.1.

3. Known PD-L1 expression.

4. No known EGFR mutations or ALK fusions.

5. Written informed consent and HIPAA obtained from the subject prior to performing anyprotocol-related procedures.

6. Age > 18 years at time of study entry.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

8. No prior therapy for lung cancer

9. Adequate organ and bone marrow function as defined below:

• Absolute neutrophil count (ANC) ≥1.5 x10(3)/uL

• Platelets ≥75 x10(3)/uL

• Hemoglobin ≥9 g/dL

• Serum creatinine ≤1.5 X upper limit of normal (ULN) OR calculated CrCl ≥50 ml/min (using the Cockcroft-Gault formula).

• Serum total bilirubin ≤1.5 X ULN, except in patients with clinically documentedGilbert's Syndrome where ≤3x the ULN is permitted

• Aspartate aminotransferase (AST)/ Alanine aminotransferase (ALT) ≤3 X ULN

10. WOCBP* must have a negative serum (beta-hCG) at screening. a) *WOCBP are defined aswomen who are fertile following menarche until becoming postmenopausal, unlesspermanently sterile. Permanent sterilization methods include hysterectomy, bilateralsalpingectomy, and bilateral oophorectomy.

• A postmenopausal state is defined as no menses for 12 months without analternative medical cause. A high FSH level in the postmenopausal range may be usedto confirm a postmenopausal state in women not using hormonal contraception orhormonal replacement therapy. However, in the absence of 12 months of amenorrhea, asingle FSH measurement is insufficient to determine the occurrence of apostmenopausal state. The above definitions are according to the CTFG guidance.Pregnancy testing and contraception are not required for women who arepost-menopausal or with documented permanent sterilization. b) Male study patients with WOCBP partners are required to use condoms unless theyare vasectomized or practice sexual abstinence. c) Vasectomized partner or vasectomized study patient must have received medicalassessment of the surgical success. d) Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and LAM are not acceptable methods ofcontraception. Female condom and male condom should not be used together.

11. WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assistedreproduction during the entire trial and until 6 months after last treatment.

12. All men must agree not to donate sperm during the trial and for 6 months afterreceiving the last therapy dose.

Exclusion Criteria:

1. History of another primary malignancy except for:

-Malignancy treated with curative intent and with no known active disease ≥2 yearsbefore the first dose of the study drug and of low potential risk for recurrence.

-Adequately treated non-melanoma skin cancer or lentigo maligna without evidence ofdisease.

• Adequately treated carcinoma in situ without evidence of disease e.g., cervicalcancer in situ, in-situ urinary bladder cancer, treated localized prostatecancer, and ductal carcinoma in-situ.

• Indolent hematological malignancies

2. Current or prior use of immunosuppressive medication within 14 days before the firstdose of cemiplimab, with the exceptions of intranasal, inhaled, topical steroids, orlocal steroid injections (e.g.intra articular injection), corticosteroids orsystemic corticosteroids at physiological doses which are not to exceed 10 mg/day ofprednisone or an equivalent corticosteroid, and steroids as premedication forhypersensitivity reactions (e.g., CT scan premedication).

2.a. Any condition that requires ongoing/continuous corticosteroid therapy (>10mg 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.

3. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]. No active diverticulitis within the previous 3 months. The following are exceptions to this criterion:

• Patients with vitiligo or alopecia

• Patients with endocrinopathies (such as hypothyroidism or type 1 diabetes (e.g.,following Hashimoto syndrome) stable on hormone replacement, or psoriasis that doesnot require systemic treatment.

• Any chronic skin condition that does not require systemic therapy

• Patients with childhood asthma that has resolved 4. Uncontrolled, intercurrentillness including, but not limited to: ongoing or active infection requiringantibiotics (exception is a brief (≤10 days) course of antibiotics to be completedbefore initiation of treatment), symptomatic congestive heart failure, unstableangina pectoris, or psychiatric illness/social situations that would limitcompliance with study requirements as determined by the Investigator.

5. Interstitial lung disease (eg, idiopathic pulmonary fibrosis, organizingpneumonia) or active, noninfectious pneumonitis that requires immune-suppressivedoses of glucocorticoids to assist with management. A history of radiationpneumonitis in the radiation field is permitted as long as pneumonitis is resolved ≥6 months prior to study treatment.

6. Receipt of a live vaccine within 30 days of the planned start of studymedication.

Note: If a patient intends to receive a COVID-19 vaccine before the start of the study drug, participation in the study should be delayed at least 4 weeks after any COVID-19 vaccination. During the neoadjuvant treatment period, it is recommended to delay any COVID-19 vaccination or any other vaccination until patients have undergone radical surgery for the lung. A vaccine dose should not be administered less than 48 hours (ideally by at least one week) before or after study drug dosing.

7. Prior allogeneic stem cell transplant or solid organ transplant. 8. Uncontrolled HIV, active hepatitis B or C, or diagnosis of immunodeficiency, and/or tuberculosis (active or latent).

8. Participants with known controlled HIV infection (undetectable viral load or HIV RNAPCR) and CD4 count above 250 either spontaneously or on a stable antiviral regimenare eligible. For these participants monitoring will be performed per localstandards.

9. Participants with HBsAg positive who have controlled infection (serum HBV DNA PCRthat is below the limit of detection and receiving antiviral therapy for hepatitisB) are eligible. Participants with controlled infections must undergo periodicmonitoring of HBV DNA. Participants must remain on antiviral therapy for at least 6months beyond the last dose of investigational study medication.

10. Participants with HBsAg negative but total HBcAb positive are permitted with thefollowing requirements: if HBV DNA PCR is above limit of detection at screening,initiate HBV antiviral therapy before study entry. If serum HBV DNA PCR is below thelimit of detection, periodic monitoring of HBsAg must be performed.

11. Participants who are HCV Ab+ who have controlled infection (undetectable HCV RNA byPCR either spontaneously or in response to successful prior course of anti-HCVtherapy) are eligible.

12. Female patients who are pregnant or breastfeeding. 10. Sexually active men andWOCBP who are unwilling to practice highly effective contraception prior to theinitial dose/start of the first treatment, during the study, and for at least 6months after the last dose. Highly effective contraceptive measures include:

13. 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 moremenstrual cycles prior to screening

14. IUD; IUS

15. bilateral tubal ligation (occlusion)

16. vasectomized partner (provided that the male vasectomized partner is the sole sexualpartner of the WOCBP study patient and that the vasectomized partner has obtainedmedical assessment of surgical success for the procedure); and or

17. sexual abstinence

• Sexual abstinence is considered a highly effective method only if defined asrefraining from heterosexual intercourse during the entire period of riskassociated with the study treatments. The reliability of sexual abstinenceneeds to be evaluated in relation to the duration of the clinical trial and thepreferred and usual lifestyle of the subject.

• Periodic abstinence (calendar, symptothermal, post-ovulation methods),withdrawal (coitus interruptus), spermicides only, and LAM are not acceptablemethods of contraception. Female condom and male condom should not be usedtogether.

• Sexually active men and their partners must use highly effective contraceptionas described above. Contraception is not required for men with documentedvasectomy. Pregnancy testing and contraception are not required for women whoare post-menopausal or with documented permanent sterilization.

• Male participants: a male participants will be excluded from the study ifthat participant does not agree to use condoms or practice sexualabstinence, unless vasectomized, prior to the initial dose/start of studymedication, during the study, and for at least 4 months after the lastdose. Sperm donation is also prohibited during the same period. Vasectomysuccess must be confirmed by semen analysis.

11. Adjuvant hormonotherapy used for breast cancer or otherhormone-sensitive cancers in long term remission is allowed.
12. Presence of cardiovascular disease, as defined by: a. New York Heart Association heart failure classifications of Class II,III, or IV; or myocardial infarction, or acute coronary syndrome within 12months of first dose of study medication; or b. Transient ischemic attackor stroke within 1 year 13. Known hypersensitivity to the activesubstances or to any of the excipients.
13. Any infection requiring hospitalization or treatment with IVanti-infectives within 2 weeks of first dose of study medication.