The goal of this study is to explore if, for locally advanced non-small cell lung cancer patients whose tumors have high levels of PD-L1 (a marker associated with benefits from immunotherapy), a combination of immunotherapy and a personalized 4-week radiotherapy course could be more effective than standard treatment, which is a combination of chemotherapy and radiotherapy.

This is a Phase II trial evaluating the efficacy and safety of sequential pembrolizumab (200 mg every three weeks) and accelerated, dose-painted radiotherapy for patients with locally advanced NSCLC with PD-L1 expression ≥ 50%. Patients with PD-L1 expression < 50% will be treated with concurrent chemoradiotherapy as part of standard of care.

Inclusion Criteria:

Participants are eligible to be included in the study only if all the following criteria apply:

1. Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of non-small cell lung cancer will be enrolled in this study.

2. Previously untreated, pathologically proven NSCLC with measurable disease (at least 1 unidimensional, radiographically measurable lesion based on RECIST v1.1) and one of the following stages: (prior resection for early stage disease is allowed)

   1. AJCC version 8 Stage II disease, medically or technically unresectable
   2. AJCC version 8 Stage III disease

3. Whole body PET/CT within 42 days prior to study entry demonstrating hypermetabolic pulmonary lesion(s) and/or thoracic lymph node(s). If PET/CT was obtained more than 42 days prior to study entry and is not repeated, CT within 28 days prior to study entry demonstrating no evidence of metastatic disease is required.

4. MRI of the brain or head CT with contrast within 42 days prior to study entry.

5. PFTs within 42 days of study entry

6. ECOG performance status 0-1

7. Adequate end-organ function, based on routine clinical and laboratory workup:

   1. ANC >1,500 cells/µl, Platelets ≥ 100,000 cells/µl, Hemoglobin ≥ 9.0 g/dl
   2. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 ml/min
   3. Total bilirubin ≤ 1.5 x ULN (or direct bilirubin below the ULN), AST and ALT ≤ 2.5 x ULN
   4. International normalized ratio (INR) (or prothrombin time (PT)) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy, as long as values are within the intended therapeutic range
   5. Thyroid stimulating hormone (TSH) within normal limits. If TSH is not within normal limits, the participant may be eligible if T3 and free T4 are within normal limits.

8. A female participant is eligible to participate if she is not pregnant (see Exclusion Criteria), not breastfeeding, and at least one of the following conditions applies:

   1. Not a woman of childbearing potential (WOCBP) as defined in the Appendix
   2. A WOCBP who agrees to follow the contraceptive guidance in the Appendix during the treatment period and for at least 120 days after the last dose of study treatment with pembrolizumab (pembroRT cohort) or at least 180 days after the last dose of chemotherapy (chemoRT cohort).

9. A male participant must agree to use contraception during the treatment period and for at least 28 days after the last dose of study treatment and refrain from donating sperm during this period.

10. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

1. Malignant pleural or pericardial effusion, based on clinical, imaging, or pathologic evaluation.

2. Systemic therapy for lung cancer within the past year.

3. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137).

4. Contraindication to protocol-specified radiotherapy, such as prior thoracic radiotherapy or active serious collagen vascular disease (e.g. scleroderma).

5. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.

6. Active malignancy other than lung cancer that requires active treatment other than hormonal therapy or is deemed by the treating physicians to be likely to affect the subject's survival duration.

7. A history of (non-infectious) pneumonitis that required steroids or current pneumonitis.

8. Active infection requiring antimicrobial therapy.

9. Has a known history of active TB (Bacillus Tuberculosis).

10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for

    the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

12. Pregnancy, assessed in WOCBP (defined in Appendix) with urine pregnancy test within 72 hours prior to study treatment allocation. If urine pregnancy test is positive or cannot be confirmed as negative, a serum pregnancy test is required. If more than 72 hours elapse between screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative.

13. For patients receiving pembrolizumab/radiotherapy

    1. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
    2. Active autoimmune disease other than vitiligo, thyroid disorders, Sjogren's disease, and well-controlled rheumatoid arthritis not requiring disease-modifying therapy.
    3. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
    4. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.

Patients were monitored for adverse events for up to 18 months following treatment for a total of up to 30 months.