NEOMUN is designed as an open-label, single arm, prospective, monocenter, phase II study of pembrolizumab in a neoadjuvant setting in patients with non-small cell lung cancer of Stage II/IIIA suitable for curative intent surgery.

The study is designed as an open-label, single arm, prospective, monocenter, phase II study of pembrolizumab in a neoadjuvant setting in patients with resectable NSCLC stage II/IIIA suitable for curative intent surgery, taking place in Germany. Planned sample size is N=30.

Investigational drug is Pembrolizumab at fixed dose, given 200 mg q3w i.v. for 2 cycles. After completion of immunotherapy lobectomy/ bilobectomy with curative intent is scheduled.

Primary objectives are to assess feasibility and safety of a neoadjuvant application of pembrolizumab and to assess antitumor activity of pembrolizumab with regard to clinical and pathologic tumor response. Secondary objective is to assess the impact of neoadjuvant pembrolizumab on patient disease free and overall survival. Exploratory objective is o explore potential predictive biomarkers for pembrolizumab efficacy (immune cell imaging).

Inclusion Criteria:

1. Cooperation and willingness to complete all aspects of the study

2. Signed and dated written informed consent must be given prior to study inclusion

3. Histological or cytological confirmed NSCLC

4. Clinical stage II-IIIA according to the TNM classification, 7th edition:

   stage IIIa: T1/T2 N2 (IIIa1-3 Robinson classification)

5. Adequate disease staging by PET/CT and brain MRI

6. At least 1 measurable lesion according to RECIST 1.1

7. Age ≥ 18 years

8. ECOG performance status 0 - 1

9. Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

10. Male subjects of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

11. Adequate bone marrow function, liver and renal function:

    1. Absolute neutrophil count ≥ 1.5 x 109/L
    2. Thrombocytes ≥ 100 x 109/L
    3. Hemoglobin ≥ 9 g/dL without transfusion or EPO dependency (within 7 days of assessment)
    4. INR < 1.4 ULN and PTT < 40 seconds during the last 7 days before therapy
    5. Bilirubin < 1.5 x upper limit of normal
    6. AST (GOT) and ALT (GPT) < 2.5 x ULN
    7. Albumin >2.5 mg/dL
    8. Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl): ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN

12. Adequate lung and cardiac function for intended lung resection according to German S3 guideline

Exclusion Criteria:

1. Anticancer treatment during the last 30 days prior to start of treatment, including systemic therapy, radiotherapy or major surgery
2. Participation in a clinical trial within the last 30 days prior to study treatment
3. History of allogeneic tissue/solid organ transplant
4. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
5. Evidence of interstitial lung disease.
6. cT4 tumor
7. Symptomatic acute cardiovascular or cerebrovascular disease
8. Known active HBV, HCV or HIV infection
9. Has any other active infection requiring systemic therapy.
10. Patients with active tuberculosis
11. Prior therapy with an anti-Programmed cell death protein 1 (anti-PD-1), anti-PD-L1, anti-Programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB ligand, a member of the Tumor Necrosis Factor Receptor [TNFR] family), or anti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
12. A diagnosis of immunodeficiency or patient is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
13. Patient has had a prior monoclonal antibody within 4 weeks prior to study Day 1
14. Patient has had prior chemotherapy, targeted small molecule therapy, or radiation therapy in history.
15. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study.
16. Has received a live vaccine within 30 days prior to the first dose of trial treatment. [Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines are live attenuated vaccines, and are not allowed.]
17. Has known hypersensitivity to pembrolizumab or any of the constituents of the product.
18. Other active malignancy requiring treatment Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
19. Lactating or pregnant women, women of child-bearing potential who do not agree to the usage of highly effective contraception methods (allowed methods of contraception, meaning methods with a rate of failure of less than 1% per year are implants, injectable contraceptives, combined oral contraceptives, intrauterine pessars (only hormonal devices), sexual abstinence or vasectomy of the partner). Women of childbearing potential must have a negative pregnancy test (serum β-hCG) at Screening.
20. Any psychiatric illness that would affect the patient's ability to understand the demands of the clinical trial
21. Patient has already been recruited in this trial
22. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.
23. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].

Adverse events were recorded from signing of informed consent until 90 days after last dose of IMP (total: 20-22 weeks) or for 6 weeks after surgery (total: 12-14 weeks) if the subject initiated new anticancer therapy. Deaths were recorded for up to 26 months after treatment initiation.

Note that deaths were recorded for up to 26 months after treatment initiation, but only for the purpose of collecting data for the overall survival efficacy endpoint. Of the total of 5 recorded deaths, only 1 fell within the time frame for safety reporting, and therefore, only 1 adverse event with fatal outcome is recorded in the safety database. This was a case of Acute Hepatic Failure reported as related to study treatment.