This is a single arm, multi-centre, phase II open label study of nivolumab with stereotactic body radiotherapy (SBRT) for early stage non-small cell lung cancer.

SBRT will be delivered in either 3 or 5 fractions for peripheral disease or 8 fractions in central disease. A flat dose of 240 mg nivolumab infusion will begin after the final fraction of SBRT, within 24 hours and typically on the same day. Nivolumab will subsequently be given every 2 weeks at a flat dose of 240 mg for a further 13 cycles followed by Nivolumab 480mg Q4W for 7 cycles until 20 cycles in total are complete, unless any study drug discontinuation criteria are met. Treatment (20 cycles) will take a minimum of 1 year to complete but may exceed this timeframe if treatment delays are encountered.

(Patients who have enrolled on Nivolumab Q2W 240mg regimen for 26 cycles and are beyond cycle 14 will receive 26 cycles Q2W in total to complete treatment).

Assessment of toxicities will be performed at each clinic visit during treatment, at 30 days after the final nivolumab infusion and until 100 days after the final nivolumab infusion. Changes in spirometry values and PFTs will be assessed throughout the trial.

Relapse rates will be assessed with staging CT scans at 3, 6, 12, 18 and 24 months post SBRT.

An exploratory assessment will be made of the effect pre-treatment pulmonary function tests (PFTs) have on outcome measures.

This is a single arm, multi-centre, phase II open label study of nivolumab with stereotactic body radiotherapy (SBRT) for early stage non-small cell lung cancer.

Current United Kingdom (UK) guidelines for SBRT do not specify exclusion pulmonary function criteria. Severely reduced Forced Expiratory Volume in 1 second (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) (<40% predicted) are common reasons for medical inoperability leading to the choice of SBRT. In a large prospective study of patients undergoing SBRT, poor baseline PFT was not predictive of toxicity including pneumonitis. At the 2 year follow up, the mean decline in percentage of predicted forced expiratory volume in one second (FEV1) and diffusion capacity of carbon monoxide (DLCO) were only 5.8% and 6.3% respectively. Focal SBRT is a well-tolerated procedure and acute complications are generally transient. Symptomatic radiation pneumonitis has been reported at rates of 4-25% of patients.

Drug induced pneumonitis is reported at 6% in lung cancer patients receiving nivolumab and at 2% with grade 3-4 toxicity. Of note, such rates are similar or lower to other drugs used in NSCLC including docetaxel for which no PFT restrictions occur. In this study, frequent assessment of spirometry values may help to predict patients that are developing subclinical pneumonitis and prompt for early intervention.

SBRT will be delivered in either 3 or 5 fractions for peripheral disease or 8 fractions in central disease. A flat dose of 240 mg nivolumab infusion will begin after the final fraction of SBRT, within 24 hours and typically on the same day. Nivolumab will subsequently be given every 2 weeks at a flat dose of 240 mg for a further 13 cycles followed by Nivolumab 480mg Q4W for 7 cycles until 20 cycles in total are complete, unless any study drug discontinuation criteria are met. The study will recruit 31 patients. We anticipate it will take approximately 18 months to recruit 31 patients.

The study will include subjects with histologically verified NSCLC deemed by a local multidisciplinary team (MDT) to have anatomical stage T1-3 [≤6cm] N0 M0 by means of computed tomography (CT) and fludeoxyglucose-positron emission tomography (FDG-PET) , amenable to radical treatment with SBRT and inoperable due to medical co-morbidity, being technically unresectable or patient declining surgery after offer of surgical assessment.

Subjects will receive nivolumab as per the treatment schedule unless any withdrawal criteria are met. The first nivolumab infusion will be given after the final fraction of SBRT, within 24 hours and generally on the same day. Clinical follow up and investigations are as detailed in the schedule of assessment.

The first 5 patients to enroll must have Eastern Co-operative Oncology Group (ECOG) performance status (PS) < 2 at the time of first dose of investigational medical product (IMP). An Independent Data Monitoring Committee (IDMC) will meet when the first 5 patients have reached 3 months follow up from their 1st dose of nivolumab or have withdrawn consent to follow-up. Patients that have enrolled but did not receive IMP will be replaced. The IDMC, if satisfied with the safety data from the initial 5 patients, may recommend escalation to include recruitment of patients with ECOG performance status of 2. Further patients of PS <2 may enroll while awaiting the outcome of the IDMC meeting.

The IDMC will perform a further safety review when the first 5 patients enrolled with ECOG performance status 2 have reached 3 months follow up from their final fraction of radiotherapy or have withdrawn consent to follow-up. Patients that have enrolled but did not receive IMP will be replaced. Further patients with ECOG performance status 2 will not be able to enroll unless recommendation is given by the IDMC. In the event that 5 PS 2 patients have not enrolled by the point that the 15th recruited patient has reached 3 months follow up, then there will be a further mandated IDMC meeting to assess safety data from the study. Patients may continue to enroll while awaiting the outcome of this IDMC meeting.

Assessment of toxicities will be performed at each clinic visit during treatment, at 30 days after the final nivolumab infusion and until 100 days after the final nivolumab infusion. Changes in spirometry values and PFTs will be assessed throughout the trial.

Relapse rates will be assessed with staging CT scans at 3, 6, 12, 18 and 24 months post SBRT.

An exploratory assessment will be made of the effect pre-treatment pulmonary function tests (PFTs) have on outcome measures.

Inclusion Criteria:

• Subjects must have signed and dated a Research Ethics Committee (REC) approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care

• Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory tests

• ECOG Performance status (PS) 0-2

• Minimum of first 5 patients to be PS 0-1

• PS 2 patients to be enrolled only following recommendation by the Independent Data Monitoring Committee (IDMC)

• Patients with histological diagnosis of NSCLC, all histological sub-types are eligible

• Not suitable for surgery because of medical co-morbidity, lesion is technically inoperable or patient declines surgery after surgical assessment (or option of assessment)

• Single or synchronous/metachronous primary NSCLC lesions, tumour stage T1-3 (≤6cm), N0 M0 (UICC v.8) as determined by the local MDT based on minimum investigations of CT chest/abdomen within 8 weeks and FDG-PET within 6 weeks of 1st fraction of SBRT. Where the radiological nodal status is equivocal then only eligible if possible nodal disease is subsequently confirmed as pathologically negative with mediastinoscopy or endoscopic bronchial or oesophageal ultra-sound biopsy as necessary

• For synchronous tumours one lesion must have a histological diagnosis of NSCLC. For the other lesion a radiological diagnosis of NSCLC as determined by lung MDT is sufficient. (Upon diagnosis of metachronous primary NSCLC these lesions require biopsy for trial entry)

• Metachronous (single) primary NSCLC lesions, tumour stage T1-3 (≤6cm) N0 M0 (UICC v.8) presenting after previous treatment of T1-3(≤6cm) N0 M0 (UICC v.8) with surgery or SBRT are eligible for inclusion. Lung constraints must be able to feasibly achieved (according to dose constraints in 7.1.2

• Tumour stage T1-3 termed as 'central' disease within 2cm of main airways and proximal bronchial tree, but not abutting these structures (ultra-central), are suitable for entry. Up to 5 patients with 'central' primary NSCLC (up to 2 lesions) can be enrolled and followed up for 3 months following their final fraction of radiotherapy at which stage an IDMC meeting is required to assess further 'central' primary NSCLC recruitment

• Screening laboratory values must meet the following criteria prior to commencement of treatment:

  i) WBCs ≥ 2000/μL ii) Neutrophils ≥1500/μL iii) Platelets ≥ 100 X10³/μL iv) Haemoglobin ≥ 9.0 g/dL v) Serum creatinine of ≤ 1.5 X ULN or creatinine clearance (CrCl)/glomerular filtration rate (GFR) > 40 mL/minute (using Cockcroft/Gault formula or as assessed by local practice)

  1. . Female CrCl= [(140- age in years) X weight in kg X 0.85) ÷ (72 X serum creatinine in mg/ dL)]
  2. . Male CrCl= [(140- age in years) X weight in kg X 1.00) ÷ (72 X serum creatinine in mg/ dL)] vi) AST ≤ 3 X ULN vii) ALT ≤ 3 X ULN viii) Total bilirubin ≤ 1.5 X ULN (except subjects with Gilbert Syndrome, who must have total bilirubin < 50 μmol/L)

• No prior adjuvant or foreseen neo-adjuvant or adjuvant chemotherapy is allowed

• Males and Females ≥ 18 years of age

• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) in the screening period and within 24 hours prior to the start of study drug.

• Women must not be breastfeeding during the study treatment and for a period up to 23 weeks post treatment completion

• WOCBP must agree to follow instructions for method(s) of contraception during the study treatment and for a total of 23 weeks post treatment completion

• Males who are sexually active with WOCBP must agree to follow instructions for method(s) for contraception for a total of 31 weeks post treatment completion.

Exclusion Criteria:

• Any tumour that is not clinically definable on the treatment planning CT scan e.g. surrounded by consolidation or atelectasis

• 'Ultra-central' tumours, i.e. those adjacent to the hilar structures, with the gross tumour volume directly abutting a main bronchus

• Subjects with active, known autoimmune disease. Subjects with Type I diabetes mellitus, residual hypothyroidism due to an autoimmune condition requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enrol.

• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of the first dose of study drug administration. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease

• Subjects with previous malignancies (except non-melanoma skin cancers, early stage NSCLC treated with SBRT or surgery and current lesion not considered to be relapsed NSCLC, and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry AND no additional therapy is required during the study period

• Patient with known interstitial lung disease or active, non-infectious pneumonitis

• Previous conventional radiotherapy to the chest or mediastinum. Patients who have had previous breast radiotherapy may be eligible at the discretion of the Chief Investigator

• Any serious or uncontrolled medical disorder or active infection that, in the opinion of the Investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the subject to receive protocol therapy

• All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE v.4.0) or baseline before administration of study drug

• Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of study treatment

• Subjects who received prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) or who have previously taken part in a randomized BMS clinical trial for nivolumab or ipilimumab

• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)

• Positive test for hepatitis B virus (HBV) using HBV surface antigen (HBVsAg) test or positive test for hepatitis C virus (HCV) using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic infection

  o Patients with a positive HCV antibody but no detection of HCV RNA indicating no current infection are eligible

• Patients who have received a live vaccine within 30 days prior to the first dose of trial treatment

• History of allergy to study drug components