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.
