1. What data in particular will be shared?
   Response - Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices).
   


2. What additional supporting information will be shared?
   Response - Clinical Study Report
   
   
3. Who will be able to view these files?
   Response - Researchers who provide a methodologically sound proposal.
   


4. For what types of analyses will this data be available?
   Response - For individual participant data meta-analysis.
   


5. By what mechanism will data be made available?
   Response - Proposals should be directed to [pavan14281@gmail.com].
   


6. For how long will this data be available start date provided 20-08-2027 and end date provided 20-08-2032?
   Response - Beginning 3 months and ending 5 years following article publication.
   


7. Any URL or additional information regarding plan/policy for sharing IPD? 
   Additional Information - NIL

Lung cancer remains a leading cause of cancer-related mortality worldwide. The last decade has witnessed remarkable progress in lung cancer therapeutics. One exciting development has been that of immune checkpoint inhibitors. PD-1 inhibitors and PD-L1 inhibitors block the activity of PD-1 and PDL1 immune checkpoint proteins on the surface of cells and have demonstrated a survival benefit in patients with advanced non-small cell lung carcinoma.

Multiple studies have reported the feasibility and efficacy of endobronchial intratumoral chemotherapy (EITC) using various agents ranging from 99.5% ethanol to cisplatin. Adverse events reported have been limited to fever, cough, and minor bleeding. The commonly reported endpoints have been improvement in airway patency, reduction in tumor bulk, and safety measures.  Local delivery of immunotherapy holds great promise to improve the outcome of patients with NSCLC, as draining nodes are accessible via EBUS. Clinical studies have also demonstrated an immune phenotype in tumor-draining versus non-draining lymph nodes (van de Ven R et al. ERJ Open Res 2017; 3: 00110-2016; Murthy V et al. Lung Cancer 2019; 137: 94–99.). Only a small fraction of the systemic dose reaches the tumor-draining lymph node. Therefore, direct intranodal injection may be equally efficacious at a significantly lower dose.

Nivolumab (PD1 inhibitor) has been demonstrated to be efficacious in treating advanced NSCLC. Intratumoral instillation of nivolumab (10mg) has been tried in recurrent glioblastoma (Schwarze JK et al. Journal of Clinical Oncology 2020 38:15) along with ipilimumab and was found to be feasible and safe. The study shall enable us to evaluate the feasibility and safety of EBUS-guided intranodal immunotherapy in managing locally advanced NSCLC. So far, intratumoral administration of immunotherapy has been done; however, intranodal EBUS-guided administration has not been studied. If successful, this shall pave the way for a novel mode of administration, with the potential of being effective at a fractional dose as compared to systemic immunotherapy and being cost-effective. Intralesional nivolumab has been tried earlier in other cancers.

1.  Study design: Proof of concept feasibility and safety study Phase 1
2.  Study period: Two years.
3.  Place of study: Department of Pulmonary Critical Care and Sleep Medicine, All India Institute of Medical Sciences, New Delhi
4.  Sample size: 12
5.  Inclusion Criteria:
a.  Patients with histopathologically proven non-small cell lung carcinoma with significant mediastinal lymphadenopathy on Chest Computed Tomography
b.  Non-resectable disease on staging
c.  Target mediastinal node size >2cm
d.  Not eligible for oral TKI therapy, and non affording for immunotherapy
e.  Patients without contraindications for Endobronchial ultrasound
f.  Written informed consent.
6.  Exclusion Criteria:
a.  EBUS Inaccessible mediastinal lymph nodes
b.  Not giving written informed consent
c.  Poor performance status
d.  Patients with a life expectancy of less than four weeks
e.  Contraindications to endobronchial ultrasound guided needle aspiration
f.  Contraindications to nivolumab or conventional chemotherapy regimens
g.  Severe sepsis/septic shock
h.  Unstable concurrent medical condition like recent myocardial infarction, recent major surgery
i.  Therapeutic anticoagulation
j.  Prior receipt of conventional chemotherapy or systemic immunotherapy for current disease
7.  Controls: None

Methodology

Clinical details of the patient shall be recorded in a predesigned proforma, including demographic and socioeconomic characteristics, a detailed smoking history, previous treatment history, details of imaging findings, and diagnostic investigations. Disease staging shall done using either a whole-body positron emission tomogram-computerized tomogram (PET-CT) or CT scan of chest and upper abdomen, bone scan, and magnetic resonance imaging/CT Brain. The disease shall be staged according to the IASLC (the International Association for the Study of Lung Cancer)-AJCC-UICC TNM staging (8th edition). Pathological and molecular characteristics of tumor, baseline laboratory investigations, treatment details shall be recorded. All patients shall receive standard-of-care treatment, i.e., conventional palliative chemotherapy as per institutional protocol, one week after EBUS TBNI. If there are no safety concerns, patients shall receive the second cycle of EBUS TBNI one week prior to the next cycle of chemotherapy. Patients shall continue to receive standard of care treatment subsequently. Patients shall be assessed every two to three weeks or as clinically indicated, till the completion of 4 cycles of palliative conventional chemotherapy. Treatment response shall be assessed at the end of 4 cycles of chemotherapy, and patients shall be classified into complete response, partial response or progression. Complications and adverse effects of chemotherapy shall be recorded.

Nivolumab shall be diluted in 0.9% sodium chloride injection to prepare a final concentration of 10 mg/ml. All standard precautions and recommendations for the preparation of nivolumab shall be followed as the manufacturer prescribes. Using this formula, the volumes required shall be calculated. For example, for a node with 2 cm diameter, 4 ml instillation can be done. TBNI shall be done using multiple passes at different angles to cover the whole node. A maximum of 40 mg of nivolumab shall be instilled for each patient in one sitting.
As the dead space of EBUS TBNA needle is calculated to be around 0.14 ml, needle shall be flushed with similar amount using a small volume insulin syringe post drug instillation.
Periprocedural and post-procedural complications shall be recorded, including bleeding, arrhythmias, hypotension, pneumothorax, etc. Adverse reactions to nivolumab instillation shall be recorded. Patients shall be observed for 24 hours for the development of any complications. The treatment administered to patients during hospital stay shall be recorded.
The feasibility of TBNI shall be assessed based on:
a.  Successful localization of the target node/lesion, and
b.  Delivery of at least 80% of the calculated dosage of nivolumab to the accessible lesions/node.

STATISTICAL ANALYSIS
Data will be recorded on a predesigned proforma and managed on Excel spread sheet. Descriptive statistics for patient clinical characteristics and laboratory parameters shall be expressed as mean ± standard deviation (SD) for normally distributed data and median (25th, 75th percentiles) if data are not normally distributed. Statistical analysis shall be performed using SPSS or STATA software. A p value of < 0.05 will be considered significant. Overall response rate shall be defined as the number of patients experiencing PR or better (i.e. PR + CR) divided by the number evaluable for efficacy. Comparisons between groups shall be performed using Student t-test for normally distributed data and the Wilcoxon rank sum test for non-normally distributed data. The relationship between the continuous variables shall be explored using Pearson correlation coefficient for normally distributed data, or Spearman correlation test if data is not normally distributed. Univariate and multivariate analysis will be performed to find variables affecting outcomes.