Safety and Tolerability of Low Dose Radiotherapy Concurrent SBRT and PD-1 Inhibitors in Advanced NSCLC.

This exploratory phase I study will be conducted in West China Hospital, Sichuan University. A dose escalation of low dose radiotherapy (LDRT) and partial SBRT, 3 patients per cohort (a total of 9 patients) will be enrolled to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT).

All eligible patients will receive LDRT + partial SBRT at different dose levels (decried as below), followed by PD-1 inhibitors starting within 7 days after radiation completed. PD-1 inhibitors will be given at doses as recommended in the instruction manual every 3 weeks until disease progression, unacceptable toxicities, the patient withdraws informed consent, or PD-1 inhibitors reaches a maximum of up to 48 months.

Patients in the dose escalation will receive LDRT + partial SBRT at 3 cohorts with increasing dose levels: 2 Gy (2 Gy/f) + 10 Gy (10 Gy/f) in 1 fraction in dose level 1; 4 Gy (2 Gy/f) + 20 Gy (10 Gy/f) in 2 fractions in dose level 2; 6 Gy (2 Gy/f) + 30 Gy (10 Gy/f) in 3 fractions in dose level 3.

Inclusion criteria

• Be willing and able to provide written informed consent/assent for the trial.
• Be ≥18 years of age on day of signing informed consent.
• Patients with histologically or cytologically confirmed stage IV NSCLC.
• Be willing to undergo repeat biopsy of tumor lesions according to the study protocol.
• Patients who have failed the standard therapy, or who are unsuitable for standard treatment, or refuse chemotherapy.
• At least one measurable lesion according to RECIST 1.1. A lesion that has previously received radiotherapy can be considered a target lesion only if this lesion is clearly progressed after radiotherapy.
• The target lesions (irradiated lesions) are > 5cm in in diameter
• ECOG 0-2.
• Life expectancy of > 3 months.
• Patients must have normal organ and bone marrow function as defined below: Total bilirubin </= 1.5 x upper limit of normal (ULN). Aminotransferase (AST) Serum Glutamic Oxaloacetic Transaminase (SGOT)/ Alanine Aminotransferase (ALT) Serum Glutamic-Pyruvic Transaminase (SGPT) <2.5 X institutional upper limit of normal (</= 5 X institutional ULN for subjects with liver metastases) *WBC >/= 3500/uL, ANC >/= 1500/uL *Platelets >/= 90K/ul *Hemoglobin >/= 9g/dL *Creatinine </= 1.5 x ULN, or creatinine clearance ≥ 50 ml/min（Cockcroft-Gault equation）. Coagulation: International Normalized Ratio (INR)≤ 1.5 × ULN, Partial thromboplastin time (PTT) ≤1.5 × ULN; left ventricular ejection fraction (LVEF) >/= 50% and QTcF (Fridericia's formula) ≤ 450ms
• Patients has recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
• Wash out period for chemotherapy is more than ≥ 4 weeks, for targeted small molecule therapy ≥ 5 half-lives; palliative radiotherapy must have been completed for at least ≥ 2 weeks, chest radiotherapy must have been completed for at least ≥ 4 weeks, and major surgery must have been completed for ≥ 4 weeks.
• Subjects with no severe pulmonary ventilation dysfunction, no acute heart failure, and no contraindication to radiotherapy as judged by the radiotherapist. Subjects who agree to receive immunotherapy and radiotherapy treatment.
• Subjects should agree to use an adequate method of contraception.

Exclusion criteria

• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis and/or spinal cord compression, etc.
• With oncologic emergencies that require immediate treatment
• EGFR/ALK/ROS-1 mutation or mutation status unknown.
• Has evidence of interstitial lung disease or active and/or non-infectious pneumonitis (drug-induced pneumonia, radiation-induced pneumonia, etc.) requiring steroid therapy.
• History of pulmonary fibrosis, pulmonary hypertension, severe irreversible airway obstruction disease
• Patients with peripheral neuropathy.
• Significant heart disease or impairment of cardiac function
• Fluid accumulating in the third space, such as pericardial effusion, pleural effusion and peritoneal effusion that remains uncontrolled by aspiration or other treatment
• Known allergy to drugs or excipients, known severe allergic reaction to any of the PD-1 monoclonal antibodies
• Severe infection within 4 weeks prior to the start of study treatment, including but not limited to hospitalization for infection, bacteremia, or severe pneumonia; treatment with oral or intravenous antibiotics within 2 weeks prior to the start of study treatment; patients receiving prophylactic antibiotic therapy (e.g., to prevent urinary tract infection or exacerbation of COPD) are eligible for this study.
• Known or suspected active autoimmune disease (congenital or acquired) such as uveitis, enterocolitis, hepatitis, pituitary inflammation, vasculitis, nephritis, thyroiditis, etc. (patients with vitiligo, or resolved childhood asthma may be enrolled; patients with type I diabetes with good insulin control may also be enrolled)
• Known allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation.