sbrt combined with pd-1 inhibitor and thoracic hyperthermia for advanced nsclc

Conditions: Stereotactic Body Radiation Therapy; PD-1 Inhibitor; Hyperthermia; NSCLC

Summary: the aim of this trial is to investigate the primary efficacy of sbrt combined with pd-1 inhibitor and thoracic hyperthermia in patients with egfr, alk, and ros1 negative stage iv nsclc patients who progressed after first-line treatment. at least one lesion (primary or metastatic) was selected for sbrt treatment, and the radiotherapy dose of each lesion was 32gy/4fx. sbrt was combined with thoracic hyperthermia from the first fraction, and hyperthermia was performed 6 times, twice a week. pd-1 inhibitor was used on the second day after the completion of sbrt. the pd-1 inhibitor was administered at a dose of 200mg every time, every 3 weeks for 2 years (35 times total), or until the investigators deem that the patient need to discontinue the drug because of treatment-related toxicity or disease progression. during the period, the overall response rate and toxicities were regularly evaluated.


Eligibility criteria:
inclusion criteria: * 1.age≥18. * 2.ecog ps 0-1. * 3.histopathologically confirmed stage iv non-small-cell lung cancer. * 4.egfr/alk/ros-1 negetive. * 5.disease progression after first-line therapy including platinum chemotherapy, but not include pd-1/l1 inhibitors. * 6.subjects with brain metastases were eligible, but only if they had no neurologic symptoms or disease stable without systemic glucocorticoid. * 7.at least one lesion with a diameter of 1-5cm which could be treated with sbrt at a dose of 32gy/4fx, and at least one lesion which could be measured other than sbrt (recist1.1); lymph nodes can be used as independent measurable lesions or receive sbrt. brain lesions should not be used as separate sbrt lesions or as measurable lesions. * 8.the subjects did not had radiotherapy before. * 9.the subjects did not currently need palliative radiotherapy at any part according to the researchers. * 10.it was necessary for the subjects who underwent surgery to fully recover from the toxicity and complications caused by surgical intervention prior to treatment. * 11.subjects should provide appropriate biopsy specimens before and during treatment according to the clinical trial protocol. * 12.male or female subjects agree to contraception during the trial (surgical ligation or oral contraceptive/iud + condom). * 13.life expectancy ≥ 3 months. * 14.the organ function level meet the following standards one week before enrollment: ①bone marrow: hemoglobin ≥80g/l, white blood cell count ≥4.0\*10\^9/l or neutrophil count ≥1.5\*10\^9/l, platelet count ≥100\*10\^9/l. ②liver: serum total bilirubin level ≤1.5 upper limit of normal (uln), when serum total bilirubin level \> 1.5 uln, direct bilirubin level must be ≤ uln, aspartate aminotransferase (ast) and alanine aminotransferase (alt) ≤ 2.5 uln. ③ kidney: serum creatinine level \< 1.5 uln or creatinine clearance rate ≥ 50ml/min, urea nitrogen ≤ 200mg/l; serum albumin ≥ 30g/l. * 15. subjects must be able to understand and voluntarily sign informed consent. exclusion criteria: * 1.prior treatment with anti-pd-1 /l1 drugs or other investigational immunotherapy agent. * 2.subjects had prior radiotherapy. * 3.subjects had severe autoimmune diseases: active inflammatory bowel disease (including crohn's disease and ulcerative colitis), rheumatoid arthritis, scleroderma, systemic lupus erythematosus, autoimmune vasculitis (such as wegener's granuloma), etc. * 4.symptomatic interstitial lung disease or active infectious/noninfectious pneumonia. * 5.subjects had risk factors for bowel perforation: active diverticulitis, intra-abdominal abscess, gastrointestinal (gi) obstruction, abdominal cancer, or other risk factors for bowel perforation. * 6.history of other malignant tumors. * 7.subjects who have current infection, heart failure, heart attack, unstable angina, or unstable arrhythmia in the last 6 months. * 8.subjects with physical examination or clinical trial findings, or other uncontrolled conditions that the investigator believes may interfere with the outcome or increase the risk of treatment complications. * 9.subjects without platinum-based combination chemotherapy included as first-line treatment. * 10.the pathology reports showed a mixture of small cell lung cancer components. * 11.lactating or pregnant women. * 12.congenital or acquired immunodeficiency diseases including human immunodeficiency virus (hiv), or a history of organ transplantation, allogeneic stem cell transplantation. * 13.known hepatitis b virus (hbv), hepatitis c virus (hcv), active pulmonary tuberculosis infections. * 14.subjects had cancer vaccines other vaccines within 4 weeks before treatment initiation. (seasonal influenza vaccines are usually inactivated and are permitted, whereas intranasal preparations are usually live attenuated vaccines and therefore are not permitted) * 15.subjects who currently use other immune agents, chemotherapy agents, other investigational drugs or long-term cortisol therapy. * 16.subjects with mental illness, substance abuse, and social problems that affected compliance were not included in the study according to doctor's evaluation. * 17.allergic or contraindicated to pd-1 inhibitors.