SBRT Combined With PD-1 Inhibitor and Thoracic Hyperthermia for Advanced NSCLC

An Open, Single-arm, Multicenter Phase II Trial to Evaluate SBRT Combined With PD-1 Inhibitors and Thoracic Hyperthermia for Advanced Non-Small-Cell Lung Cancer

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.

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.