Single arm, multicentre phase II trial evaluating the efficacy in terms of 1-year PFS rate of immunotherapy and chemotherapy plus stereotactic radiotherapy to metastases, followed by definitive surgery or radiotherapy to the locoregional primary tumour in patients with oligo-metastatic NSCLC.
Intervention
The protocol treatment has two phases: Phase I consists of an induction treatment before restaging and Phase II of definitive local treatment, after restaging. The treatment in the induction phase consists of immunotherapy (durvalumab plus tremelimumab) combined with platinum-based doublet chemotherapy (carboplatin plus paclitaxel) and stereotactic body radiation therapy (SBRT) to all oligo-metastatic lesions. Patients who have not progressed at the time of restaging will proceed to the definitive local treatment phase , where patients will receive radical treatment to the primary tumour, by either surgical resection or radical radiotherapy. Immunotherapy will continue in this phase.
Key inclusion criteria
Patient Selection – Cohort 2 (Amendment 1) Most important inclusion criteria (zie protocol voor volledige lijst)
Histologically confirmed NSCLC
Synchronous oligo-metastatic stage IV disease: – maximum of three distant metastases, one of which must be extra-cerebral for SBRT – Initial mediastinal staging is recommended (except for lymph nodes <1 cm on CT and PET-negative) preferentially by endobronchial ultrasound (EBUS) – Neurosurgical resection of one single CNS metastasis or laparoscopic resection of one adrenal metastasis before study inclusion is allowed (one extra-cerebral metastasis must be available for SBRT)
Able to understand and give written informed consent and comply with study procedures
Age ≥18 years
ECOG Performance Status 0-1
Availability of tumour tissue for translational research
Adequate haematological, renal and liver function
Key exclusion criteria
Most important exclusion criteria (zie protocol voor volledige lijst):
Prior chemotherapy, radiotherapy or therapeutic surgery for NSCLC (an exception is the resection of one single CNS or adrenal metastasis, as above)
Activating driver mutation: EGFR, ALK, ROS1
More than three distant metastases
Brain metastases not amenable for radiosurgery or neurosurgery
Extra cranial metastatic locations such as malignant ascites, pleural or pericardial effusion, diffuse lymphangiosis of skin or lung, diffuse bone marrow metastasis, abdominal masses/abdominal organomegaly, identified by physical exam that is not measurable by reproducible imaging techniques.
Primary lung cancer not suitable for radical therapy (pneumonectomy excluded)
History of leptomeningeal carcinomatosis
Major surgery or significant traumatic injury from which the patient has not recovered at least 28 days before enrolment
Any uncontrolled intercurrent illness, including but not limited to: ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease or serious chronic gastrointestinal conditions associated with diarrhoea, which in the investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol
Active tuberculosis, hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection
Active autoimmune disease requiring systemic treatment
Severe or uncontrolled cardiac disease requiring treatment
History of primary immunodeficiency
History of allogeneic organ transplant
Receipt of live attenuated vaccines within 30 days prior to enrolment
Known allergies or hypersensitivity to trial drugs or to any excipient.
Sexually active men and women of childbearing potential who are not willing to use a highly effective contraceptive method during the trial and for up to 90 days after last dose of durvalumab monotherapy and up to 180 days after last dose of durvalumab plus tremelimumab combination therapy.
