The primary objective of the study is to assess the efficacy in terms of CNS-specific PFS of the combination of standard systemic treatment plus SRS vs. standard systemic treatment alone in patients with newly diagnosed and untreated (except for surgery) asymptomatic or oligosymptomatic brain metastases from melanoma or NSCLC. This proposed randomised phase III clinical study addresses one of the most controversial issues in the current approach to patients with brain mets: the timing of SRS in patients eligible for systemic immune checkpoint inhibition or targeted therapy in order to guide therapeutic options as to what strategy allows the best compromise between best survival and best QoL.
Newly diagnosed, previously untreated (except for surgery, see below) asymptomatic or oligo-symptomatic brain metastases, e.g., controlled symptomatic seizure disorder. Note: patients with neurological symptoms or signs that require more than a stable dose of 4 mg dexamethasone equivalent for more than one week are not considered oligo-symptomatic.
Brain metastases must be previously untreated, except for surgery.
Prior surgery (including biopsies, resection, and cyst aspiration) for brain metastases is allowed. Residual and measurable disease after surgery is not required, but surgery must have confirmed the diagnosis. An MRI performed within 72 hours post-surgery should be available.
Maximum 1-10 brain metastases at screening
Confirmed or probable leptomeningeal metastases according to EANO ESMO criteria
Symptomatic brain metastases at time of randomisation, e.g., neurological symptoms or signs that require more than a stable dose of 4 mg dexamethasone equivalent for more than one week.
Patients must be off steroids or on a stable dose of ≤4 mg dexamethasone equivalent at randomisation.
Patients experiencing seizures controlled by anti-epileptic drugs are eligible.
Parallel
Stereotactic radiosurgery
RadiationDepending on the investigator's preference, the following standard of care fractionation schedules are recommended: 1x 18-22 Gy, 3x 9 Gy or 5x 6 Gy. Fractionated stereotactic radiotherapy is favoured in principle, but not mandated, for postoperative radiotherapy and for metastases with a diameter of \>20 mm or for \>4 brain metastases. For patients randomised to Arm A, radiotherapy should be initiated within 14 days after randomisation.
Immune checkpoint inhibitor
DrugSystemic therapy follows the current standard of care, according to the type of the primary tumour. * For patients with melanoma, with or without BRAF-mutation, systemic therapy consists of * an approved immune-checkpoint inhibition combination therapy (cohort 1a) or * an approved immune-checkpoint inhibition monotherapy (cohort 1b). * For patients with NSCLC and a targetable oncogenic driver alteration (cohort 2a), systemic therapy consists of an approved targeted therapy (for example: EGFR-, ALK- or ROS1-targeted treatment). * For patients with NSCLC without a targetable oncogenic driver alteration (cohort 2b), systemic therapy consists of an approved immune-checkpoint inhibition therapy (with or without chemotherapy).
CNS-specific PFS, locally assessed as per iRANO criteria
The primary objective of the study is to assess the efficacy in terms of CNS-specific progression-free survival (PFS) of the combination of standard systemic treatment plus SRS versus standard systemic treatment alone in patients with newly diagnosed and untreated (except surgery) asymptomatic or oligo-symptomatic brain metastases from melanoma or non-small cell lung cancer, with indication for systemic therapy.
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ETOP IBCSG Partners Foundation
Lead sponsor
USZ Foundation
Collaborator
