Clinical Trial Finder

Inclusion Criteria:

1. 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. Requirements for brain metastases:

• - 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.

• - Number and size of metastases at diagnosis of brain metastases (as per Yamamoto et al.

7):

• - Maximum 1-10 brain metastases.

• - At least one brain metastasis must be of ≥5 mm in diameter.

• - In case of 1-4 brain metastases: - Longest diameter of largest brain metastasis must be ≤30 mm.

• - In case of 5-10 brain metastases: - Largest metastasis must be ≤10 mL in volume and longest diameter must be ≤30 mm.

• - Maximum cumulative brain metastases volume must be ≤30 mL.

2. Primary disease of histologically confirmed (from primary tumour or from a metastatic lesion, including in the brain) melanoma or NSCLC. Requirements for patients with melanoma:

• - Prior treatment, including treatment with immune-checkpoint inhibitors is permitted, but brain metastases must be newly diagnosed and previously untreated (except for surgery).

• - BRAF-mutation status, locally assessed, should be known (previous BRAF-targeted therapy is allowed).

Requirements for patients with NSCLC:

• - Newly diagnosed, treatment-naïve (except for prior surgery) metastatic NSCLC, with or without a targetable oncogenic driver alteration: sensitising EGFR-mutation (exon 19-del and 21-L858R), ALK- or ROS1-fusion.

• - Known PD-L1 expression status (from primary tumour or from a metastatic lesion, including brain) - Known driver mutation status (from primary tumour or from a metastatic lesion, including brain).

3. Age of 18 years or older. 4. Karnofsky performance status of 60 or more. 5. Life expectancy >12 weeks. 6. Patients must be candidates for systemic treatment, with one of the following treatment cohorts planned:

• - Immune-checkpoint inhibition therapy (combination of ipilimumab and nivolumab) for metastatic melanoma with or without a BRAF-mutation.

• - anti-PD-1/L1 monotherapy for metastatic melanoma with or without a BRAF-mutation.

• - targeted therapy for metastatic NSCLC with targetable oncogenic driver alteration (EGFR-mutation or ALK- or ROS1-fusion).

• - Immune-checkpoint inhibition therapy (including an anti-PD-1/L1 compound) alone or in combination with chemotherapy for metastatic NSCLC without targetable oncogenic driver alteration.

7. Women of childbearing potential, including women who had their last menstruation in the last 2 years, must have a negative urinary or serum pregnancy test within 7 days before randomisation. 8. Written IC for study participation must be signed and dated by the patient and the investigator prior to any study-related intervention.

Exclusion Criteria:

1. Confirmed or probable leptomeningeal metastasis according to EANO ESMO criteria1. 2. 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 for one week prior to randomisation.

• - Patients experiencing seizures controlled by anti-epileptic drugs are eligible.

3. Prior whole brain irradiation or focal radiation therapy to the brain. 4. Prior systemic treatment for brain metastases. 5. Contra-indication for SRS. 6. For patients with NSCLC: any previous anticancer systemic therapy other than those under investigation in this study. 7. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements. 8. Women who are pregnant or in the period of lactation. 9. Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the study.

Arms

Experimental: standard systemic treatment with stereotactic radiosurgery (SRS)

Arm A

Active Comparator: standard systemic treatment without stereotactic radiosurgery

Arm B

Interventions

Radiation: - Stereotactic radiosurgery

The following SRS therapy is foreseen: Two fractionation schedules according to radiation oncologist's preferences and patterns of brain metastases: 1 x 18-22 Gy (18-22 Gy) or 5 x 6 Gy (30 Gy). The following fractionation schedules will be allowed (based on the latest AAPM report on a systematic review and dose response modelling): Single fraction SRS (1 x 18-22 Gy) is the preferred schedule for 1-4 brain metastases, each with a longest diameter of ≤20 mm. Fractionated SRT (5 x 6 Gy) is preferred for lesions >20 mm diameter or in case of the presence of 5-10 brain metastases. For resection cavity irradiation the same selection criteria may be chosen.

Drug: - Immune checkpoint inhibitor

Systemic therapy follows the current standard of care, according to the type of the primary tumour. For patients in cohort 1a (Melanoma, treated with ipilimumab plus nivolumab), systemic therapy consists of the combination of ipilimumab plus nivolumab. For patients in cohort 1b (Melanoma, treated with anti-PD-1/L1 monotherapy), systemic treatment consists of anti-PD-1/L1 monotherapy. For patients in cohort 2a (NSCLC, treated with targeted therapy), systemic therapy consists of targeted therapy (EGFR-, ALK- or ROS1-targeted treatment). For patients in cohort 2b (NSCLC, treated with anti-PD-1/L1 therapy with or without chemotherapy), systemic therapy consists of immune-checkpoint inhibition therapy (including an anti-PD-1/L1 compound) with or without chemotherapy.