Immunotherapy or Targeted Therapy With or Without Stereotactic Radiosurgery for Patients With Brain Metastases From Melanoma or Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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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.

Official Title
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A Multicentre Randomised Open-label Phase III Study of Stereotactic Radiosurgery, in Addition to Standard Systemic Therapy for Patients With Metastatic Melanoma or Newly Diagnosed Metastatic NSCLC and Asymptomatic or Oligo-symptomatic Brain Metastases

Conditions
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Non-Small Cell Lung Cancer, Melanoma

Intervention / Treatment
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* Radiation: Stereotactic radiosurgery
* Drug: Immune checkpoint inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 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). Age of 18 years or older Karnofsky performance status of 60 or more Life expectancy >12 weeks 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. 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. Written IC for study participation must be signed and dated by the patient and the investigator prior to any study-related intervention. Exclusion Criteria: Confirmed or probable leptomeningeal metastasis according to EANO ESMO criteria1 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. Prior whole brain irradiation or focal radiation therapy to the brain Prior systemic treatment for brain metastases Contra-indication for SRS For patients with NSCLC: any previous anticancer systemic therapy other than those under investigation in this study. 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. Women who are pregnant or in the period of lactation. Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: standard systemic treatment with stereotactic radiosurgery (SRS)<br>Arm A | Radiation: Stereotactic radiosurgery<br>* 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.<br>Drug: Immune checkpoint inhibitor<br>* 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.<br>* Other names: standard of care treatment;|
| Active Comparator: standard systemic treatment without stereotactic radiosurgery<br>Arm B | Drug: Immune checkpoint inhibitor<br>* 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.<br>* Other names: standard of care treatment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | from date of randomization until the date of documented CNS-specific progression, assessed up to 42 months |