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

NCT05522660 | Recruiting Phase 3 DMC

• 1 other identifier: ETOP 19-21
• Study Type: interventional
• Target: 180
• Locations: 5 countries
• Sites: 15

Brief Summary

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.

Conditions

Non-Small Cell Lung Cancer; Melanoma

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (2)

Standard systemic treatment with stereotactic radiosurgery (SRS)

EXPERIMENTAL

Arm A

Radiation: Stereotactic radiosurgery; Drug: Immune checkpoint inhibitor

Standard systemic treatment without stereotactic radiosurgery

ACTIVE COMPARATOR

Arm B

Drug: Immune checkpoint inhibitor

Interventions

Immune checkpoint inhibitor DRUG

Systemic 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).

Also known as: standard of care treatment

Standard systemic treatment with stereotactic radiosurgery (SRS); Standard systemic treatment without stereotactic radiosurgery

Stereotactic radiosurgery RADIATION

Depending 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.

Standard systemic treatment with stereotactic radiosurgery (SRS)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• Maximum 1-10 brain metastases at screening
• 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).

You may not qualify if:

• 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.
• Prior whole brain irradiation or focal radiation therapy to the brain
• Prior systemic treatment for brain metastases
• Contra-indication for SRS
• 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.

Sponsors & Collaborators

• ETOP IBCSG Partners Foundation: lead
• USZ Foundation: collaborator

Study Sites (15)

Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"

Naples, Italy

RECRUITING

Instituto Oncologico Veneto IRCCS

Padova, Italy

NOT YET RECRUITING

Santa Maria della Misericordia Hospital

Perugia, Italy

RECRUITING

Istituto Nazionale Tumori "Regina Elena"

Roma, Italy

RECRUITING

Policlinico Umberto 1

Rome, Italy

RECRUITING

Azienda ospedaliero-universitaria Senese Siena

Siena, Italy

RECRUITING

NKI-AVL

Amsterdam, Netherlands

RECRUITING

Vall Hebron Institute of Oncology (VHIO)

Barcelona, Spain

RECRUITING

Hospital Puerta de Hierro

Majadahonda, Spain

RECRUITING

Hospital La Fe

Valencia, Spain

RECRUITING

Inselspital

Bern, Switzerland

RECRUITING

Kantonsspital Winterthur

Winterthur, Switzerland

RECRUITING

Universitätsspital Zürich

Zurich, Switzerland

RECRUITING

Royal Marsden (Sutton)

London, United Kingdom

RECRUITING

Christie NHS Manchester

Manchester, United Kingdom

RECRUITING

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Melanoma

Interventions

Radiosurgery; Immune Checkpoint Inhibitors

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Antineoplastic Agents, Immunological; Antineoplastic Agents; Therapeutic Uses

Study Officials

• Michael Weller, MD

  University of Zurich

  STUDY CHAIR

• Rolf Stahel, MD

  ETOP IBCSG Partners Foundation

  STUDY CHAIR

Central Study Contacts

Heidi Roschitzki-Voser, Dr.

CONTACT

+41 31 511 94 18; heidi.roschitzki@etop.ibcsg.org

Susanne Roux

CONTACT

+41 31 511 94 17; susanne.roux@etop.ibcsg.org

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 23, 2022
• First Posted: August 31, 2022
• Study Start: November 30, 2022
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: April 27, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

ES (3); NL (1); GB (2); CH (3); IT (6)