Clinical trial NCT05522660: Immunotherapy or Targeted Therapy with or Without Stereotactic Radiosurgery for Patients with Brain Metastases from Melanoma or Non-small Cell Lung Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Non-Small Cell Lung Cancer
Melanoma
Lead sponsor: ETOP IBCSG Partners Foundation
Sponsor class: NETWORK
Collaborators: name: USZ Foundation
First posted: 2022-08-31
Enrollment: 190
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: CNS-specific PFS, locally assessed as per iRANO criteria
timeFrame: from date of randomization until the date of documented CNS-specific progression, assessed up to 42 months
Secondary outcomes:
Other outcomes:
Locations:
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"
city: Perugia
country: Italy
facility: Santa Maria della Misericordia Hospital
city: Roma
country: Italy
facility: Istituto Nazionale Tumori "Regina Elena"
city: Rome
country: Italy
facility: Policlinico Umberto 1
city: Siena
country: Italy
facility: Azienda ospedaliero-universitaria Senese Siena
city: Amsterdam
country: Netherlands
facility: NKI-AVL
city: Barcelona
country: Spain
facility: Vall Hebron Institute of Oncology (VHIO)
city: Majadahonda
country: Spain
facility: Hospital Puerta de Hierro
city: Valencia
country: Spain
facility: Hospital La Fe
city: Bern
country: Switzerland
facility: Inselspital
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zürich
country: Switzerland
facility: Universitätsspital Zürich
city: London
country: United Kingdom
facility: Royal Marsden (Sutton)
city: Manchester
country: United Kingdom
facility: Christie NHS Manchester
Study officials:
affiliation: University of Zurich
name: Michael Weller, MD
role: STUDY_CHAIR
affiliation: ETOP IBCSG Partners Foundation
name: Rolf Stahel, MD
role: STUDY_CHAIR
References: