A Phase II, Multi-centre Study, to Evaluate the Efficacy and Safety of Osimertinib Treatment for Patients with EGFR-mutated Non-small Cell Lung Cancer (NSCLC) with Brain or Leptomeningeal Metastases
Overview
- Phase
- Phase 2
- Intervention
- Osimertinib
- Conditions
- Non Small Cell Lung Cancer Metastatic
- Sponsor
- Intergroupe Francophone de Cancerologie Thoracique
- Enrollment
- 57
- Locations
- 36
- Primary Endpoint
- Objective Response Rate
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
Treatment of non-small cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) mutation is mainly based on tyrosine kinase inhibitors (TKIs) targeting EGFR. 1st or 2nd generation inhibitors have been shown to be superior to chemotherapy in terms of Progression-Free Survival (PFS) when used as 1st line treatment.
In case of progression at several metastatic sites, systemic treatment will be considered and will depend on the presence of the TKI resistance mutation, the T790M mutation. In the presence of the T790M mutation, osimertinib is superior to chemotherapy in terms of progression-free survival, while in the absence of the T790M mutation, platinum salt chemotherapy is recommended. In case of local progression, treatment of the site in progression by radiotherapy and/or surgery is considered. As these local treatments can cause long-term adverse effects, systemic treatments are increasingly being considered in this indication.
Brain and leptomeningeal metastases are the most frequent isolated site of progression in EGFR mutated patients treated with TKI. The high frequency of isolated cerebral and leptomeningeal progression is a consequence of the lower diffusion of 1st and 2nd generation TKIs in the central nervous system (CNS). Osimertinib is a 3rd generation TKI that has the particularity of overcoming the T790M mutation and having greater brain penetration than 1st or 2nd generation TKIs, which could make it an attractive therapeutic option in the event of brain progression or leptomeningeal progression. However, its efficacy in patients with cerebral or leptomeningeal metastases is still poorly understood.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patient with NSCLC (histological or cytological diagnosis) stage IV (8th UICC TNM edition, 2017).
- •Patients with brain and/or leptomeningeal metastases. For cohort 1, the diagnosis of leptomeningeal metastasis requires either 1) detection of cancer cell or EGFR mutation in the CSF, or 2) presence of both clinical and neuro-imaging findings typical of LM, according to EANO-ESMO criteria.
- •Presence of an activating EGFR mutation. The following mutations are considered to be activating: L858R, exon 19 deletions, exon 19 insertions, L861Q, G719X. The inclusion of patients with other mutations should be discussed on a case-by-case basis with IFCT.
- •The presence of co-mutations on an oncogenic driver should be discussed with the IFCT before inclusion of the patient.
- •Testing for T790M mutation in circulating tumour DNA or tumour tissue sample at progression on the last treatment received before inclusion.
- •Maximum lines of anti-cancer treatment received before inclusion:
- •For Cohort 1, patients could have been previously treated with maximum 3 lines of anti-cancer treatment.
- •For cohort 2, patients could have been previously treated with maximum 1 line of anti-cancer treatment.
- •In case of previous chemotherapy, a wash-out period of 28 days will be applied. If there was any prior therapy with an investigational agent, a washout period of five half-lives of the compound or 3 months, whichever is greater, is needed.
- •Patient having recovered from all grade ≤ 1 toxicities related to previous anticancer therapies (CTCAE v 5.0) except for alopecia, platinum-therapy-related neuropathy (where ≤2 is allowed).
Exclusion Criteria
- •Small cell lung cancer histology (SCLC) or tumours with mixt histology including a SCLC component.
- •Previous treatment with osimertinib or another 3rd generation EGFR inhibitor.
- •Previous treatment with any EGFR TKI (cohort 2 only)
- •Brain progression requiring whole brain radiation without delay.
- •Local treatments (neurosurgical or stereotactic treatment) for brain metastases performed less than 2 weeks prior to enrolment.
- •Local brain treatment scheduled during study treatment.
- •Patient who received radiotherapy including the lung fields ≤ 4 weeks before enrolment or patient who has not recovered from radiotherapy-induced toxicities. For all other body sites (including radiotherapy on thoracic vertebrae and ribs), radiotherapy ≤ 2 weeks before enrolment or who have not recovered from radiotherapy-induced toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks before enrolment is authorised.
- •Any of the following cardiac criteria:
- •Mean resting corrected QT interval (QTc) \> 470 msec using the screening clinic ECG machine derived QTc value
- •Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g. complete left bundle branch block, third degree heart block and second degree heart block).
Arms & Interventions
Osimertinib
Osimertinib 80 mg/d
Intervention: Osimertinib
Outcomes
Primary Outcomes
Objective Response Rate
Time Frame: 6 months
Objective Response Rate at 6 months using EANO-ESMO criteria (cohort 1) and RECIST1.1 criteria (cohorts 2)
Secondary Outcomes
- Overall Survival(About 24 months)
- Progression-free survival(About 24 months)
- CNS Progression-free survival(About 24 months)
- Incidence, type and severity of adverse event(From time of informed consent through treatment period and up to 30 days post last dose of study treatment (about 24 months))
- Evaluate the Quality of life(From time of randomisation through treatment period (about 24 months))
- CNS Overall response Rate (ORR)(6 months)