Targeted therapy with or without dose intensified radiotHerapy for oligo-progressive disease in oncogene-Addicted Lung Tumours
The aim of this study is to determine whether in patients with mutation positive advanced NSCLC the use of SBRT to ≤ 3 sites of oligoprogressive disease (OPD) with continuation of TKI improves progression-free survival (PFS) compared with continuation of TKI alone.
London – Fulham Research Ethics Committee, 10/07/2017, ref: 17/LO/0980
Randomised; Interventional; Design type: Treatment, Radiotherapy
Primary study design
Secondary study design
Randomised controlled trial
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Specialty: Cancer, Primary sub-specialty: Lung Cancer; UKCRC code/ Disease: Cancer/ Malignant neoplasms of respiratory and intrathoracic organs
Eligible participants are randomised to receive either Stereotactic Body Radiotherapy (SBRT) or no SBRT at a ratio of 2:1 (SBRT : no SBRT), with all participants continuing to receive background treatment with TKI therapy as clinically indicated and as per standard care.
Participants allocated to TKI (Tyrosine kinase inhibitor) alone arm continue on the same background TKI treatment as prior to trial entry.
Participants allocated to SBRT and TKI arm receive a dose and fractionation schedule dependent on the metastatic site and proximity to critical normal tissues. Patients continue to receive TKI treatment as prior to trial entry. Repeat SBRT is permissible upon development of subsequent OPD (oligoprogressive disease) lesions dependent on SBRT suitability and total progression lesion number at any one point remaining ≤ 3.
All patients are seen eight weeks post randomisation, then three monthly in line with routine care. Tumour imaging and toxicity assessment is assessed monthly ever three months until disease progression. Quality of Life is assessed at baseline, eight weeks and at the first three month visit. Research bloods is collected at baseline, after the first SBRT fraction (treatment group), eight weeks and three monthly until change in systemic therapy.
Primary outcome measures
Progression free survival defined as the time from randomisation to the first of one of the following events or death from any cause:
1.1. Clinically symptomatic progression requiring palliative tumour-specific oncological intervention (e.g. change in systemic therapy or localised non-SBRT radiotherapy) as determined by the treating physician.
1.2. New or existing intra-cranial lesions not amenable to radical surgery or SRS.
1.3. Development of new extra-cranial lesions or progression of existing extra-cranial lesions not meeting the criteria for SBRT treatment (e.g. size >5cm)
1.4. Development of >3 new or progressing extra-cranial lesion at any one point in time (i.e. widespread progression)
Secondary outcome measures
1. Time to next line of systemic therapy or palliative care – time from randomisation to change in therapy or referral to palliative care due to clinical progression as determined by the treating physician, or death.
2. Overall survival is measured from the time of randomisation until death from any cause.
3. Patterns of disease progression are identified using CT scans to further document natural history of oncogene-addicted NSCLC at 3 monthly intervals
4. Radiotherapy toxicities (acute and late) assessed using CTCAE v4.0 (clinician and patient versions (where available)) and RTOG. Acute events are defined as ≤ 90 days post SBRT start date (applicable for each subsequent course of SBRT where relevant); late events > 90 days.
5. Quality of Life is assessed using EQ-5D-5L and the EORTC QLQ-C30 at baseline, eight weeks and at the first three month visit
6. Measurement of resistant sub-clones in ctDNA is from blood samples collected at baseline, eight weeks post-randomisation and three-monthly during follow-up
7. Time to failure of next line treatment is measured from the time of randomisation to disease progression on next line of active systemic therapy
Overall trial start date
Overall trial end date
Participant inclusion criteria
1. Male or female, ≥ 16 years of age
2. Established histological diagnosis of advanced NSCLC, not suitable for radical treatment, with defined actionable mutation receiving targeted TKI therapy
3. Clinical and/or radiologically confirmed response to TKI therapy (assessed locally usually 2-3 months post commencing TKI)
4. Confirmed OPD defined as ≤ 3 extracranial sites of progressive disease. All sites must be visible, imaging defined targets and suitable for treatment with SBRT as determined by the virtual MDT and in accordance with the HALT Radiotherapy planning and delivery guidance document.
5. Adequate baseline organ function to allow SBRT to all relevant targets
6. Predicted life expectancy ≥ 6 months
7. Karnofsky Index ≥ 60% and ECOG 0-2
8. Provision of written informed consent
Target number of participants
Planned Sample Size: 110; UK Sample Size: 110
Participant exclusion criteria
1. > 3 extracranial sites of progressive disease
2. Brain metastases not amenable to radical surgery or SRS
3. Prior radiotherapy near the oligoprogressive lesion precluding ablative SBRT
4. Co-morbidities considered clinically to preclude safe use of SBRT e.g. IPF in patients with an oligoprogressive lung lesion, inflammatory bowel disease in patients with an oligoprogressive pelvic lymph node
5. Any psychological, sociological or geographical issue potentially hampering compliance with the study
Recruitment start date
Recruitment end date
Countries of recruitment
Trial participating centre
The Royal Marsden Hospital
Trial participating centre
The Royal Marsden Hospital
Fulham Road Chelsea
Cancer Research UK
Funding Body Type
private sector organisation
Funding Body Subtype
Results and Publications
Publication and dissemination plan
The main trial results will be published in a peer-reviewed journal, on behalf of all collaborators. Study results will aim to be published within 1 year after trial ends.
IPD sharing statement:
The datasets generated during and/or analysed during the current study are/will be available upon request from email@example.com
Intention to publish date
Participant level data
Available on request
Results - basic reporting