Osimertinib and Locally Ablative Radiotherapy in Patients With Synchronous Oligo-metastatic EGFR Mutant NSCLC (STEREO) (STEREO)

  • STATUS
    Recruiting
  • End date
    Mar 14, 2026
  • participants needed
    60
  • sponsor
    ETOP IBCSG Partners Foundation
Updated on 4 October 2022

Summary

STEREO is single-arm phase II study, which aims to evaluate the safety and efficacy of osimertinib combined with early locally ablative radiotherapy of all cancer sites in patients with synchronous oligo-metastatic (primary tumour and maximum 5 metastases) EGFR-mutant (exon 19 deletion or exon 21 L858R) NSCLC. Eradication of all macroscopic cancer sites at the time of primary diagnosis by combined modality treatment is expected to decrease the risk of resistance development with only microscopic disease potentially remaining. This will result in an improvement of PFS and OS without added high-grade toxicity.

Description

Targeting Epidermal Growth Factor Receptor (EGFR) mutation has fundamentally changed the treatment of metastatic Non-Small Cell Lung Carcinoma (NSCLC).

Several randomised phase III studies have compared first-generation (erlotinib or gefitinib) or second-generation (afatinib) EGFR-targeting TKIs with standard platinum-based chemotherapy and all reported significantly improved objective response rates (ORR) and progression-free survival (PFS). For patients with TKI resistance development by T790M mutation, which is the resistance mechanism in about 50% of the patients, osimertinib is superior compared to platinum-based chemotherapy with significant and clinically relevant improved ORR and PFS. Recently, the FLAURA study reported improved PFS of osimertinib compared to first-generation TKI (erlotinib or gefitinib) for untreated EGFRmutant advanced NSCLC, without differences in ORR. On longer follow-up, first-line osimertinib was also associated with improved survival.

Integration of local therapy into a multimodality treatment is a promising strategy to overcome the limitations of EGFR-targeting TKIs alone, despite patients suffering from a metastatic stage of disease. This is based on the observations that disease progression under EGFR-targeting TKI most frequently occurs at the original sites of metastatic disease and that the majority of patients show disease progression in a limited number of metastatic lesions, a situation defined as oligoprogression. Al-Halabi et al. reported in a series of 49 patients that 47.0%, 32.6%, and 20.4% of the patients developed original site failure, combined original site and distant site failure and distant site failure as first progression of disease to EGFR-targeting TKI. Primary tumour size was the most significant predictor for original site failure. Li et al. reported about 266 patients treated with first-line EGFR-targeting TKI and disease progression was reported at original and distant sites in 39% and 61%, respectively. Guo et al. reported disease progression in original sites, combined original and distant sites and distant sites in 50%, 28% and 22%, respectively. Consequently, EGFR-targeting TKIs appear less effective in controlling sites of macroscopic disease, where residual cancer cells ultimately acquire resistance and become the source of further disease progression.

Early imaging-based detection of oligoprogressive disease sites and their local ablation combined with continuation of TKI is one strategy to overcome this resistance development: metastatic sites with acquired resistance to EGFR-targeting TKI are eradicated by locally ablative treatment, irrespective of the underlying resistance mechanism, whereas non-progressing and EGFR-sensitive sites are continuously targeted and controlled by TKI therapy. This combined modality strategy has shown promising results in several retrospective studies, including a recent Swiss cohort study, where locally ablative treatment added to continuation of osimertinib in oligoprogressive T790M-mutant NSCLC patients was identified as the intervention which prolonged overall survival (OS). A randomised phase II trial is currently testing this hypothesis of locally ablative radiotherapy for oligoprogressive driver mutated NSCLC patients (NCT03256981); assessment of liquid biopsy for response evaluation is an important translational endpoint to identify patients with residual resistant disease after locally ablative treatment.

However, the strategy of local eradication of oligoprogressive disease has the limitation that imaging can only detect resistance development when this has already translated into macroscopically progressive disease. Systemic dissemination of resistant disease beyond the initial sites of acquired resistance development may then have already occurred, which is supported by the finding that the majority of patients develop further disease progression after locally ablative treatment. Consequently, there is a strong rationale of early targeting of local disease sites at high risk for developing acquired EGFR resistance, before imaging-based progression has developed. This strategy is supported by retrospective data of patients with brain metastases, where early radiosurgery combined with EGFR-targeting TKI improved OS compared to EGFR-targeting TKI alone and delayed radiotherapy at the time of disease progression (HR 0.39, 46 months vs 25 months). The hypothesis of upfront SBRT is supported by a recent randomised phase III trial of patients with oligo-metastatic EGFR-mutated NSCLC treated with first-generation EGFR TKIs presented at ASCO 2020, which demonstrated a PFS and OS benefit for early use of SBRT compared to systemic therapy alone. However, this study is limited by the use of first-generation TKIs only, and especially by chemotherapy as mandatory second line treatment.

The value of combined modality systemic therapy with locally ablative therapy for oligo-metastatic NSCLC has recently been evaluated in several randomised trials. All studies reported a significantly and clinically relevant improved OS or PFS for adding locally ablative therapy to standard of care systemic therapy. However, these studies included only very few NSCLC patients with activating driver mutations and the benefit of adding upfront local radiotherapy might be smaller or larger in this NSCLC patient population with activating driver mutations and treatment with TKIs: smaller because of the higher systemic efficacy of TKIs compared to chemotherapy or larger because the benefit of local treatment might become most obvious if potential microscopic disease is successfully controlled by TKIs.

Consequently, there is a clinical need to evaluate locally ablative therapy in oligo-metastatic EGFR-mutant NSCLC patients and simultaneously a strong rationale that this population might benefit in particular from a combined modality treatment: the benefit of locally ablative therapy is expected to be largest in situations of effective systemic therapies to control locally untreated microscopic disease which is true for EGFR targeting.

Details
Condition NSCLC Stage IV, EGFR Gene Mutation
Treatment Stereotactic Body Radiation Therapy (SBRT), Osimertinib
Clinical Study IdentifierNCT04908956
SponsorETOP IBCSG Partners Foundation
Last Modified on4 October 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Histologically confirmed, treatment naïve EGFR-mutant NSCLC, with or without T790M resistance mutation. Presence of the sensitising EGFR-mutation (exon 19 deletion and/or exon 21 L858R) detected by an accredited laboratory
Synchronous oligo-metastatic stage IV disease (max 5 lesions)
Measurable disease as defined according to RECIST v1.1
All lesions amenable for radical radiotherapy according to local judgment
Age ≥18 years
ECOG performance status 0-2
Life expectancy ≥12 months
Adequate haematological, renal & liver function
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 enrolment
Written IC for protocol treatment

Exclusion Criteria

Prior chemotherapy, immunotherapy, radiotherapy or therapeutical surgery for NSCLC (an exception is the resection and postoperative radiotherapy of the resection cavity of CNS or adrenal metastases)
More than 5 distant oligo-metastases (any second intra-thoracic lesion will count as a distant metastasis; regional nodal metastases will not count towards 5 oligo-metastases) and more than 2 intra-thoracic lesions
Brain metastases not amenable for radiosurgery or neurosurgery
Presence of leptomeningeal metastases
Symptomatic spinal cord compression
Extracranial metastatic locations not amenable for radical radiotherapy
Currently receiving medications or herbal supplements known to be potent CYP3A4 inducers
Any evidence of severe or uncontrolled systemic diseases
Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib
Any of the following cardiac criteria: QTcF >470 msec; Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG; Any factors that increase the risk of QTc prolongation or risk of arrhythmic events
Past medical history of Interstitial Lung Disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD
Idiopathic pulmonary fibrosis which is a contraindication to lung radiation
History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib
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 trial and up to 6 weeks for women and up to 4 months for men, after the last osimertinib dose
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