ES21.05 Clinical Trials to Advance the Field of OMD

Abstract

Oligometastatic disease (OMD) in non-small cell lung cancer (NSCLC) is a complex pathology. Four settings can be displayed where synchronous OMD (sOMD), occurring at the time of initial diagnosis, was the most evaluated in clinical trials. Other potential situations are oligorecurrence (rOMD), developed after optimal local control of a localised tumour, oligoprogression (pOMD) corresponding to a progression in a limited number of metastatic sites, and oligopersistant disease (peOMD) after/on systemic therapy. Several non-randomised phase II studies demonstrated the feasibility adding local ablative therapy (LAT) to systemic therapy in sOMD. Design, number of metastatic sites, type of LAT (chemoradiotherapy [CTRT], surgery, stereotactic radiotherapy [SBRT]) and endpoints largely differed among studies. A first pilot study (1) showed that surgery at the primary and the single metastatic sites after induction chemotherapy (CT) was feasible with 57% complete resection (R0) and 11 months median survival (MST). The same approach was recently confirmed in another prospective study with 71% R0 and 46.5% 5-years survival (2). Later, a phase II study conducted in The Netherlands and recently updated (3) demonstrated, when combining LAT (surgery or radiotherapy) to systemic therapy, MST of 13.5months but more essential, 5 and 6-years survival rates of 7.7% and 5.1% respectively. Other phase II studies, including NSCLC with <6 metastases, confirmed those results whether considering overall survival (4), metabolic response (5) or progression-free survival (PFS) (6). The first randomised phase II trial (RCT) compared, in sOMD with < 3 metastases non-progressing after CT, LAT (surgery, SBRT, CTRT) plus maintenance to maintenance only. The study closed early after first interim analysis and 49 randomised patients. Updated data confirmed improved PFS (14.2 months vs 4.4 months; p = 0.022) and MST (41.2 months vs 17 months; p = 0.017) favouring the LAT arm. A second small-sized phase II RCT closed early after interim analysis (8). 29 sOMD patients (≤5 metastases) not progressing after CT were randomised between SBRT plus maintenance or maintenance. Also, median PFS improved from 3.5 months to 9.7 months (p = 0.01) in the LAT arm. All these data need confirmation in larger RCT. Four phase III trials are or will be ongoing. SARON (NCT02417662) is comparing standard CT alone to CT plus SBRT in sOMD with ≤ 3 metastases. In the OMEGA trial (NCT03827577), patients with synchronous or metachronous oligometastatic NSCLC (1-3 metastatic lesions) were considered for LAT (surgery or RT) or not in addition to systemic therapy. SINDAS (NCT02893332) is assessing the role of SBRT in addition to tyrosine kinase inhibitor in sOMD EGFR muted NSCLC with ≤ 5 tumoral sites (inclusive primary site; lymph nodes being considered as a metastatic site). Finally, HALT (NCT03256981) is a phase II-III RCT evaluating SBRT for pOMD during targeted therapy in NSCLC harbouring activating mutations. All these studies are presenting with various designs and primary endpoints, but also differences in staging procedures resulting in major difficulties for definite conclusions on the usefulness of LAT in OMD patients. In order having similar populations among clinical trials, we need that a common definition is used by all investigators. In this way, the EORTC Lung Cancer Group proposed a definition for sOMD based on a consensus from thoracic oncology experts (8). Using common definition and staging assessment and finding predictive factors for a better patient’s selection should be addressed in future clinical trials. 1. Downey et al. A phase II trial of chemotherapy and surgery for non-small cell lung cancer patients with a synchronous solitary metastasis. Lung Cancer 38:193-7, 2002 2. Endo et al. A prospective study of surgical procedures for patients with oligometastatic non-small cell lung cancer. Ann Thorac Surg 98:258-64, 2014. 3. De Ruysscher et al. PFS and OS beyond 5 years of NSCLC patients with synchronous oligometastases treated in a prospective phase II trial (NCT 01282450) OA07.07 J Thorac Oncol 2018 4. Arrieta et al. Radical consolidative treatment provides a clinical benefit and long-term survival in patients with synchronous oligometastatic non-small cell lung cancer: A phase II study. Lung Cancer. 130:67-75, 2019 5. Petty et al. Long-Term Outcomes of a Phase 2 Trial of Chemotherapy With Consolidative Radiation Therapy for Oligometastatic Non-Small Cell Lung Cancer. Int J Rad Oncol Biol Physics. 102:527-535, 2018. 6. Collen et al. Phase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic nonsmall-cell lung cancer patients. Ann Oncol. 25:1954-9, 2014. 7. Gomez et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol JCO1900201, 2019. 8. Dingemans et al, MA25.02 Journal of Thoracic Oncology 2018;13:S445-S446 Oligometastasis, non-small cell lung cancer