ESTRO 36 Abstract Book

S3 ESTRO 36 _______________________________________________________________________________________________

adequate. Large treatment volumes were successfully treated by dose escalated hyperfractionated and accelerated radiotherapy schedules in patients with locally advanced lung cancer together with concurrent chemotherapy. Limited volume hypofractionation at the primary tumor site and limited hilum or mediastinum is another way to overcome repopulation. Adenocarcinomas with druggable driver mutations have a considerably better prognosis than tumors without. Targeted therapies are attractive partners for radiotherapy to inhibit repopulation and perhaps repair. New concepts emerge for using genetic vulnerabilities of tumor cells other than driver mutations for drug-induced synthetic lethality resulting in a highly selective treatment of tumor cells in combination with radiotherapy. For relapsing patients or patients with synchronous oligometastatic disease, stereotactic ablative radiotherapy RT to various sites can offer long term control complementing better systemic therapy options. Immunotherapy is now an established second line treatment in metastatic NSCLC and an interesting combination partner for radiotherapy whereas the latter can increase expression of tumor-associated antigens. These advantages will be bundled into new radiotherapeutic concepts that have to be tested against standard conventionally fractionated radiotherapy and concurrent chemotherapy in future well designed randomized trials. SP-0011 The use of biomarkers for individualized treatment in NSCLC J. Belderbos 1 1 Netherlands Cancer Institute Antoni van Leeuwenhoek H ospital, Amsterdam, The Netherlands A biomarker is a biological substance, that can be detected by a laboratory or imaging technique allowing an assessment of the disease presence and/or progression. Blood samples to analyze biomarkers have the advantage that they are fast, minimal invasive and easy to obtain. Blood-biomarkers may be related to hypoxia (osteopontin (OPN), carbonic anhydrase IX (CA-IX)), inflammation (Transforming growth factor beta1 (TGF-β1), interleukin- 6 (IL-6), IL-8, and C-reactive protein (CRP)), tumour load (carcinoembryonic antigen (CEA), and cytokeratin fragment 21-1 (Cyfra 21-1)) or growth factors (vascular endothelial growth factor(VEGF)). Besides clinical factors like patient characteristics (age, gender, WHO-PS, weight loss) and tumor characteristics (tumor volume, stage, lymph nodes) several biomarkers have been shown to be associated with disease progression and survival of NSCLC patients treated with radio(chemo)therapy. In addition to dosimetric parameters biomarkers may also be helpful to predict toxicity or radio-resistance. Blood-biomarkers to predict the risk of normal tissue damage by radio(chemo)therapy pre-, during and post- radio(chemo)therapy: Inflammatory cytokines are made by many cells within the lung, including the alveolar macrophages, Type II pneumoncytes, T lymphocytes and lung fibroblasts. Transforming growth factor beta1 (TGF-β1) is a cytokine that has been extensively studied as a marker predictive of radiation pneumonitis (RP). Patients with NSCLC have increased pre-treatment levels of TGFb1 and that increased levels were associated with a higher mean lung dose (MLD) and a higher incidence of RP. But especially the observation of an increasing ratio of pre- to intra-treatment TGFb1 for Stage III NSCLC treated with definitive radio(chemo)therapy was predictive of RP. More recently single nucleotide polymorphism rs1982073:T869C of the TGF-β1gene was reported to be associated with the risk of RP in NSCLC patients treated with definitive radio(chemo)therapy. Therefore genotype rs1982073:T869C of the TGF-β1 gene may serve as a reliable predictor of RP (Yuan JCO 2009). Certain

polymorphisms of the VEGF gene have also been correlated with the incidence and severity of RP. Circulating interleukin-6 (IL-6) and interleukin-8 (IL-8) levels levels pre-, during and post-RT have been correlated with an increased risk of RP as well. Blood-biomarkers associated with disease progression and survival of NSCLC patients treated with radio(chemo)therapy: A prediction model for 2-year survival was developed for NSCLC patients treated with curative intent with radio(chemo)therapy using different blood-biomarkers related to hypoxia, inflammation, immune response and tumour load by the MAASTRO group (Dehing-Oberije IJROBP 2011). They concluded that biomarkers CEA and interleukin-6 (IL-6) have an added prognostic value for survival of NSCLC patients. More recently the same group demonstrated and validated in two large cohorts of NSCLC patients the added value of blood-biomarkers related to hypoxia (OPN) and tumour load (Cyfra 21-1) (Carvalho Radiother Oncol, 2016) on survival. Blood-biomarkers associated with radio-resistance: Deletion of KEAP1 has been linked with tumor aggressiveness, metastasis and resistance to oxidative stress and radiotherapy in lung squamous cell carcinomas. Using the pre-RT plasma samples KEAP1/NRF2 mutations increased radio-resistance in a small group of patients with NSCLC and predicted local tumor recurrence in radiotherapy patients (Jeong Cancer Discovery 2017). These recent findings are of potential clinical relevance and could lead to personalized treatment strategies for tumors with KEAP1/NRF2 mutations. Conclusion: Combining blood-biomarkers and established prediction parameters into a single model is expected to improve the ability to predict normal tissue damage and treatment response as compared to either variable alone and could lead to personalized treatment strategies. SP-0012 Abscopal responses in metastatic non-small cell lung cancer (NSCLC): a phase II study of combined radiotherapy and ipilimumab S. Formenti 1 E. Golden, A. Chachoua, K. Pilones, S. Demaria 1 Weill Cornell Medical Center of Cornell University, New York- NY, USA CTLA-4 immune checkpoint blockade in metastatic and locally advanced NSCLC patients has demonstrated disappointing results (J Clin Oncol 2009, 27: suppl; abstr 8071). Conversely, our group has generated extensive pre- clinical evidence that the combination of CTLA-4 blockade and local radiotherapy induces responses outside the radiation field (abscopal effect) in syngeneic models of metastatic cancer (Clin Cancer Research 2005, 11: 728- 734). We also reported a dramatic abscopal response in a patient with refractory metastatic NSCLC treated with combined radiotherapy (RT) and ipilimumab, a monoclonal antibody against CTLA-4, (Cancer Immunol Res 2013, 1: 365-372), who remains alive and disease free five years later, without any other additional treatment. We have conducted a phase I-II trial to investigate effectiveness and safety of ipilimumab and localized RT to a metastasis in patients with metastatic NSCLC, to elicit an individualized vaccine, that is effective systemically, as reflected by objective abscopal responses (Formenti and Demaria, JNCI 2013). Patients with chemo-refractory metastatic NSCLC, PS 0-2, and ³2 measurable lesions (³1cm) were eligible. Patients received ipilimumab (3mg/kg i.v.) within 24 hrs of starting RT (6Gy x5 or 9.5GyX3 daily fractions) to one lesion. Ipi was repeated every 21 days x3. Optional biopsies and serial blood draws were obtained for immune monitoring. Patients were evaluated for abscopal responses with baseline and post- treatment (day 88) PET/CTs. Metastases outside the RT field were measured on axial CTs in 2 perpendicular dimensions. The products of the measurements (l x w) in