Oligometastases: Radiotherapy

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1 Oligometastases: Radiotherapy Prof. Dirk De Ruysscher, MD, PhD Radiation Oncologist Maastro clinic, Maastricht University Medical Center/ GROW Maastricht The Netherlands

2 Disclosure Advisory board of Bristol-Myers Squibb Merck Serono Pfizer

3 NSCLC: Meta-analysis based on retrospective data Ashworth et al. Clin Lung Cancer 2014

4 Netherlands Cancer Registry Hendriks et al. Eur J Cancer 2015

5 Hendriks et al. Eur J Cancer 2015

6 Hendriks et al. Eur J Cancer 2015

7 Hendriks et al. Eur J Cancer 2015

8 Synchronous oligometastases NSCLC: Radical local therapy after response to systemic therapy (chemotherapy or TKI) Gomez et al. Lancet Oncol 2016

9 Local Treatment ( Primary tumour and M+) LCT: Hypofractionated RT/ SABR: 12 (48 %) Combination surgery and RT: 6 (24 %) Chemo-RT: 2 (8 %) Combined hypofractionated RT and chemo-rt: 3 (12 %) Surgery to all sites: 1 (4 %) Gomez et al. Lancet Oncol 2016

10 Patterns of Failure Disease progression: 30 patients (61 %): 13 in LCT group, 17 in no-lct LCT: Distant: 10 Loco-regional: 1 Both: 2 No-LCT Distant: 6 Loco-regional: 4 Both: 7 Gomez et al. Lancet Oncol 2016

11 Where do patients with oligometastases recur? De Ruysscher et al. JThor Oncol 2012

12 Conclusion In synchronous metastases, recurrences at distant sites remains the key problem Gomez et al. Lancet Oncol 2016

13 Radiation in immune therapy Demaria et al. JAMA Oncology 2015

14 Upregulation of MHC class I by radiation Reits et al. J Exp Med 2006

15 Upregulation of TAAs by radiation Caco-2, HCT116, WiDr, HT-29, LS 174T, SW1463, SW403, SW480, SW620, T84, LoVo, and COLO 205 A549, SK-LU-1, SW900, HLF-a, NCI-H23, NCI-H647, Calu-1, H460, Calu1 and Calu3 22Rv1, DU 145, PC-3, PC3, DU145 and LNCaP MelJuSo, SK-MEL-37, CaSki and SiHa MDA-MB-469, MDA-MB-231 and MCF 7 Saos, LM5, 143B, HOS, HU09, and M132 Dudek et al. Cyt Growth Fact Rev 2013

16 Radiation alters the MHC class I associated peptide profile Reits et al. J Exp Med 2006

17 Main mechanisms of ICD-inducers Dudek et al. Cytokine & Growth Factors Rev 2013

18 Biomarkers for ICD Cancer cell-associated pro-tumorigenic cytokines/ factors IL1A, IL10, IL6,TGF-B, VEGFA, VEFGC, IDO enzyme, CXCL12, IL8 Immune cell-associated pro-tumorigenic cytokines/ chemokines/ factors IL10, IDO enzyme,tgf-b, IL4, IL5, IL13,TNF, M-CSF, GM-CSF, IL26, CXCl5, CCL7 Danger signals HMGB1, HSP70 and autoantibodies against CRT/HSP90 Cancer cell-associated viral response-like chemokine signature IFN-a, IFN-b, CXCL9, CXCL10, CXCL1 and CCL2 Immune cell-associated anti-tumorigenic cytokines or chemokines IL1B, IL12p70, IL15, IFNG, IL22, IL23, IL17A, IL2, CCL4, CCL5, CXCL13, CCL8, CCL19, CXCL11,CCL12, CCL17, CCL23, CCL22, CCL13, CCL24, CCL1, CCL26, CXCL2, CXCL16 Garg A et al. Front Immunol 2015

19 Prognostic value of ICD-genes Garg A. et al. OncoImmunology 2016

20 Radiation + anti-ctla4 promotes regression of irradiated and unirradiated tumours and is inhibited by PD-L1 on tumour cells. Twyman-Saint Victor et al. Nature 2015

21 Maximum clonal frequency in post-treatment blood of the most frequent TCR clonotypes found in TILs. Twyman-Saint Victor et al. Nature 2015

22 Abscopal effect of L19-IL2 and radiation Rekers N et al. Nature Comm 2015

23 Radiotherapy primary tumour 5x4 Gy, followed by selectikine 2/13 (15 %) patients no progression after 4 years!

24 Phase I trial SBRT + L19-IL2 NCT Synchronous or metachronous oligometastatic solid tumor (NSCLC, RCC, HNSCC, CRC, melanoma) SBRT to all (up to 5) oligometastatic sites L19-IL2 (6 cycles: day 1,3,5; Q 21 days) Location dependent: 1 x 30 Gy 3 x 10 Gy 3 x Gy 5 x 12 Gy 8 x 7.5 Gy 12 x 5 Gy ETOP 6-14 NICOLAS

25 HORIZON 2020 ETOP 6-14 NICOLAS

26 What do we know? A rare subgroup of patients - in a good general condition (WHO performance status 0-1) - with a few metastases (0-3) - at diagnosis (synchronous metastases) experience long-term disease-free survival (10-15 %) - when treated with radical local therapy (surgery or highdose radiotherapy) on all detectable cancer deposits

27 Treat brain disease first (if present/ gross/ symptomatic): SRS ± WBRT, resection + WBRT Systemic treatment: in case of response Treat chest disease N0/N1: surgery, SABR N2/N3: radiotherapy Radical local treatment of distant metastases Surgery/ SABR

28 Conclusions Improvements of systemic treatment are obviously the key to success Immune therapy is a trend, not a hype Radiotherapy helps to increase the proportion of patients experiencing a sustainable antitumour immune response Biomarkers are being developed