Inmunoterapia Desarrollo clínico: oportunidades entorno a SBRT

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1 Inmunoterapia Desarrollo clínico: oportunidades entorno a SBRT Felipe A. Calvo Hospital General Universitario Gregorio Marañon Madrid, España ALATRO 2017

2 Radio-inmunotherapy: clinical update 2017 From spatial cooperation to systemic bio-effects Precise + multitarget + hypo-fractionated RT: clinical models Abscopal! Systemic cancer control effects of RT: phase III data Toxicity of combination of RT and immunotherapy agents Potential for practice: present and data in progress 2

3 1982 Gordon Steel & Michael Peckham

4 Radio-imnunotherapy: clinical update 2017 Precise + multi-target + hypo-fractionated RT: clinical models 4

5 bio-dinamics of radiation effects

6 targeted agents and radiation effects

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8 Exclusion Desert Inflamed

9 seed and soil

10 and soil

11 Radio-imnunotherapy: clinical update 2017 Precise + multitarget + hypo-fractionated RT: clinical models 11

12 Extreme Precision = i-fusion + cone beam CT = Extreme Hipofractionation PET-TAC FUSION 1 3 SBRT fractions CONEBEAM VERIFICATION

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14 Breast cancer Non-breast cancer SBRT body (no brain SRS) 121 pts < 5 mets Breast cancer 16 / 39 alive Other sites 7 / 82 alive Breast cancer Non-breast cancer

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16 1fr Gy 3fr Gy 4fr-40 Gy 5fr Gy 6fr-42 Gy 10fr-50 Gy Toxicity G3 3-30% G4 3-9% Lancet Oncol 2013; 14: e28 37 (12 modern SBRT olimetastatic trials)

17 Super-RT-ablation single-dose >30 Gy? Lancet Oncol 2013; 14: e28 37

18 Local treatment of metastatic disease with SBRT would effectively be a new indication for radiotherapy, resulti in potentially dramatic growth in the average raditherapy practice. Interestingly, the rational becomes even stronger with the discovery of more effective systemic therapies. 15

19 Studies Oligometastatic Disease: Cancer-Type Oriented Clinical Trials. Gov 2 / 1 / 2015 CANCER # REFERENCES EU / USA / Others Tx ALGORITHM OUTCOME End-p Lung NSCLC RT + Erlotinib TKI EGFR Pembrolizumab SBRT Prostate IMRT + HT SBRT Breast HD-CT + RT; RT + CT SBRT + MK-3475 SBRT +/- Trastuzumab PFS OS Toxicity Response BC; ADT- FS;Toxicity; Inmune effect CTCs TTP PFS Melanoma SBRT + Ipilimumab PFS Sarcoma SBRT Local C; OS Colo-rectal RT + Beva + Cape PFS 6 cancer types 29 references 55% USA SBRT/90% systemic 65% PFS

20 Radio-imnunotherapy: clinical update 2017 Abscopal! 20

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22 67 abscopal reported (<2012) melanoma + clear cell > 70%... hipofractionation >80%... > 50% 12 mo duration

23 Prog Ipili WBRT abscopal Prog Ipili WBRT abscopal 26

24 Abscopal surprise! Oncoimunotherapy 2014 Metastatic melanoma Progresion after Ipilimumab 21 patients recieved RT (13 brain mets ; 8 extra-cranial) Abscopal effect MTT from RT to response 11 (52%) 9.PR 2 SD 1 month MOS months 22,4 (abscopal +) vs 8,3 (no) Cancer Res 2014 ECI301 Lancet Oncol 2014 renal cancer SBRT Local response to RT Abscopal effect in responders 13 pts 100%

25 During Ipi superior

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27 Radio-imnunotherapy: clinical update 2017 Systemic cancer control effects of RT: phase III data 27

28 NSCLC 74 pts estables o respondedores 1ra línea QT < 3 mets (75% SBRT) PFS 3.9 vs 11.9 meses (p= 0.005)

29 ipilimumab 10 mg/kg or placebo every 3 weeks x 4 doses. Non-progressing patients receive ipilimumab at 10 mg/kg every 3 months until disease progression, unacceptable toxic effect, or death at least one bone metastasis from CRPC that had progressed after docetaxel 8 Gy RT sequentail bone directed RT (8Gy) + ipilimumab 10mg/kg sequentail bone directed RT (8Gy) + placebo

30 Overall survival in the intention-to-treat population 22 months sustained effect 20

31 Progression free survival 21

32 Radio-imnunotherapy: clinical update 2017 Toxicity of combination of RT and immunotherapy agents 32

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35 2016 SBRT + targeted / inmunotherapy + grade 3 toxicity

36 any RT technique

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39 Cetuximab vs Ipilimumab + RT <grade 3 toxicity g4 g5 total in-field pruritus, pyrexia, fatigue, endocrine, necrosis 39

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41 Radio-imnunotherapy: clinical update 2017 Potential for practice: present and data in progress 41

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45 SBRT + Hypofractionation + immunotherapy: the new local + systemic scenario

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49 Nature Review Clin Oncol 2017 Weichselbaum et al inmune-checkpoint blockade + RT PD-1; PD-L1 + RT # studies CANCER model Radiotherapy Pembrolizumab 9 NSCLC (3),breast,bladder,solid (2),SCCHN,esophageal Hypof, brachy Pidilizumab 1 glioma Standard RT AMP-224a 1 Colo-rectal Hypof REGN281 1 Advanced malignacies Hypof Nivolumab 1 NSCLC Hypof Atezolizumab 3 NSCLC (2), Merkel Hypof Avelumab 1 Merkel Hypof Durvalumab 1 glioma Standard RT

50 Radio-imnunotherapy: clinical update 2017 Is here: patients are already under IT and will need RT SBRT is our best technical proposal for combined modality therapy Abscopal! Look for it (practical strategies in clinic.) Systemic cancer control effects of RT: phase III data. Very relevant in unfavorable disease models Toxicity of combination of RT and immunotherapy agents: not that limiting Data in progress: the need to access to clinical trials design with RO strategies

51 1982 Gordon Steel & Michael Peckham