Inmunoterapia Desarrollo clínico: oportunidades entorno a SBRT
Felipe A. Calvo
Hospital General Universitario Gregorio Marañon
Madrid, España
ALATRO 2017
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
1982 Gordon Steel & Michael Peckham
Radio-imnunotherapy: clinical update 2017
• Precise + multi-target + hypo-fractionated RT: clinical models
4
bio-dinamics of radiation effects
targeted agents and radiation effects
Desert…
Exclusion…
Inflamed…
“seed and soil”
“…and soil”
Radio-imnunotherapy: clinical update 2017
• Precise + multitarget + hypo-fractionated RT: clinical models
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CONEBEAM VERIFICATION
PET-TAC FUSION
Extreme Precision = i-fusion + cone beam CT = Extreme Hipofractionation
1 – 3 SBRT
fractions
25
• Breast cancer
• Non-breast cancer
• Breast cancer
• Non-breast cancer
SBRT body (no brain SRS) 121 pts < 5 mets Breast cancer 16 / 39 alive Other sites 7 / 82 alive
Lancet Oncol 2013; 14: e28–37 (12 modern SBRT olimetastatic trials)
1fr-18-24 Gy 3fr-24-60 Gy 4fr-40 Gy 5fr-40-60 Gy 6fr-42 Gy 10fr-50 Gy
Toxicity G3 3-30% G4 3-9%
Lancet Oncol 2013; 14: e28–37
Super-RT-ablation single-dose… >30 Gy?
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“Local treatment of metastatic disease with SBRT would effectively be a new indication for radiotherapy, resulting in potentially dramatic growth in the average raditherapy practice. Interestingly, the rational becomes even stronger with the discovery of more effective systemic therapies”.
CANCER # REFERENCES EU / USA / Others Tx ALGORITHM OUTCOME End-p
Lung NSCLC 9 1 5 3 RT + Erlotinib
TKI EGFR
Pembrolizumab
SBRT
PFS
OS
Toxicity
Response
Prostate 8 4 3 1 IMRT + HT
SBRT
BC; ADT-
FS;Toxicity;
Inmune effect
Breast 6 2 3 1 HD-CT + RT; RT +
CT
SBRT + MK-3475
SBRT +/- Trastuzumab
CTCs
TTP
PFS
Melanoma 3 - 3 - SBRT + Ipilimumab PFS
Sarcoma 2 - 2 - SBRT Local C; OS
Colo-rectal 1 1 - - RT + Beva + Cape PFS
Studies Oligometastatic Disease: Cancer-Type Oriented Clinical Trials. Gov CTG @ 2 / 1 / 2015
6 cancer types 29 references 55% USA SBRT/90%
systemic
65% PFS
Radio-imnunotherapy: clinical update 2017
• Abscopal!
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67 abscopal reported (<2012)… melanoma + clear cell > 70%... hipofractionation >80%... > 50% 12 mo duration
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Prog Ipili WBRT abscopal Prog Ipili WBRT abscopal
Abscopal surprise! Oncoimunotherapy 2014
Metastatic melanoma
Progresion after Ipilimumab
21 patients recieved RT (13 brain mets ; 8 extra-cranial)
Cancer Res 2014 ECI301
Lancet Oncol 2014 renal cancer SBRT
Abscopal effect 11 (52%) 9.PR 2 SD
MTT from RT to response 1 month
MOS months 22,4 (abscopal +) vs 8,3 (no)
Local response to RT 13 pts
Abscopal effect in
responders
100%
During Ipi…superior
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Radio-imnunotherapy: clinical update 2017
• Systemic cancer control effects of RT: phase III data
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2012 – 2016 NSCLC 74 pts estables o respondedores 1ra línea QT
< 3 mets (75% SBRT) PFS 3.9 vs 11.9 meses (p= 0.005)
at least one bone metastasis from CRPC that had progressed after docetaxel
sequentail bone directed RT (8Gy)
+ ipilimumab 10mg/kg
sequentail bone directed RT (8Gy)
+ placebo
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
8 Gy RT
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Overall survival in the intention-to-treat population
22 months sustained effect
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Progression free survival
Radio-imnunotherapy: clinical update 2017
• Toxicity of combination of RT and immunotherapy agents
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SBRT + targeted / inmunotherapy + grade 3 toxicity
…2016
any RT technique
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Cetuximab vs Ipilimumab + RT <grade 3 toxicity g4 g5 total in-field
pruritus, pyrexia, fatigue, endocrine, necrosis
Radio-imnunotherapy: clinical update 2017
• Potential for practice: present and data in progress
41
SBRT + Hypofractionation + immunotherapy:
the new local + systemic scenario
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
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
1982 Gordon Steel & Michael Peckham