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

11

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?

15

“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!

20

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

26

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

24

Radio-imnunotherapy: clinical update 2017

• Systemic cancer control effects of RT: phase III data

27

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

20

Overall survival in the intention-to-treat population

22 months sustained effect

21

Progression free survival

Radio-imnunotherapy: clinical update 2017

• Toxicity of combination of RT and immunotherapy agents

32

SBRT + targeted / inmunotherapy + grade 3 toxicity

…2016

any RT technique

39

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