Radiotherapy, abscopal effect &

immunotherapy

Prof. Eric F. Lartigau General Director, Centre Oscar Lambret

Lille, France

C. O. I.

Eric F. LARTIGAU has been

consultant in the last 5 years for

Accuray, Amgen, Astellas & Merck-

Serono

DEFINITION of OLIGOMETASTASES :

1995 : Hellman & Weichselbaum, JCO 1995 ; 13 : 8-10

« tumors early in the chain of progression may have metastases limited in

number and location because the facility for metastatic growth has not

been fully developed… »

« some patients so affected should be amenable to a curative therapeutic

strategy ! »

2011 : the patient shows distant relapse in only a

« limited » number of regions (5 ?).

Oligo recurrence = same with primary cancer site controlled

Local treatment : an issue ?

Concept of ablative treatment :

• Surgery : (brain, liver) brings long survival….

• Radiotherapy : high dose, few fractions ???

• Radiosurgery (brain)

• SBRT: liver, lung, nodes…….

SBRT=

we have

the tools !!!!

SBRT is a standard

in many clinical situations

Today : brain, lung, spine, retreatment

Tomorrow : liver, prostate, partial breast

After tomorrow : most of ???

2 months

Colorectal liver metastases

Results in Lille

Probability of local control :

45 Gy (3 X 15 Gy)

versus

40 Gy (4 X 10 Gy)

Overall

survival

Disease free

survival

Local relapse free survival

hepatic lung

12 months 0.8649 0.7577

24 months 0.6758 0.6062

Renal metastase 3 x 15 Gy

At 3 years

Radioresistant tumours ?

Biology of High dose / fraction : BED > 100 Gy

Melanoma

Renal tumours

Sarcomas

…

» Wachsberger ; Clin Cancer Res 2003

Apoptosis

Sphingomyelin

A-SMase

Ceramide

DNA damage

Apoptosis Survival Mitotic death

A-SMase

The sphingolipid ceramide : a new molecular actor induced after high dose of radiation

Cell signaling

Repair Misrepair

Cell cycle arrest

DNA sensor

By courtesy of F. PARIS, INSERM, ICO, Nantes Courtesy F. Paris

Limits in targeted therapies

Mutational heterogeneity in cancer

Lawrence MS. 2013 Jul 11;499(7457):214-

218.

Molecular Basis of Cancer Immunotherapy

Vasaturo A, Front Immunol. 2013 Dec 3;4:417.

Stimulatory and inhibitory molecules expressed in the tumor

microenvironment targeted for therapeutic intervention.

Checkpoint inhibitors (solid tumors)

Agent (trade mark)

[testing PDL1] Target Firm

Nivolumab (Opdivo*)

[Dako 28-8] Anti-PD1 BMS

Pembrolizumab (Keytruda*)

[Dako 22C3] Anti-PD1 Merck/MSD

Atezolizumab (Tecentriq*)

[Ventana SP 142] Anti-PDL1 Roche

Durvalumab (Imfinzi*) Anti-PDL1 AZ

Avelumab (Bavencio*) Anti-PDL1 Pfizer

Ipilmumab (Yervoy*) Ant-CTLA4 BMS

Tremelimumab Ant-CTLA4 AZ

NSCLC with PDL1 ≥ 50%. Pembrolizumab vs chemo on 1st line.

Keynote 024 trial. PO: PFS. All comers with TPS ≥ 50%

Reck M et al. N Engl J Med. 2016 Nov 10;375(19):1823-1833

PFS: 10.3 vs. 6 mois

HR 0.50, p<0.001

PD-L1 expression : IHC 22C3 Dako.

How to predict and assess the toxicity of immunotherapy?

➢ Immunotherapy may revolutionize the treatment of cancers

➢ Will toxicity be a limitation for immunotherapy ???

Immunotherapy induced toxicity (irAEs)

Pneumonitis (anti-PD-1)

Reticular erythematous

rash Perivascular lymphocyte infiltrate

extending into epidermis

Bowel oedema and ulceration in the

descending colon

Gastrointestinal adverse events (anti-CTLA-4)2

Rash (anti-CTLA-4)1

Colonoscopy Histopathology

Focal active colitis (left) with crypt destruction, loss of goblet cells, and

neutrophilic infiltrates in the crypt epithelium (right)

1. Hodi F, et al. Proc Natl Acad Sci USA. 2003;100:4712–4717

2. 2. Maker A, et al. Ann Surg Oncol. 2005;12:1005–1016.

Immunotherapy induced toxicity: Pneumonitis

(**)

(*)

(*)

Anti-PD1 induced pneumonitis

ground glass opacities (*) and condensation (**)

immunotherapy toxicity (irAEs). Kinetics of appearance

Weber JS. J Clin Oncol 2012;30:2691-2697

HOW TO ASSESS TOXICITY OF IMMUNOTHERAPY AND WHAT IS ITS

IMPACT ?

HOW TO IDENTIFY NEW PREDICTIVE BIOLOGICAL MARKERS OF TOXICITIES

OF IMMUNOTHERAPY?

HOW TO IDENTIFY NEW PREDICTIVE NEUROPHYSIOLOGICAL AND PSYCHOLOGICAL MARKERS?

Integrated research

❖ Basic research

❖ Translational research

❖ Clinical research

Integrated markers

❖ Clinical markers

❖ Biological markers

❖ Neurophysiological and

psychological markers

A Signature of high risk of toxicity based on

clinical, biological, psychological and neurophysiological markers

Immunotherapy . Financial toxicity

Immunotherapy (IT). Main factors infuencing treatment decisions

Adapted from Ascierto et al. J Transl Med (2017) 15:205

PDL1

status

New technology = New delivery/dose

New biology = New indications

High precision RT to eradicate

gross tumour burden

in combined modalities