Immunotherapy & radiotherapy

Transcription

1 Immunotherapy & radiotherapy Eric Deutsch MD PhD Gustave Roussy Cancer Campus Image courtesy of Gustave Roussy Institute

2 Disclosure & Disclaimer An honorarium is provided by Accuray for this presentation The views expressed in this presentation are those of the presenters and do not necessarily reflect the views or policies of Accuray Incorporated or its subsidiaries. No official endorsement by Accuray Incorporated or any of its subsidiaries of any vendor, products or services contained in this presentation is intended or should be inferred.

3 1 Radiation Tumor Cell Calreticulin Phagocytosis Macrophages 3 2 Endogenous release TAA MHC I Antigen Presentation 4 DAMPs HMGB1, HSP, DNA, APC TLR 6 5 Radiation X Treg Depletion Marabelle A, et al. Semin Radiat Oncol Anti-tumor Immune Response

4 ESMO 2015 Spectrum of activity PD1/PDL1 Ab TAT 2016 MCC Thymic Mel RCC NSCLC Anal Bladder Biliary Tract SCLC PD-1/ PD-L1 Blockade HNSCC Gastric Oesoph Hodgkin HCC Mesothelioma TNBC Ovarian MSI High CRC B-Cell NHL Adapted from A Marabelle

5 «Abscopal» Effect RT X X Images courtesy of Gustave Roussy Institute

6 Abscopal effect in a clinical trial with various solid tumors tumors Primary end-point : >30% decrease in the longest diameter of the abscopal lesion. Secondary endpoints : safety and survival. 6 Golden et al., Lancet Oncology, 2015 and Frey, Gaipl, Lancet Oncology,

7 Abscopal in a clinical trial Radio(chemo)-immunotherapy: the focused beam expands: works with various solid tumors Golden et al., Lancet Oncology, 2015 and Frey, Gaipl, Lancet Oncology, Primary end-point : at least a 30% decrease in the longest diameter of the best responding abscopal lesion. Secondary endpoints were safety and survival. 7

8 Which radiation doses? Vanpouille-Box, Nat Comm. 2017

9 Scheduling and volumes?

10 Stereotactic radiotherapy Bernstein, NRCO 2016

11 Mice data Different groups Different models CD8 STING/IFN PDL1.. Human trial Which tumors? Phase 1? 2? 3? Doses of IR Stereotactic RT? Abscopal..

12

13 BEFORE IPILIMUMAB AFTER IPILIMUMAB + XRT

14 BEFORE IPILIMUMAB AFTER IPILIMUMAB + XRT

15 Clinical relevance? Proof of concept?

16 Progressing after 3 lines of chemo and chest RT: Multiple lung, bone and liver metastasis Patient with Refractory Metastatic NSCLC RT to one liver met 6 Gy X 5 ( TD 30 GY) Ipilimumab, 3 mg/kg, after first RT q3 weeks, X 4 cycles Golden et al Cancer Immunology Research, 2014

17 Same patient, response to RT+ ipilimumab

18 Randomized trials, selecting the right endpoints

19 Ipilimumab + RXT to bone: Overall Survival Proportion Alive Patients at Risk Ipilimumab Placebo Ipilimumab (N=399) Placebo (N=400) Median OS (95% CI) 11.2 ( ) 10.0 ( ) HR (95% CI): 0.85 ( ) Stratified log-rank P= yr OS rate 47% 40% 2-yr OS rate 26% 15% Months Ipilimumab Censored Placebo Censored Kwon E, Lancet Oncol 2014; 15: Courtesy K Fizazi

20 Results: Updated OS n=799 Primary endpoint= OS Ipilimumab post-docetaxel phase III trial Median OS, mo (95% CI) Ipi (n=399) Pbo (n=400) 11.2 ( ) 10.0 ( ) Proportion Alive Ipi Censored Pbo Censored Months HR (95% CI) 0.84 ( ) Stratified log-rank* P= yr OS rate 47% 41% 2-yr OS rate 25% 17% 3-yr OS rate** 12% 6% Fizazi K et al., ESMO 2014

21 Long-lasting complete response after Ipilimumab in CRPC 2011: mcrpc progressing post-docetaxel Pain requiring opioids Ipilimumab + RXT to 1 bone 2016: No detectable disease at 5 years+ PSA Courtesy K Fizazi Cabel L 2017, in press

22 Choosing the right timing!

23 Impact on the shape of the curves? Auperin JCO 2010 Antonia SJ, NEJM 201 PL04a.03 abstract: M. C. Garassino et al, WCLC 2016

24 PACIFIC Study Durvalumab (N=476) Placebo (N=237) Median PFS, months (95% CI) 16.8 ( ) 5.6 ( ) 12-month PFS rate, % (95% CI) 55.9 ( ) 35.3 ( ) 18-month PFS rate, % (95% CI) 44.2 ( ) 27.0 ( )

25 Kinetics of irae with imabs C1 C2 C3 C4 DLT period Postel-Vinay S et al, EJC 2014 Kaehler, KC et al Semin Oncol 2010 DLT period Ipilumimab ir AE temporality

26 I-O and radiotherapy : normal tissue reponse any data? Therapeutic index remains pivotal! Concurrent Louvel et al, in press

27 IO and XRT : not a way to circumvent the precision medicine challenge! Betch, Genom Biol 2016

28 Imaging of inflammation Determination of an imaging-base signature of tumor immune infiltrate Immune inflamed phenotype Radiomics-based CD8+ T cells score Immune-desert Overall suvival probability 139 patients P-value : High Low Time (months) Validation: Phase 1 anti-pd-1/pd-l1 EORTC-NCI-AACR Molecular Targets 2016 ESMO 2017 EORTC-NCI-AACR Molecular Targets 2017

29 XRT to reverse resistance to IO? use of radiation to enhance the diversity of the intratumoural repertoire of T-cell receptors Syn N, Lancet Oncol 2017 NCT ; NCT ; NCT ; NCT ; NCT ; NCT ; NCT

30 Immunotherapy and radiotherapy Strong preclincial background Several ongoing trials Safety an important issue Straightforward incremental versus novel type of radiotherapy? Many questions remain..

31