The following slides are provided as presented by the author during the live educa7onal ac7vity and are intended for reference purposes only.

Transcription

1 The following slides are provided as presented by the author during the live educa7onal ac7vity and are intended for reference purposes only. If you have any ques7ons, please contact Imedex via at:

2 How can we evaluate best the activity of immune therapies in GI cancer? Beyond RECIST 1.1.: Role of immune-related response criteria (irrc), PET/CT and tumor biopsies to evaluate the activity of immune therapies in GI cancer. Guillem Argilés, MD Gastrointestinal Malignancies Program Early Drug Development Program Vall d'hebron Institute of Oncology (VHIO)

3 Disclosures None

4 Introduction to immune-therapeutics Immunotherapy is directed to the immune system, not to the tumor Tumor Progression Immune - therapies Adapted from Zitvogel et al. Nat Rev Immunol Oct;6(10):

5 Challenges to evaluate responses in immune-oncology The use of immune-therapies could lead to unconventional responses Biologic compartments implied in normal cancer therapeutics Biologic compartments implied in immune-therapeutics 1 compartment model 2 compartments model

6 Atypical immune responses with anti-ctl-4 agents O. Hamid, W. et al ASCO 2007

7 Defining the paradigm of immune anti-tumor activity In 2004 and 2005, near 200 experts discuss their experience with immunotherapeutic agents in cancer patients. Differential traits of immune-responses The appearance of measurable activity may take longer Responses to immune therapies may occur after conventional PD Need to confirm PD before discontinuation of therapy Durable SD may represent antitumor activity Hoos A, et al. J Immunother 2007;30: 1 15.

8 Radiological Immune-related response criteria (irrc) definition -Based on WHO criteria ( bi-dimensional measurements) -First evaluation at 12 weeks, -Progressions need to be confirmed by a re-assessing the patient in 4 weeks Wolchok J D et al. Clin Cancer Res 2009;15:

9 Practical example 64 year-old male with a metastatic colon cancer, with lung and liver mets and a non target lymph node, treated with ipilimumab.

10 Defining the paradigm of immune anti-tumor activity In 2004 and 2005, near 200 experts discuss their experience with immunotherapeutic agents in cancer patients. Differential traits of immune-responses The appearance of measurable activity may take longer Responses to immune therapies may occur after conventional PD Need to confirm PD before discontinuation of therapy Durable SD may represent antitumor activity irrc Depend on trial endpoint Hoos A, et al. J Immunother 2007;30: 1 15.

11 Different patterns of immune-responses to anti-ctl-4 agents They prospectively analyzed 487 melanoma pts. Included in 3 phase II trials exploring ipilimumab: CA CA CA For patterns of immuneresponses & for applicability of irrc criteria. Wolchok J D et al. Clin Cancer Res 2009;15:

12 Ipilimumab: Association of OS with Response irpr/irsd Association of OS with response using WHO criteria or irrc. Wolchok J D et al. Clin Cancer Res 2009;15:

13 HOWEVER irrc are complex 64 year-old male with a metastatic colon cancer, with lung and liver mets and a non target lymph node, treated with ipilimumab.

14 Optimizing irrc IrRC (WHO criteria) 2 diameters Vs. irrc (RECSIT 1.0): longest diameter) irrc (RECIST 1.0): 5 lesions/organ- 10 lesions in total Vs. IrRC (RECIST 1.1): 2 lesions per organ- 5 in total Nishino et al. Clin Cancer Res 2013, 19(14): Nishino et al. Journal for Immune-Therapy of Cancer 2014

15 Expanding irrc to anti-pd1 axis agents F. Hodi et al JCO March 7, 2016

16 Expanding irrc to anti-pd1 axis agents 15% of patients rescued from PD with irrc F. Hodi et al JCO March 7, 2016

17 Atezolizumab monotherapy: RCC RECIST: PD irrc: PD So even in the case of confirmed irrc PD continuing beyond progression still has to be considered. Weinstock C, ASCO 2016

18 Role of PET/CT scan in assessing immune-responses 18 FDG PET and PET/CT could capture immune-related responses Immune activation phenomena in secondary lymphoid organs Wilgehhof S, et al. Cancer Investigation 2012

19 Role of immune-related phenomena in PET/CT and outcome with anti-ctla 4 SUV max SUV mean Analysis of FLT, intake in spleen Ribas A, et al. JNM, March 2013

20 Role of 18 FDG-PET a predictive marker of response to ipilimumab C1 C2 C3 C4 Follow up -22 pts with unrespectable melanoma -3mg/kg of ipilimumab x 4 cycles -Underwent 18 FDG PET/CT: baseline, C3D1 and after 4 cycles log-rank p < FDG PET/CT after 2 cycles and after 4 log-rank p < could be used as a surrogate marker of benefit to ipilimumab. Sachpekidis C, et al. Eur, J Nucl Med Mol Imaging 2015

21 Role of 18 FDG-PET a predictive marker of response to anti-pd1 axis agents 103 NSCLC pts with PD-L1 positive expression. Underwent 18 FDG-PET/CT scans: -Base-line -Week 6 -At PD Patients with metabolic response had higher RR than pts with no metabolic response. However only 2 pts had radiological pseudo-progression so the utility of 18 FDG- PET/CT scan to distinguish pseudo-progression could not be determined. Fredrikson J, et al. J Nucl Med, May 2016

22 Future directions of PET/CT in immune-therapeutics Wait for results of other trials exploring the role of 18 FDG-PET/CT in assessing immune responses. -NCT NCT Juergens et al.. Biomarkers in Cancer 2016:8(S2) Travaré R, et al. Can. Res. March 2015

23 Role of biopsies in assessing immuneresponses Biopsies can discriminate immune responses in pts. with unclear clinic and radiologic evol. Adapted from Karanikas V, with permision

24 Role of paired-biopsies to molecularly determine immune-responses Lymphocytes activation status markers could be determined in tumor paired-biopsies to adapt therapy combinations Adapted from Karanikas V - Adapted from Callahan MK et al. ASCO Meet Abstr. 2013

25 NEXT STEPS in molecular follow up of tumors Callahan MK et al. ASCO Meet Abstr Lipson E, Journal for ImmunoTherapy of Cancer2014

26 Conclusions irrc characterize better the immune responses than classical WHO or RECIST criteria. However this could be still difficult in some patients The role of PET/CT scan as a tool for follow up patients still needs to be clarified. Maybe new tracers need to be explored In case of doubt tumor biopsies, if feasible, may help to characterize the response-status of the most difficult patients. Liquid biopsies will make us easier in a near future taking therapeutic decisions in this patients.