1. D. Cortinovis S.C. Oncologia Medica H S. Gerardo Monza L’immunoterapia per pochi selezionati pazienti Camogli, 29 apr 2016 Camogli, 29 apr 2016

2. AGENDA LOOKING FOR A BIOMARKER CLUES IN THE CLINICAL SETTING CLUES IN THE CLINICAL SETTING BEYOND THE CLINICAL PERSPECTIVE

3. AGENDA LOOKING FOR A BIOMARKER CLUES IN THE CLINICAL SETTING CLUES IN THE CLINICAL SETTING BEYOND THE CLINICAL PERSPECTIVE

4. VS Pennel vs Lisberg JAMA ONCOL 2016

5. SELECTION IS AN ATTITUDE

6. IS PDL1 A GOOD CANDIDATE? Garon NEJM 2015

7. PEMBROLIZUMAB: KEYNOTE 010 Herbst Lancet 2015

8. PDL1> 1%PDL1> 50% Herbst Lancet 2015 PEMBROLIZUMAB: PDL1>>EFFICACY

9. PDL1>> NO DISCORDANT mPFS PDL1> 50%PDL1> 1% Herbst Lancet 2015

10. PDL1>> ACTIVITY

11. PDL1 EXPRESSION AND ORR Garon NEJM 2015

12. ATEZOLIZUMAB: POPLAR Fehrenbacher LANCET 2016

13. EXHAUSTIVE SCORING SYSTEM: SAME RESULTS Fehrenbacher LANCET 2016

14. DURVALUMAB EARLY TRIALS Rizvi ASCO 2015

15. NIVOLUMAB + PDL1 STATUS: PREDICTIVE OR NOT… SCC NSQ Borghaei & Brahmer NEJM 2015

16. PDL1 < 1% mOS mPFS ORR Abdel –Rahman Crit rev Oncol Hematol 2016

17. PDL1 > 1% mOS mPFS ORR Abdel –Rahman Crit rev Oncol Hematol 2016

18. WEIGHT OF SELECTION

19. BEYOND PDL1 Fehrenbacher LANCET 2016

20. Inoue Oncotarget 2016 Topalian Nat Cancer Rev 2016 MULTIFACTORIAL BIOMARKER

21. AGENDA LOOKING FOR A BIOMARKER CLUES IN THE CLINICAL SETTING CLUES IN THE CLINICAL SETTING BEYOND THE CLINICAL PERSPECTIVE

22. In studies of nivolumab, a history of smoking in patients with NSCLC was associated with improved clinical response and PFS HR = hazard ratio; mPFS = median progression-free survival; ORR = objective response rate; PFS = progression-free survival. Hellmann MD, et al. Poster presented at ESMO 2014 (asbtr. 1229PD). Smoking status and response to immunotherapy in NSCLC Variable ORR, % (n/N) [95% CI] P-value Smoking exposure ≤5 pack-yrs 0 (0/14) [0, 23] 0.018 >5 pack-yrs 30 (20/66) [20, 43] 1431111 7528161271 ≤5 pack-yrs smokers >5 pack-yrs smokers 0 20 40 60 80 100 PFS (%) 0612182430 Months Since Treatment Initiation ≤5 pack-yrs smokers (mPFS 1.7 months) >5 pack-yrs smokers (mPFS 2.2 months) HR (95% CI) = 0.41 (0.22, 0.74), P = 0.003 PFS by smoking exposure

25. MPDL3280A Phase Ia: Response by Smoking and Mutational Status a ORR includes investigator-assessed u/c PR by RECIST 1.1. Patients first dosed at 1-20 mg/kg by Oct 1, 2012. Data cutoff: Apr 30, 2013. Former / Current Smokers Never Smokers Response by Smoking Status (ORR a )Smoking Status (NSCLC; n = 53) Pts With PR, % EGFR Mutant EGFR Status (NSCLC; n = 53) Unknown Response by EGFR Status (ORR a ) Pts With PR, % KRAS Status (NSCLC; n = 53) Response by KRAS Status (ORR a ) Pts With PR, % KRAS Mutant Unknown 11/43 1/10 9/40 1/6 8/27 1/10

26. Treatment Effect on OS in Predefined Subgroups

27. Herbst Lancet 2015 EGFR OVEREXPRESSION AND MHC I LOSS

28. Pembro: Immune-Related Events & Steroids Leighl N ORAL31.02 PFS and OS and Steroids Use to Manage Immune- Mediated AEs KEYNOTE-001, Data from 505 pts

29. 29 Steroid use and ipilimumab responses by mWHO criteria Baurain JF, J Clin Oncol 2012 Clinical Factors: IMMUNOTHERAPY-How to select patients Steroids ?

30. AGENDA LOOKING FOR A BIOMARKER CLUES IN THE CLINICAL SETTING CLUES IN THE CLINICAL SETTING BEYOND THE CLINICAL PERSPECTIVE

31. Clinically Meaningful Outcomes in Clinical Trials in Cancer: an ASCO Cancer Research Committee Initiative Ellis, et al., JCO 32:1277, 2014 Presented By Lowell Schnipper at 2015 ASCO Annual Meeting

32. Slide 20 Presented By Lowell Schnipper at 2015 ASCO Annual Meeting

33. Slide 10 Presented By Elisabeth De Vries at 2015 ASCO Annual Meeting

34. SUSTAINABILITY

35. UNSUSTAINABLE

36. Immune Checkpoint Therapy: What Is Next? Anti–PD-1/PD-L1 Your favorite treatment The future of cancer therapy

37. Sex ♀/♂ Age > 18 PDL1+ (strong) Smoker KRAS mut Steroid free Director (CEO) > 200000 €/y