1. Immuno-checkpoints: pitfalls and promises
Perspectives in Lung Cancer: 16th European Congress
March 6-7, 2015 Turin - Italy
Immuno-checkpoints: pitfalls and promises
Michele Maio
Medical Oncology and Immunotherapy
University Hospital of Siena
Istituto Toscano Tumori
SIENA, ITALY 1

2. T-cell costimulatory receptors
D E C E M B E R | VO L | N AT U R E | 4 8 1

3. Melanoma as a tool for cancer research
Tissue samples readily accessible
Adaptable to tissue culture
Amenable to testing of novel therapies

5. Lawrence et al, Nature 2013

6. Chemotherapy/Targeted Agents and
Immuno-therapy Differ in Action and Outcome
Chemotherapy and
Targeted Therapies
IMMUNOTHERAPY
Response 6 12
Time (months)
Maio M. et al, unpublished 6

7. Anti-CTLA4 antibodies
Tremelimumab (CP675,206) IgG2 isotype antibody half-life time: 22 days
Ipilimumab (MDX-010) IgG1 isotype antibody half-life time: 12.5 days
T-cell
potentiation
T cell
CTLA-4
TCR
CTLA-4 mAb
MHC B7
APC

8. Kaplan-Meier Plot of Overall Survival CA184024
Maio M et al., J Clin Oncol, in press

9. Presented By Mario Sznol at 2014 ASCO Annual Meeting
Slide 13
Presented By Mario Sznol at 2014 ASCO Annual Meeting

10. Clin Cancer Res 2009

11. ir-PFS RESULTS Phased Schedule (NSCLC) Phased Schedule (SCLC) R
A Randomized, double-blind, parallel, three arm, phase II trial evaluating the efficacy and safety of Ipilimumab in combination with Taxol/Paraplatin compared to Taxol/Paraplatin alone, in previously untreated subjects with lung cancer (CA )
Stage IIIb/IV NSCL
Extended SCLC R
*CT + PBO
*CT + IPI concomitant
*CT + IPI phased
*CT= CBCDA/Taxol
ir-PFS RESULTS
Phased Schedule (NSCLC)
Phased Schedule (SCLC)
Study met primary end-point
Phased schedule significantly improved irPFS
No significant improvement for concurrent schedule
Lynch T, JCO 2012
Reck M, Ann Oncol 2013

12. CA : Phase III double blind study in Squamous Non Small Cell Lung Cancer Subjects Comparing Ipilimumab Plus Paclitaxel and Carboplatin Versus Placebo Plus Paclitaxel and Carboplatin
CA : Phase III double blind study in Extensive-Disease Small Cell Lung Cancer (ED-SCLC) Subjects Comparing Ipilimumab Plus Etoposide and Platinum Therapy to Etoposide and Platinum Therapy Alone

13. [TITLE]

14. PD1/PD-L1 Inhibitors in clinical developments
Target
Agent
Class
Phase
PD-1
Nivolumab (MDX 1106, BMS , BMS-ONO)
IgG4 3
Pembrolizumab (MK-3475, Merck&Co)
IgG4 engineered humanized
Pidilizumab (CureTech-Teva)
IgG1 humanized 2
AMP-514 (AstraZeneca/MedImmune)
IgG 1
AMP-224 (AstraZeneca/MedImmune)
PD-1/B7 Fc fusion protein
Novartis (Co-stim)
PD-L1
MPDL3280A (Bavituximab, Genetech/Roche)
IgG1; Fc engineered
MEDI4776 (AstraZeneca/MedImmune)
IgG1-k
1/2
BMS (MDX 1105, BMS-ONO)
MSB C (EMD Serono, Merck kgA)

15. Upcoming trials of anti-PD-1/PD-L1 therapy in advanced NSCLC
Population/setting
Treatment arms
Phase
Clinicaltrial.gov
Monotherapy
NSCLC PDL1+ 1st line
NSCLC 2nd/3rd line squamous
NSCLC 2nd/3rd line non squamous
NSCLC pretreated
NSCLC 2nd line
Nivolumab vs Chemotherapy (investigator choice)
Pembrolizumab in NSCLC versus CT (platinum-based)
Nivolumab vs Docetaxel (BMS017)
Nivolumab vs Docetaxel (BMS057)
Nivolumab (BMS153)
Pembrolizumab versus Docetaxel
III
II/III
NCT
NCT
NCT
NCT
NCT
NCT
Combination with CT
NSCLC multi-arm, 1st line
NSCLC first line
NSCLC+solid tumors
Nivolumab + Cisplatin/Gemcitabine or Cisplatin/Pemetrexed, or
Carboplatin/Paclitaxel, or Bevacizumab maintenance
Pembrolizumab with CT (platinum based)
MPDL3280A with Beva+/-CT I
I/II II
NCT
NCT
NCT
Combination with target therapy
NSCLC EGFR mut
NSCLC + solid tumors
Pembrolizumab with Gefitinib or Erlotinib
MEDI-4736+Gefinitib
MDPL3280A with erolotinib
MDPL3280A with cobimetinib (GDC-0973)
NCT
NCT
NCT
Combination with Immunotherapy
NSCLC
SCLC + solid tumors
All NSCLC 2nd/3rd line
Pembrolizumab with Ipilimumab
MEDI with Tremelimumab
MEDI-4736 with antiPD1 (AMP514)
Nivolumab +IL-21
Anti-LAG-3+/-Nivolumab
Nivolumab +anti-KIR
Nivolumab +/- Ipilimumab
Azacitidine oral or Azacitidine/Entinostat Nivolumab
NCT
NCT
NCT
NCT
NCT
NCT
NCT

16. CA209-003 OS by Dose in NSCLC OS (%) 2-year OS = 42% 3-year OS = 27%
Pts at Risk
Group
Died/Treated
Median OS, mo (95% CI)
1-year
2-year
3-year
9.2 (5.3, 11.1)
14.9 (7.3, 30.3)
9.2 (5.2, 12.4)
Months Since Initiation of Treatment
100 90 80 70 60 50 40 30 20 10 3 6 9 12 15 18 33 27 24 21 36 39 42 45 48 51 54 66 63 57
Censored
3-year OS = 27%
2-year OS = 42%
Nivolumab 1 mg/kg
Nivolumab 3 mg/kg
Nivolumab 10 mg/kg
OS (%)
33 (17, 49)
56 (38, 71)
38 (26, 50)
15 (5, 30)
42 (24, 58)
20 (11, 31)
27 (12, 43)
14 (7, 25)
26/33
23/37
50/59
1 mg/kg
3 mg/kg
10 mg/kg 37 59 26 34 35 16 29 17 22 7 14 13 4 11 1 5 2
OS rate, % (95% CI)

18. Phase 3 trials of nivolumab in NSCLC
Primary Objectives
• ORR and OS
Secondary Objectives
• PFS
• ORR and OS by PD-L1 status
• Duration of OR
• Time to OR
• Proportion of patients exhibiting
disease-related symptom progression (Lung Cancer Symptom Scale) CA
NCT
(Phase 3; N = 264)
Patients with stage
IIIb/IV squamous
cell NSCLC
Docetaxel
Nivolumab CA
NCT
(Phase 3; N = 574)
Patients
with stage IIIb/IV
non-squamous cell
NSCLC
Primary Objective
• OS
Secondary Objectives
• ORR
• PFS
• ORR and OS by PD-L1 status
• Duration of OR
• Time to OR
• Proportion of patients exhibiting disease-related symptom progression (Lung Cancer Symptom Scale)
Docetaxel
Nivolumab
PFS = progression-free survival

19. Sponsor

20. nivolumab

21. Keynote 001: Pembrolizumab in NSCLC (phase 1 dose ranging study)
Tot 21% ORR
-26% in CT naive pts
-20% in pre-treated pts

23. PREDICTIVE MARKERS OF RESPONSE TO PD1/PD-L1 BLOCKADE
PD-L1 tumor expression
Topalian S, et al., NEJM 2012

24. PD-L1 expression in NSCLC lung cancer: a key driver of response in monotherapy?
Agent
ORR PDL1+
ORR PDL1-
Source
Pembrolizumab*
25% (55/222)
13% (5/40)
2014 ESMO
Nivolumab*
15% (5/33)
14% (5/35)
2014 ASCO
MPDL3280A**
46% (6/13)
15% (6/40)
MEDI4736**
26% (12/47)
10% (7/74)
*DAKO test
**VENTANA test

25. PD-L1 expression : a key driver of response in combination regimen?
Agent
Tumor
ORR PDL1+
ORR PDL1-
Source
Nivo+Ipi
Melanoma*
57% (8/14)
40% (17/42)
2014 ASCO
Kidney
- 1%
- 5%
50% (8/16)
25% (1/4)
55% (11/20)
56% (18/32)
Lung
19%
14%
*Dako automated
5% cutoff tumor staining

26. PD-L1 negative tumours: Potentially better response with anti-PDL1 + tremelimumab combination
PD-L1 negative patients in NSCLC
70% (7/10) 1 2
42% (31/74)
30% (3/10)
10% (7/74)
1Mono: ORR 10% (7/74), 95%CI (3.9%, 18.5%) SD≥12weeks 32.4% (24/74), 95%CI (22.0%, 44.3%)
2Combination: ORR 30% (3/10), 95%CI (6.7%, 65.2%) SD≥12weeks 40% (4/10), 95%CI (12.2%, 73.8%)

27. Effect in the CNS?

28. 3-years survival update
NIBIT - M1
3-years survival update
Secondary Endpoints
Study population
(N=86)
Patients with MBM (N=20)
Median OS, months (95% CI)
12.9 ( )
12.7 ( )
3-year survival rate, % (95% CI)
28.5 ( )
27.8 ( )
Median ir-PFS, months (95% CI)
4.5 ( )
3.4 ( )
Di Giacomo AM et al., Annals Oncol 2015

29. Evolving Therapeutic Options for Cancer Treatment
Surgery
Chemotherapy
Radiotherapy

30. Evolving Therapeutic Options for Cancer Treatment
Surgery
Chemotherapy
Radiotherapy
Immunotherapy

31. Science “Areas to Watch” 2015: COMBINED IMMUNOTHERAPY

32. Medical Oncology and Immunotherapy, University Hospital of Siena