1. Immunoterapia
Silvia Novello

2. Lung Vaccination in Lung Cancer: ph III trials

3. Giaccone G et al, ESMO 2013
MAGRIT ha screenato più di pazienti

4. Rationale for immunotherapy in nsclc
“…we show that in NSCLCs treated with pembrolizumab, elevated nonsynonymous
mutation burden strongly associates with clinical efficacy. …clinical efficacy correlates
with a molecular signature characteristic
of tobacco carcinogen–related mutagenesis, certain
DNA repair mutations, and the burden of
neoantigens.”
In the current study, we show that in NSCLCs
treated with pembrolizumab, elevated nonsynonymous
mutation burden strongly associates with
clinical efficacy.
Rizvi NA et al, Science April 2015

5. Clinical development of pd-1 and pd-l1 inhibitors
Nivolumab
Fully human IgG4 mAb
BMS
ph III
Pidilizumab
Humanized IgG1 mAb
Cure Tech
ph II
Pembrolizumab
Humanized IgG4 mAb
Merck
AMP-224
Recombinant PD-L2 Fc fusion protein
GSK
ph I
PD-L1
BMS
MEDI4736
Engineered human IgG1 mAb
MedImmune
MPDL3280A
(Atezolizumab)
Genentech
MSB C
EMD Serono

6. The efficacy
Finally something in Squamous and in Smokers
Time to response & the duration of response
Which criteria to assess the response
Which Biomarkers
Think about “combo” or forget “combo” (?)
The toxicity profile
How to inform the patient
Approval issues

7. The efficacy
Finally something in Squamous and in Smokers
Time to response & the duration of response
Which criteria to assess the response
Which Biomarkers
Think about “combo”
The toxicity profile
How to inform the patient
Approval issues

8. CheckMate 057 (NCT01673867) Study Design
Randomize 1:1
Stage IIIB/IV non-SQ NSCLC
1 prior PT-DC
Prior maintenance therapy with pemetrexed, bevacizumab, or erlotinib alloweda
Prior TKI therapy allowed for known ALK translocation or EGFR TKI for known EGFR mutation
ECOG PS 0–1
N = 582
NIVO 3 mg/kg IV Q2W until PD or unacceptable toxicity
n = 292
DOC
75 mg/m2 IV Q3W until PD or unacceptable toxicity
n = 290
Endpoints
Primary OS
Secondary
Investigator-assessed ORR and PFS
Efficacy by tumor PD-L1 expression level
Quality of life (LCSS)
Pts stratified by prior maintenance therapy and line of therapy (second- vs third-line)
a Not considered a separate line of therapy. ALK = anaplastic lymphoma kinase; DBL = database lock; ECOG PS = Eastern Cooperative Oncology Group performance status; EGFR = epidermal growth factor receptor; IV = intravenous; LCSS = Lung Cancer Symptom Scale; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PD = progressive disease; TKI = tyrosine kinase inhibitor

9. Minimum follow-up for OS was approximately 13.2 mo
Overall Survival
NIVO
DOC
Number of pts at risk
292
232
194
169
146
123 62 32 9
290
244
150
111 88 34 10 5 50 80
Time (months)
OS (%)
100 90 70 60 40 30 20 27 21 18 15 12 6 3 24
1-yr OS rate = 51%
1-yr OS rate = 39%
NIVO
N = 292
DOC
N = 290
mOS, mo
12.2
9.4
HR = 0.73 (96% CI: 0.59, 0.89); P =
Minimum follow-up for OS was approximately 13.2 mo
Symbols represent censored observations. CI = confidence interval; HR = hazard ratio.
Paz Ares L et al, ASCO 2015

10. Treatment Effect on OS in Predefined Subgroups
Unstratified HR (95% CI)
Overall
582
0.75 (0.62, 0.91)
Age Categorization (years)
<65
339
0.81 (0.62, 1.04)
≥65 and <75
200
0.63 (0.45, 0.89)
≥75 43
0.90 (0.43, 1.87)
Gender
Male
319
0.73 (0.56, 0.96)
Female
263
0.78 (0.58, 1.04)
Baseline ECOG PS
179
0.64 (0.44, 0.93) ≥1
402
0.80 (0.63, 1.00)
Smoking Status
Current/Former Smoker
458
0.70 (0.56, 0.86)
Never Smoked
118
1.02 (0.64, 1.61)
EGFR Mutation Status
Positive 82
1.18 (0.69, 2.00)
Not Detected
340
0.66 (0.51, 0.86)
Not Reported
160
0.74 (0.51, 1.06)
NIVO
DOC 1 2
All randomized pts (NIVO, n = 292; DOC, n = 290). HR was not computed for other subsets with less than 10 pts per treatment group.

11. Baseline Tumor PD-L1 Expression
PD-L1 expression level
1%a
5%a
10%a
Not quantifiableb
Positive (≥1%)
Negative (<1%)
Positive (≥5%)
Negativ e (<5%)
Positive (≥10%)
Negative (<10%)
NIVO
n (%)
123 (53)
108 (47)
95 (41)
136 (59)
86 (37)
145 (63)
61 (21)
DOC
123 (55)
101 (45)
86 (38)
138 (62)
79 (35)
145 (65)
66 (23)
78% (455/582) of randomized pts had quantifiable PD-L1 expression
a Number and percent of evaluable pts with membranous staining at the respective expression level in ≥100 tumor cells; b Number and percent of randomized pts with PD-L1 expression not quantifiable.
Paz Ares L et al, ASCO 2015

12. Garon EB, ESMO 2014
Garon EB et al , NEJM Apr

13. Keynote001: outcomes on the basis of PD-L1 staining
PFS OS
proportion score of at least 50% was associated
with a higher response rate and longer progression-
free and overall survival than was a proportion
score of less than 50% in both previously
untreated patients and previously treated patients,
which indicates that this is a subgroup of patients
in whom the PD-L1 pathway can be successfully
targeted.
Garon EB et al , NEJM Apr

14. Phase II Trial of Pembrolizumab for Untreated Brain Metastases
Consider radiation or surgery to progressing lesions
Key Eligibility:
Advanced NSCLC or melanoma
At least 1 untreated or progressive brain metastasis 5-20mm
No neurologic symptoms or steroid requirement
PS 0-1
PD-L1 expression after the most recent systemic therapy
Brain metastasis PD
Pembrolizumab 10mg/kg
q2 weeks
Continue pembrolizumab
if systemic control achieved
Brain metastasis CR, PR, or SD
Safety evaluation at 4 weeks:
Brain MRI
Response evaluation every 8 weeks:
CT chest/abdomen/pelvis
Primary Endpoint:
Brain Metastasis Response Rate
Secondary Endpoints:
Overall response rate, safety, PFS, OS
Brain metastasis response by modified RECIST allows up to 5 target lesions with diameter >5mm
Data presented from an interim analysis with cut-off date June 30, 2015
Sarah B. Goldberg, et al; WCLC 2015, ORAL 31

15. Phase II Trial of Pembrolizumab for Untreated Brain Metastases
Total evaluable patients
Brain Metastasis Responses
(CR + PR)
Duration of BrM Response
Systemic Responses N
No. of patients %
95% CI
Individual duration (months) 18 6* 33
3.2+, 6.0+, 6.1+, 6.6, 7.0+ 6
Median Survival 7.7 months (95% CI 3.5-NR)
Sicuramente piccoli N ma c’è una certa attività e in 4 casi su 18 una RCompleta
Sarah B. Goldberg, et al; WCLC 2015, ORAL 31

16. The efficacy
Finally something in Squamous and in Smokers
Time to response & the duration of response
Which criteria to assess the response
Which Biomarkers
Think about “combo” or forget “combo” (?)
The toxicity profile
How to inform the patient
Approval issues

17. CheckMate 017 (NCT01642004) - Study Design
Endpoints
Primary: OS
Secondary:
Investigator-assessed ORR
Investigator-assessed PFS
Correlation between PD-L1 expression and efficacy (ORR, OS, PFS),
Quality of life (LCSS)
NIVO 3 mg/kg IV Q2W, until PD or unacceptable toxicity
n = 135
Stage IIIb/IV SQ NSCLC
1 prior platinum doublet-based chemotherapy
ECOG PS 0–1
N = 272
Randomize 1:1
DOC
75 mg/m2 IV Q3W, until PD or unacceptable toxicity
n = 137
DBL: December 15, 2014
At time of DBL, 199 deaths (of 272 randomized pts) were reported (86% of 231 deaths required for final analysis)
The boundary for declaring superiority for OS at the pre-planned interim analysis was P <0.03
DBL, data base lock; ECOG PS = Eastern Cooperative Oncology Group performance status; IV = intravenous; LCSS = lung cancer symptom scale; PD = progressive disease; PD-L1 = programmed cell death ligand 1; SQ = squamous; Q2W = every 2 weeks; Q3W = every 3 weeks
Brahamer J et al, NEJM 2015

18. Checkmate 017: Updated follow-up
Reckamp K et al. , WCLC 2015 ORAL 02.01

19. Checkmate 017: Updated follow-up
Reckamp K et al. , WCLC 2015 ORAL 02.01

20. Smoking status and response to immunotherapy in NSCLC
In studies of nivolumab, a history of smoking in patients with NSCLC was associated with improved clinical response and PFS
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] 14 3 1 75 28 16 12 7
≤5 pack-yrs
smokers
>5 pack-yrs 20 40 60 80
100
PFS (%) 6 18 24 30
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
HR = hazard ratio; mPFS = median progression-free survival; ORR = objective response rate; PFS = progression-free survival.
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).

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

22. Topalian S, ASCO 2015

23. PDL-1 expression, T cell infiltrate, smoking status and Pembrolizumab
Studi di associazione (non correlazione) fra infiltrato linfocitario T e l’effetto e anche in correlaz con status tabagico
Anche correlato con infiltrato B (anche su malattia resecata)
Siwen Hu-Lieskovan, et al; WCLC 2015, ORAL 31.05

24. The efficacy
Finally something in Squamous and in Smokers
Time to response & the duration of response
Which criteria to assess the response
Which Biomarkers
Think about “combo” or forget “combo” (?)
The toxicity profile
How to inform the patient
Approval issues

25. Time and Durability of response with
pembrolizumab in NSCLC (keynote 001)
RECIST v1.1 Central Review 10 20 30 40 50
Time, weeks
Individual Patients Treated With Pembro
irRC Investigator Review 10 20 30 40 50 60
Time, weeks
Individual Patients Treated With Pembro
Partial Response
Progression
On Treatment
Pembro 2 mg/kg Q3W
Pembro 10 mg/kg Q3W
Pembro 10 mg/kg Q2W
11 of 11 (100%) responses are ongoing
Median duration of response not reached (median follow-up, 36 weeks)
7 of 11 (64%) responders remain on treatment
Median duration of treatment: 27.1 weeks (range, – 48.3+)
19 of 21 (90%) responses are ongoing
Median duration of response not reached (median follow-up, 36 weeks)
18 of 21 (86%) responders remain on treatmentb
Median duration of treatment: 27.1 weeks (range, 6.1 – 57.1+)
Garon EB et al, ESMO 2014

26. Time and Durability of response with
NIVOLumab in NSCLC (checkmate 063)
Rizvi NA et al, Lancet Oncol 2015

27. The efficacy
Finally something in Squamous and in Smokers
Time to response & the duration of response
Which criteria to assess the response
Which Biomarkers
Think about “combo” or forget “combo” (?)
The toxicity profile
How to inform the patient
Approval issues

28. Comparison: RECIST-irRC criteria

29. Unidimensional evaluation (RECIST)
Immuno-response (irRC)

30. Results: Landmark Analysis Sensitivity Analysis
Response at Month-3.5
# of pts
# of deaths
Median months from month 3.5 (95% CI)
Responder 10 NR
Non-responder 73 42
7.4 (4.5, 10.1)
83 of the 98 patients were alive at 3.5 months since treatment start
This analysis suggested that responders had longer survival than non-responders
Retrospective analysis Checkmate 063: Patients were grouped in RECIST responder and non-responder categories

31. FDG-PET: EORTC criteria
FDG-PET as a predictive biomarker in Ph2 study (FIR) of atezolizumab. Week 6 FDG-PET: relation to response and OS (n=88)
FDG-PET: EORTC criteria
Whole body
%ID
CT target lesions
1.0
1.0
1.0
0.8
0.8
0.8
0.6
0.6
0.6
OS probability
OS probability
0.4
0.4
OS probability
0.4
CMR (n=2)
0.2
PMR (n=19)
0.2
0.2
PR (n=12)
SMD (n=27)
Δ %ID < 0 (n=36)
SD (n=46)
PMD (n=40)
0.0
Δ %ID ≥ 0 (n=52)
0.0
PD (n=28)
0.0 20 40 60 80
100
300
500 20 40 60 60
Study week
Study week
Study week
FDG-PET CT
1.0
Base SLD < median, Chg < median
Base SLD < median, Chg ≥median
Base SLD ≥ median, Chg < median
Base SLD ≥ median, Chg ≥ median
1.0
Dati con atezolizumab in cui la risposta correla con l’attività metabolica e l’attività metabolica (anche basale) correla con la prognosi
The main point to communicate for top 3 is that changes in FDG-PET at week 6, either by EORTC criteria or whole body tumor burden (%ID), are significant predictors of OS.  However, results are pretty similar when compared to CT at week 6 (right top). From bottom plots: while both baseline and week 6 changes are significant, baseline effect is stronger, both for CT and PET.
0.8
0.8
Both baseline and week 6 changes in whole body metabolic tumor burden are significant predictors of OS based on multivariate analysis
0.6
0.6
OS probability
OS probability
0.4
Base %ID < median, Δ %ID < 0
Base %ID < median, Δ %ID ≥ 0
0.4
Base %ID ≥ median, Δ %ID < 0
0.2
Base %ID ≥ median, Δ %ID ≥ 0
0.2
0.0
0.0 20 40 60 80 20 40 60 80
Study week
Study week
Δ = change from baseline; base = baseline; CMR = complete metabolic response; PMR = partial metabolic response
SMD = stable metabolic disease; PMD = progressive metabolic disease; PR = partial response; SD = stable disease
Jamie Chaft et al, WCLC 2015

32. The efficacy
Finally something in Squamous and in Smokers
Time to response & the duration of response
Which criteria to assess the response
Which Biomarkers
Think about “combo” or forget “combo” (?)
The toxicity profile
How to inform the patient
Approval issues

33. ……do we really have THE biomarker??

34. Change in baseline target lesions (%)
Nivolumab activity was observed in patients with PD-L1+ tumors and also in some patients with PD-L1 tumors
PD-L1 cut-off
PD-L1 status
Evaluable biopsies, %
(n/N)
ORR,a % 1%
Positive
56 (38/68)
13 (5/38)
Negative
44 (30/68)
17 (5/30) 5%
49 (33/68)
15 (5/33)
51 (35/68)
14 (5/35)
More patients with PD-L1+ than PD-L1 tumors had a decrease in tumor burden
150
100 50
-50
-100
Positive
Negative
PD-L1 status (5% cut-off)
Change in baseline target lesions (%)
aORR of patients evaluable for PD-L1; ORR includes complete or partial responders determined by RECIST Six patients with unconventional ‘immune-related’ responses were not included as responders.
ORR = objective response rate; PD-L1 = programmed cell death-ligand 1; RECIST = Response Evaluation Criteria for Solid Tumors.
Patients
Brahmer JR, et al. ASCO 2014 (abstr. 8112).

35. Pembrolizumab activity was observed in patients with PD-L1+ tumors and also in some patients with PD-L1 tumors
9.1% pem
8.8% txt [Hanna N, JCO 2004]
7.1% txt [Shepherd FA, JCO 2000]
8.9% erlo[Shepherd FA, JCO 2005]
Garon EB, ESMO 2014

36. The Biomarker Issue: PD-L1 & Histology
CheckMate 017
[Squamous]
CheckMate 057
[non-Squamous]
Mettendo insieme i due studi ho un effetto differente
NO effetto nello squamoso a prescindere dal cutoff utilizzato
SI effetto nel non squamoso a prescindere dal cutoff utilizzato
Modified – Spigel ASCO 2015; Paz-Ares ASCO 2015

37. Sample Source and Collection Definition of Positivity†
PD-L1 as a predictive immune biomarker: assays, sample collection and analysis in NSCLC studies
Pembrolizumab
Merck
Prototype or clinical trial IHC assay (22C3 Ab)1
Surface expression of PD-L1 on tumor specimen*
Ph I: Fresh tissue
Ph II/III: Archival or fresh tissue2
IHC Staining:
Strong vs weak expression2
PD-L1 expression required for NSCLC for enrollment2
Note that one arm of KEYNOTE 001 trial requires PD-L1- tumors1
Tumor PD-L1 expression:1
≥50% PD-L1+ cut-off: 32% (41/129)
1-49% PD-L1+ cut-off: 36% (46/129)
Nivolumab
Bristol-Myers Squibb
Dako automated IHC assay (28-8 Ab)3,4
Surface expression of PD-L1 on tumor cells*
Archival4 or fresh tissue
IHC Staining:
Strong vs weak expression3,4
Patients not restricted in PD-L1 status in 2nd- & 3rd-line4
Ph III 1st-line trial in PD-L1+3
Tumor PD-L1 expression:4
5% PD-L1+ cut-off: 49% (33/68)4
MPDL3280A
Roche/Genentech
Ventana automated IHC assay
Surface expression of PD-L1 on TILs5
Archival or fresh tissue
IHC Staining intensity
(0, 1, 2, 3):
IHC 3 (≥10% PD-L1+): Ph III trial5
IHC 2,3 (≥5% PD-L1+)5
IHC 1,2,3 (≥1% PD-L1+)5
IHC 1, 0, or unknown
PD-L1 expression required for NSCLC for enrollment x
TIL PD-L1 expression:5,6
IHC 3 (≥10% PD-L1+): 11% (6/53)
PD-L1 low (IHC 1, 0): 75% (40/53)
MEDI4736
AstraZeneca
1st generation or Ventana automated IHC (BenchMark ULTRA) assay (Ventana PD-L1 (SP263) clone)7,8
Surface expression of PD-L1 on TILs
PhI: Fresh tissue
IHC Staining intensity:
Not presented to date7,8,9
TIL PD-L1 expression:
PD-L1 Assay
Sample Source and Collection
Definition of Positivity†
*Tumor cells are stained, but not TILs and other tissue areas.
†Definition of PD-L1 positivity differs between assay methodologies.
IHC = immunohistochemistry; NSCLC = non-small cell lung cancer; PD-L1 = programmed cell death-ligand 1; TILs = tumor-infiltrating lymphocytes.
References
1. Garon EB, et al. Presented at ESMO 2014 (abstr. LBA43); 2. Rizvi NA, et al. Presented at ASCO 2014 (abstr. 8007); 3. Gettinger S et al. Poster p38 presented at ASCO 2014 (abstr. 8024); 4. Brahmer JR et al. Poster 293 presented at ASCO 2014 (abstr. 8112); 5. Rizvi NA et al. Poster presented at ASCO 2014 (abstr. TPS 8123); 6. Soria J-C, et al. ESMO 2014 (abstr. 1322P); 7. Brahmer JR, et al. Poster presented at ASCO 2014 (abstr. 8021); 8. Segal NH, et al. Presented at ASCO 2014 (abstr. 3002); 9. Segal NH, et al. ESMO 2014 (abstr. 1058PD).

38. IASLC:PDL-1 PROJECT Comparison of different antibodies
Application to different staining platforms
Intra- and inter-observer reproducibility(inter-laboratory reproducibility)
Large specimens vs small specimens vs cytology from same tumors
Prognostic association based on a well defined cohort
Predictive association : PD1/PDL1 treated pts
ATLAS

40. NM Hahn et al, ASCO 2015

41. The efficacy
Finally something in Squamous and in Smokers
Time to response & the duration of response
Which criteria to assess the response
Which Biomarkers
Think about “combo” or forget “combo” (?)
The toxicity profile
How to inform the patient
Approval issues

42. CheckMate 012: Nivo + Ipi [1st line] Percentage Change from Baseline
Best Percentage Change in Target Lesion Tumor Burden by PD-L1
220
200
180
160
140
120
100 80 60 40 20
–20
–40
–60
–80
–100 *
PD-L1 expression
n (%)
≥1% PD-L1a
77 (68)
<1% PD-L1a
36 (32)
Unknownb
35 (24)
Percentage Change from Baseline
* Confirmed ongoing responses
Effetto del marcatore (a differenza di quanto descritto nel melanoma)
Low frequency of treatment-related grade 3–4 AEs leading to discontinuation: 3–10%
(No treatment-related deaths)
Rizvi N ORAL02.05

43. Phase Ib GP28328: ATEZO + Chemo [1st line]
ATEZO no unexpected toxicities
No pneumonitis or other respiratory AEs of concern
ORR 50%
ORR 76.5%
ORR 56.3%
Rizvi N ORAL02.05

44. E se in I linea ci dimenticassimo della combinazione?
Besse B et al, ECCO 2015

45. The efficacy
Finally something in Squamous and in Smokers
Time to response & the duration of response
Which criteria to assess the response
Which Biomarkers
Think about “combo” or forget “combo” (?)
The toxicity profile
How to inform the patient
Approval issues

46. Immune Related Adverse Events (IRAEs)
System
Adverse Events
Gastrointestinal
Colitis (Diarrhea, perforation)
Renal
Acute Interstitial Nephritis (Increased serum Creatinine)
Pulmonary
Pneumonitis (dyspnea, cough)
Dermatologic
Dermatitis (Lichenoid/ spongiotic dermatitis, rash), Vitaligo
Hepatic
Hepatitis (elevated LFTs)
Neurologic
Central and Peripheral (Aseptic Meningitis, Guillan-Barre Syndrome, Myasthenia Gravis
Endocrine
Hypophysitis, thyroiditis, adrenal insufficiency
Ocular
Uveitis, Iritis
IrAEs can manifest in nearly any organ or organ system in the body, some of which are shown here.

47. Immune Related Adverse Events (IRAEs)
Average time to onset of irAEs is 6-12 weeks after initiation of therapy
Within days of the first dose
After several months of treatment
After discontinuation of therapy
Severity: Can be mild and asymptomatic to severe and life threatening
The average time to onset of these events is 6-12 weeks, but can occur at any time, from within days of the patient receiving their first dose, until after treatment is discontinued. The majority of irAEs are quite mild, and often are asymptomatic, but they have the potential to be severe and life threatening.

48. Checkmate 017: safety
Brahmer J et al, NEJM 2015

49. CheckMate 017: Updated Safety
Time to Onset of First Treatment-related Select AE With Nivolumab by Category (Any Grade)
Eventi maggiori concentrati nei primi 3 mesi di trattamento
Pooled analyses of safety of nivolumab in metastatic SQ NSCLC is being presented at ECC (ESMO) as a poster on Sept 27, Gettinger et al., P346
Most common treatment-related select AEs were skin (9%) and GI (8%)
Median time to onset of these AEs were:
hypersensitivity wks (range 0.3 – 0.3)
GI – 3.0 wks (range 0.1 – 91.0)
Renal 10.5 wks (range 3.9 – 16.6)
Skin 7.3 wks (range 0.3 – 51.9)
endocrine wks (range 6.3 – 18.1)
Pulmonary 15.1 wks (range 2.6 – 85.1) Hepatic 17.6 wks (range 4.1 – 31.1)
Median time to resolution of treatment-related select AEs were
GI 1.7 wks (range 0.1 – 31.0); 9/11 patients resolved
Endocrine NA (range 6.3 – 18.1) 2/5 patients resolved
Hepatic NA (range 2.9 – 22.3+) 1/2 patients resolved
Pulmonary 5.0 wks (range 0.6 – 12.1) 6/6 patients resolved
Skin 2.5 wks (range 0.1 – 46.9+) 11/12 patients resolved
Hypersensitivity/infusion reaction 0.3 wks (range 0.3 – 0.3) 1/1 patient resolved
Renal NA (range 0.7 – 37.6) 2/4 patients resolved
Pts still on study, n
Pts still on treatment, n
Total pts with first event,a n
The majority of patients who experienced treatment-related select AEs with nivolumab experienced their first event within the first 3 months of treatment
Select AEs: AEs with potential immunologic etiology that require frequent monitoring/intervention. Based on December 2014 DBL. Includes events reported between first dose and 30 days after last dose of study therapy.
Within each time interval, patients with ≥1 event were counted only once in each category but could be classified into more than one category
Reckamp K ORAL02.01

50. CheckMate 017: Patient Reported Outcomes (PROs)
LCSS Average Symptom Burden Index (on-treatment)
LCSS-3 Item Index (on treatment)
QoL misurata con LCSS a 3 o 6 items a vantaggio di nivo, anche mantenuto nel tempo
Gralla R et al, WCLC 2015 ORAL31.03

51. CheckMate 017: Patient Reported Outcomes (PROs)
Tempo alla comparsa di sintomi specifici dinuovo a vantaggio di nivo
Gralla R et al, WCLC 2015 ORAL31.03

52. SCREENING STUDY POPULATION Treatment until progression or for 1 yr
CA Study Design (N=824)
SCREENING STUDY POPULATION
Advanced / metastatic (stage IIIb / IV) NSCLC (NSQ and SQ) at least 1 prior systemic therapya
COHORT B
Discontinue treatment, and if progression occurs re-treatment allowed
Enrollment period aConventional systemic therapies, excluding IO therapies
Treatment until progression or for 1 yr
Follow up for 5 yrs to collect survival information
bPatients with CR, PR, or SD
COHORT A
Continue to treat to progression, unacceptable toxicity, or withdrawal of informed consent
INTERVENTION Nivolumab 3 mg/kg IV q 2 weeks
PATIENT SUBGROUPS
SQ, PS 0-1, ≥2 prior therapies, +/- treated CNS mets
SQ, PS 0-1, 1 prior therapy, +/- treated CNS mets
NSQ, PS 0-1, ≥1 prior therapy, +/- treated CNS mets
SQ or NSQ, PS 2, ≥1 prior therapy
ENDPOINTS
Safety
ORR
PFS
DOR OS
PRO PK
Biomarkers
RANDOMIZATION at 1 yrb
Patients receive nivolumab 3 mg/kg IV (60 min) every 2 weeks until either progressive disease or unacceptable toxicity (Cohort A) or for 1 yr with the possibility of re-treatment upon disease progression (Cohort B).
The primary study objective is assessment of the incidence for high grade (grade 3-4 and grade 5) treatment-related select adverse events, defined as pneumonitis, interstitial nephritis, diarrhea/colitis, hepatitis, rash, endocrinopathies, and hypersensitivity/ infusion reaction events.
Study endpoints include safety and efficacy endpoints and PROs.
Maen Hussein et al, WCLC 2015; ORAL 02

53. Summary of Adverse Events
Nivolumab 3 mg/kg N = 824
Nivolumab 3 mg/kg ECOG PS 0–1 (n = 742)
Nivolumab 3 mg/kg ECOG PS 2 (n = 65)
Any Grade n (%)
Grade 3–4 n (%)
Grade 5 n (%)
Grade 3–4 n (%)
All adverse events
762 (93)
311 (38)
158 (19)
683 (92)
268 (36)
131 (17)
62 (95)
33 (51)
24 (37)
All serious adverse events (SAEs)
309 (38)
223 (27)
257 (35)
185 (25)
42 (65)
29 (45)
All select adverse events
282 (34)
37 (5)
5 (1)
253 (34)
32 (4)
3 (<1)
22 (34)
3 (5)
2 (3)
All treatment-related adverse events
439 (53)
59 (7)
1 (<1)
403 (54)
52 (7)
27 (42)
4 (6)
All treatment-related SAEs
23 (3)
19 (2)
1 (<1)*
18 (2)
14 (2)
All treatment-related select AEs
199 (24)
20 (2)
181 (24)
16 (2)
14 (22)
All AEs leading to discontinuation
87 (11)
53 (6)
34 (4)
69 (9)
42 (6)
27 (4)
16 (25)
9 (14)
7 (11)
All treatment-related SAEs leading to discontinuation
12 (2)
11 (2)
9 (1)
All treatment-related select AEs leading to discontinuation
11 (1)
8 (1)
Su circa 800 paz “real life” PS 0-2 non sembra che la tossicità sia troppo condizionata da PS, anche se in realtà I PS 2 qui erano solo l’8%
Across all patients, 93% experienced an adverse event; 38% had grade 3 or 4 events.
Maen Hussein et al, WCLC 2015; ORAL 02
*One fatal event was reported as drug-related respiratory failure, with known comorbidities of lymphangitic spread of tumor, recurrent pulmonary embolism, G-bacteremia, pleural effusion, pneumothorax, or tumor progression. This patient’s death was classified as ‘Other-Multifactorial’ by the investigator.

54. Pembro: Immune-Related Events & Steroids
KEYNOTE-001, Data from 505 pts
Problematica dello steroide a prescindere
NON sembra impattare su efficacia del farmaco (è RETROSPETTIVO su circa 500 casi del Keynote 001)
In questo caso (per un farmaco che noi accomuniamo a nivo) la tox è sopratt tiroidea (ipo) e compare entro i primi due mesi
PFS and OS and Steroids Use to Manage Immune- Mediated AEs
Leighl N ORAL31.02

55. The efficacy
Finally something in Squamous and in Smokers
Time to response & the duration of response
Which criteria to assess the response
Which Biomarkers
Think about “combo” or forget “combo” (?)
The toxicity profile
How to inform the patient
Approval issues

57. The efficacy
Finally something in Squamous and in Smokers
Time to response & the duration of response
Which criteria to assess the response
Which Biomarkers
Think about “combo” or forget “combo” (?)
The toxicity profile
How to inform the patient
Approval issues

58. Impact of time to drug approval on potential years of life lost: the compelling need for improved trial and regulatory efficiency
- Used phase III trials in incurable cancers published :
With statistically significant increase in survival
Drug approved by the FDA in that malignancy
21 drugs in 11 malignancies as illustrative examples
Calculated:
Life-years lost per year of approval delay:
Multiplied no. deaths per year (for specific subgroups included in phase III trial) x median survival gain (yrs):
- Life-years lost between drug discovery and approval:
Used US dates as surrogate for worldwide
- Life-years that would have been saved if time from discovery to approval reduced to < 5 years
- Life-years saved by improved trial safety
DJ Stewart et al, WCLC 2015

59. Life-years lost worldwide per year delay in drug approval
Total combined life-years lost / year:
Worldwide: ,541,274
1 for every 12 seconds delay
North America: 240,085
Life-years lost worldwide per year

60. Life-years lost worldwide from patent application to approval
Total combined life-years lost:
Worldwide: ,537,958
North America: 2,956,667
Life-years lost worldwide

62. CheckMate 012: Nivo + Ipi [1st line] Percentage Change from Baseline
Best Percentage Change in Target Lesion Tumor Burden by PD-L1
220
200
180
160
140
120
100 80 60 40 20
–20
–40
–60
–80
–100 *
PD-L1 expression
n (%)
≥1% PD-L1a
77 (68)
<1% PD-L1a
36 (32)
Unknownb
35 (24)
Percentage Change from Baseline
* Confirmed ongoing responses
Low frequency of treatment-related grade 3–4 AEs leading to discontinuation: 3–10%
(No treatment-related deaths)
Rizvi N ORAL02.05

63. Phase Ib GP28328: ATEZO + Chemo [1st line]
ATEZO no unexpected toxicities
No pneumonitis or other respiratory AEs of concern
ORR 50%
ORR 76.5%
ORR 56.3%
Rizvi N ORAL02.05