1. ONCO-INMUNOLOGÍA Cáncer de Pulmón
Enriqueta Felip, Hospital Vall d’Hebron, Barcelona
XVII Simposio “Revisiones en Cáncer”
Tratamiento Médico del Cáncer en el Año 2015
Madrid, 11, 12 y 13 de Febrero 2015

2. Este ponente ha dispuesto de total libertad para la elaboración de esta ponencia en la recogida y presentación de datos e información científica actualizada y de interés; sin embargo los principios activos y terapias mencionadas en esta ponencia podrían no estar autorizados en todos los países para las indicaciones comentadas. Pembrolizumab no está aún autorizado en la UE.

3. Lung cancer: most common malignancy and leading cause of cancer-related mortality
GLOBOCAN 2012 (worldwide, both sexes)1
1.82 million1
estimated new cases worldwide
1.59 million1
(1 in 5) estimated deaths worldwide
More people die from lung cancer than breast, colorectal and prostate cancers combined1
Within Europe, ~1,000 people die from lung cancer every day1,2
1. Ferlay J, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11[Internet]. Lyon, France: International Agency for Research on Cancer; Available from: Accessed September 2014; 2. Ferlay J, et al. Eur J Cancer. 2013;49:1374–1403.

4. ONCO-INMUNOLOGÍA: cáncer de pulmón Outline
Rationale for PD1 and PDL1 blockade
PD1 and PDL1 inhibitors in advanced NSCLC

5. Rationale for PD1 and PDL1 blockade How cancer cells evade immune destruction
Immune system recognizes and eliminates cancer cells from the body
T cells, crucial in anti-tumor immune response
T cells require a co-stimulatory signal to become fully activated
Activated T cells recognize tumor antigens
T cells kill tumor cells
Evading immune control, a hallmark of cancer (Hanahan & Weinberg Cell 11)

6. Rationale for PD1 and PDL1 blockade PD1/PDL1 pathway
Limits activity T cells and plays a role in the tumor immune escape
PDL1 expression prevalent human tumors and associated with prognosis
PDL1/PD1 inhibitors promising results
Chen D, Clin Cancer Res 2012

7. Rationale for PD1/PDL1 blockade in lung cancer
Target immune system rather than tumor
Activity in different tumor types including NSCLC, melanoma, renal cancer, bladder carcinoma and head & neck
May well have greater activity in tumors with a large number of mutations
Manageable toxicity profile
Suspected impact on long-term survival

8. PD1 & PDL1 inhibitors in advanced NSCLC

9. PD1 & PDL1 inhibitors in NSCLC
Target
Antibody
N (NSCLC)
Efficacy (ORR)
Overall %
According to PDL1 status
N for PDL status
PDL1 +
PDL1-
PD1
BMS
MK-3475
129
52 (1st line)
217
45 (1st line, all PDL1+)
24 (3 mg/kg)
21 (3 mg/kg) 20 26 68 17
194 -
13-15 31 23
17-14 10 9
PD-L1
MPDL3280A
MEDI-4736 53 47 13 32 83 39 5
Brahmer ASCO 14; Gettinger ASCO 14; Garon ASCO 14; Rizvi ASCO 14, Herbst Nature 14, Brahmer NEJM 12

10. MK-3475 (NCT01295827) treated/untreated NSCLC p. Phase I
MK-3475 in chemo-naïve NSCLC pts with
PD-L1+
(n=84)
10mg/kg q2w
Locally-advanced or metastatic disease
Any carcinoma, melanoma, NSCLC
ECOG PS 0–1
10mg/kg q3w
≥2L 10mg/kg q2w; PD-L1+ (n=58)
MK-3475 in previously treated NSCLC pts with
PD-L1+ or PD-L1- (n=217)
≥2L 10mg/kg q3w; PD-L1+ (n=86)
≥3L 10mg/kg q2w; PD-L1– (n=40)
≥3L 10mg/kg q3w; PD-L1+ (n=33)
Primary endpoints
DLTs
AEs
Response rate (primary RECIST, secondary irRC)
Biomarker expression
Garon ASCO 14, abstr 8020; Rizvi ASCO 14, abstract 8007

11. Phase I study of MK-3475 in pre-treated NSCLC p
RECIST v1.1
Immune-related response criteria
PDL1+
PDL1-
n = 159
n= 35
n = 177
n = 40
ORR, % 23 9 19 12
Disease control rate, % 42 31 51 53
Response duration, weeks, median NR
Rizvi ASCO 14, abstract 8007

12. Safety and activity of MK-3475 as initial therapy in advanced NSCLC p and PDL1 expressing tumors
RECIST v1.1 per independent central review
Immune-related response criteria per investigator assessment
ORR, % 26 47
Interim median PFS (95% CI), weeks
27.0 (13.6, 45.0)
37.0 (27.0, NR)
Responses ongoing, n/N (%)
11/11 (100)
19/21 (90)
Responders remaining on treatment, n/N (%)
7/11 (64)
18/21 (86)
Treatment-related AEs (any grade) occurring in >5% of p: fatigue (22%), pruritus (13%), hypothyroidism (9%), dermatitis acneiform (7%), diarrhoea (7%), dyspnoea (7%) and rash (7%)
Rizvi J Clin Oncol 2014; 32 (suppl 5; abstr 8007)

13. PFS (RECIST v1.1, Central Review)
Activity of MK-3475 and correlation with PDL1 expression in a pooled analysis of advanced NSCLC p
Strong PDL1 positivity defined as staining in ≥50% of tumour cells, and weak PDL1 positivity as staining in 1–49% of tumour cells. Negative staining is no PDL1 staining in tumour cells
MK-3475 effective, in particular, p with strong PDL1 tumour expression
PFS (RECIST v1.1, Central Review) OS
Strong Weak Negative 8 16 24 32 40 48
100 80 60 20
Progression-free survival, %
Time, weeks
n at risk
Strong Weak
Negative 44 53 49 28 43 30 18 17 15 12 7
9 6 1 6 3 2 4 6 8 10
100 80 60 40 20
Time, months 44 53 49 43 51 42 34 29 27 22 14 21 18 11 5 12 7 9 30 26 32 31 38 48
Overall survival, %
Garon et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA43

14. MK-3475 phase I in pre-treated p, activity across NSCLC sub-populations
Subgroup
ORR,* % (n/N) [95% CI]
Histology
Non-squamous
16 (4/26) [4, 35]
Squamous
33 (2/6) [4, 78]
Patients with measurable disease on baseline imaging and an evaluable tumour specimen for PD-L1
Score ≥ potential cut point
57 (4/7) [18, 90]
Score < potential cut point
9 (2/22) [1, 29]
Smoking
Current/former smokers
26 (NR/129) [19, 35]
Never smokers
8 (NR/60) [3, 18]
Garon et al. Ann Oncol 2014

15. NSCLC responders by histology
BMS in advanced NSCLC p: OS and clinical activity by subgroup analysis (n=129)
NSCLC responders by histology
OS by BMS dose in NSCLC
OS by histology in NSCLC
OS 1 year 56%
OS 2 year 45%
ORR 17% (24% in 3mg/kg)
Squamous
Duration of response up to discontinuation of therapy
Ongoing response
Time to response
Response duration following discontinuation of therapy
Non-squamous 8 16 24 32 40 48 56 64 72 80 88 96
104
112
120
128
136
144
152
160
Time (Week)
Similar RR in SCC vs non-SCC (16.7 vs 17.6%)
Responses in PDL1-
Similar OS by PDL1 or molecular (EGFR/KRAS) status (only 53% tissue disposition)
Brahmer ASCO 14, poster, abstr 8112

16. Responders by histology
1st-line BMS monotherapy (3mg/kg q 2 wks): Safety, efficacy, and correlation with PDL1 status (n=52)
Responders by histology
Responders by PDL1
RR 21%: 15% SCC, 23% Non-SCC
Key results
PDL1 expression status correlate with RR (31% in PDL1+; 10% PDL1-)
Grade 3–4 treatment-related AEs 20%
Rizvi, Chicago 2014

17. IRC Assessed (per RECIST v1.1)a
Phase II study of BMS in p with advanced, refractory squamous NSCLC (N=117)
IRC Assessed (per RECIST v1.1)a
ORR, % (n) [95% CI]
15 (17) [9, 22]
Disease control rate, % (n)
40 (47)
Median DOR, months (range)
NR (2+, 12+)
Ongoing responders, % (n)
76 (13)
Median time to response, months (range)
3 (2, 9)
PFS rate at 1-year, % (95% CI)
20 (13, 29)
Median PFS, months (95% CI)
2 (2, 3)
Ramalingam, Chicago 14

18. MPDL3280A phase I: efficacy
Single Agent RECIST 1.1 Response Rate (ORRa)
SD of 24 Weeks or Longer
24-Week PFS Rate
Overall population (N = 175)
21%
19%
42%
NSCLC
(n = 53)
23%
17%
45%
Nonsquamous
(n = 42)
44%
Squamous
(n = 11)
27%
18%
46%
Herbst RS Nature 2014

19. MPDL3280A phase I: RR by PDL1 IHC status
Diagnostic Population
(n = 53)
ORR
% (n/n)
PD Rate
IHC 3
83% (5/6)
17% (1/6)
IHC 2 and 3
46% (6/13)
23% (3/13)
IHC 1/2/3
31% (8/26)
38% (10/26)
All Patients
23% (12/53)
40% (21/53)
Herbst RS Nature 2014

21. RECIST response

22. Challenges with PDL1 assessment
Tumor heterogeneity
Small tumor sample
Fresh tumor vs archival samples
PD-L1 expression may change over time
Different IHC mAB, different cut-off for PDL1 positivity

23. PD-L1 analysis: differences in evaluation and interpretation
Agent
Assay
Analysis
Definition of positivity
BMS
Dako automated IHC assay
(28-8 rabbit Ab)
Analytically validated
Archival FFPE
1% and 5% cut-off among >100 evaluable tumour cells
MK-3475
(22C3 mouse Ab)
New tumour biopsy within 60 days prior to first dose of pembrolizumab
Tumour dependent:
- Melanoma > 1%
- NSCLC
PD-L1 (+): Strong (≥50%) and weak staining (1–49%)
PD-L1 (–): no staining
MPDL3280A
Ventana automated clinical research IHC assay
PD-L1 (+):
IHC 3 (≥10%), IHC 2,3 (≥5%), IHC 1,2,3 (≥1%)
PD-L1 (–):
IHC 0 (<1%)
MEDI-4736
First-generation or Ventana IHC Automated Assay (in development)
Not reported
Nivolumab
Antonia SJ, et al. Poster presented at WCLC 2013 (Abstract P );
Brahmer JR, et al. Poster 293 presented at ASCO 2014 (Abstract 8112);
Gettinger SN, et al. Poster presented at ASCO 2014 (Abstract 8024);
Topalian SL, et al. N Engl J Med 2012;366:2443–2454.
Pembrolizumab
Garon EB, et al. Poster presented at ASCO 2014 (Abstract 8020);
Gandhi L, et al. Oral presentation at AACR 2014 (Abstract CT105).
MPDL3280A Soria ECC 2013 and Horn oral 2013;
Rizvi NA et al. Poster presented at ASCO 2014 (Abstract TPS 8123).
MEDI-4736
Brahmer JR, et al. Poster presented at ASCO 2014 (Abstract 8021).
Gettinger S, et al, ASCO 2014 (Abstract 8024); Topalian S, et al. NEJM. 2012; Garon E, et al. ASCO 2014 (Abstract 8020); Gandhi L, et al. AACR 2014 (Abstract CT105); Soria J, et al. at ELCC 2013 (Abstract 3408); 8. Rizvi N, et al, ASCO 2014 (Abstract TPS 8123) Brahmer J, et al. ASCO 2014 (Abstract 8021)

24. PDL1 expression and EGFR mutation
Activation of PD1 pathway contributes to immune-escape in EGFR-driven tumors (Akbay Cancer Discov 13)
PDL1 expression by IHC associated with ADC histology and the presence of EGFR-mutation (D’Incecco Br J Cancer 14)
PDL1 expression by IHC in 164 resected NSCLC p (Azuma Ann Oncol 14)
Higher for women, for never smokers, for p with ADC
Presence of EGFR-mut and ADC significantly associated with increased PDL1 expression, in multivariate analysis

25. PD1 and PDL1 inhibitors: questions to answer
Best predictive marker for response: PD-L1, smoking history, mutations?
Optimal cut-off for PDL1 positivity and the best IHC mAB?
Optimal dose and treatment sequence?
Best surrogate of efficacy (RECIST vs irRC)?
Activity in CNS?
Any role in the adjuvant setting?

26. Clinical case A 77-yr-old man Smoker, 50 packs/year
November 2013: history of 2-month dry cough, no other symptoms
Chest-X-ray: mass in right hilus
Physical examination: normal, ECOG PS 1
CT-thorax: 8 cm mass in upper right lobe, bilateral mediastinal lymph nodes, contralateral lung metastases
Blood tests: normal except LDH 467

27. Clinical case
Bronchoscopy: tumor in anterior branch of right upper lobe
Histology: squamous cell-cell carcinoma
PET-CT: primary tumor, bilateral mediastinal nodes, right supraclavicular lymph node, contralateral lung metastases
Brain MRI: no brain metastases
No EGFR mutation or ALK rearrangement
P was enrolled in an anti-PD1 clinical trial
Central determination of PD-L1, positive

28. Clinical case
In summary, a 77-yr-old man diagnosed with stage IVa squamous cell carcinomas included an anti-PD-1 clinical trial, with a central determination of PDL-1 positivity
December 31, 2013 he started anti-PD-1 (10 mg/kg every 3 wks)
After 9 wks of treatment a CT-scan revealed PR
February 3, 2015, still on treatment, maintaining PR
Toxicity: G1 pruritus
Long PR > 12 months, no toxicity, good general health

29. December 31, 2013
February 2, 2015

30. PD1 & PDL1 inhibitors in advanced NSCLC
Responses in all histologic types
Toxicity profiles differ from that of CT; generally much better tolerated
Identification of biomarkers is complex; PDL1 the most analyzed but some PDL1 negative p also benefit
PD1 and PDL1 inhibitors, promising results in NSCLC, suspected impact on long-term survival
Targeting PD1/PDL1 means new hope for NSCLC p

31. Gracias!!! efelip@vhebron.net