Transcript Update on Immuno-oncology: A new age in therapy for

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
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.
Lung cancer: most common malignancy and leading
cause of cancer-related mortality
GLOBOCAN 2012 (worldwide, both sexes)1
Incidence
Mortality
2000
1.82 million1
estimated new cases worldwide
1500
1.59 million1
(1 in 5) estimated deaths worldwide
1000
More people die from lung cancer than
breast, colorectal and prostate cancers
combined1
500
0
Lung
Cancer
Breast Colorectal Prostate
Cancer Cancer Cancer
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; 2013. Available from: http://globocan.iarc.fr. Accessed September 2014;
2. Ferlay J, et al. Eur J Cancer. 2013;49:1374–1403.
ONCO-INMUNOLOGÍA: cáncer de pulmón
Outline
• Rationale for PD1 and PDL1 blockade
• PD1 and PDL1 inhibitors in advanced NSCLC
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)
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
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
PD1 & PDL1 inhibitors
in advanced NSCLC
PD1 & PDL1 inhibitors in NSCLC
Target
Antibody
N (NSCLC)
Efficacy (ORR)
Overall
%
PD1
BMS-936558
MK-3475
PD-L1
MPDL3280A
MEDI-4736
According to PDL1 status
N for PDL
status
PDL1 +
%
PDL1
%
129
52 (1st line)
24 (3 mg/kg)
21 (3 mg/kg)
68
17
13-15
31
17-14
10
217
45 (1st line, all
PDL1+)
20
26
194
-
23
26
9
-
53
47
23
13
53
32
83
39
31
5
Brahmer ASCO 14; Gettinger ASCO 14; Garon ASCO 14; Rizvi ASCO 14, Herbst Nature 14, Brahmer
NEJM 12
MK-3475 (NCT01295827)
treated/untreated NSCLC p. Phase I
 Locally-advanced or
metastatic disease
MK-3475 in
chemo-naïve
NSCLC pts with
PD-L1+
(n=84)
 Any carcinoma,
melanoma, NSCLC
 ECOG PS 0–1
10mg/kg q2w
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
Phase I study of MK-3475
in pre-treated NSCLC p
RECIST v1.1
Immune-related
response criteria
PDL1+
PDL1-
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
31
NR
NR
NR
Rizvi ASCO 14, abstract 8007
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
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)
7/11 (64)
18/21 (86)
ORR, %
Responders remaining on
treatment, n/N (%)
• 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)
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
OS
n at risk
Strong
Weak
Negative
Strong
Weak
Negative
100
100
Overall survival, %
Progression-free survival, %
PFS (RECIST v1.1, Central Review)
80
60
40
20
80
60
40
20
0
0
0
8
16
44
53
49
28
43
30
18
17
15
24
32
Time, weeks
17
12
7
9
6
1
40
48
6
0
0
3
0
0
0
2
4
6
8
Time, months
10
12
44 43 38 38 34 32 30 27 21 18 9
53 51 48 40 34 31 26 22 18 11 8
49 42 38 34 29 26 21 14 8 6 4
8 5
7 5
2 0
14
5
5
0
4
4
0
- MK-3475 effective, in particular, p with strong PDL1 tumour expression
Garon et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA43
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
Never smokers
26 (NR/129) [19, 35]
8 (NR/60) [3, 18]
Garon et al. Ann Oncol 2014
BMS-936558 in advanced NSCLC p:
OS and clinical activity by subgroup analysis (n=129)
Squamous
NSCLC responders by histology
ORR 17% (24% in 3mg/kg)
OS 1 year 56%
Non-squamous
OS 2 year 45%
Duration of response up to discontinuation
of therapy
Ongoing response
Time to response
Response duration following discontinuation
of therapy
0
•
•
•
OS by BMS-936558 dose in NSCLC
8
OS by histology in NSCLC
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 PDL1Similar OS by PDL1 or molecular (EGFR/KRAS)
status (only 53% tissue disposition)
Brahmer ASCO 14, poster, abstr 8112
1st-line BMS-936558 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
Phase II study of BMS-936558 in p with
advanced, refractory squamous NSCLC (N=117)
IRC Assessed (per RECIST v1.1)a
ORR, % (n) [95% CI]
Disease control rate, % (n)
Median DOR, months (range)
15 (17) [9, 22]
40 (47)
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
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)
21%
17%
44%
Squamous
(n = 11)
27%
18%
46%
Herbst RS Nature 2014
MPDL3280A phase I: RR by PDL1 IHC status
Diagnostic Population
ORR
PD Rate
% (n/n)
% (n/n)
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)
(n = 53)
Herbst RS Nature 2014
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
PD-L1 analysis:
differences in evaluation and interpretation
Agent
Assay
Analysis
BMS-936558
Dako automated IHC • Archival FFPE
assay
(28-8 rabbit Ab)
Analytically validated
• 1% and 5% cut-off among >100
evaluable tumour cells
MK-3475
Dako automated IHC • New tumour biopsy
assay
within 60 days prior to
(22C3 mouse Ab)
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 • Archival FFPE
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)
• Archival FFPE
Definition of positivity
• Not reported
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)
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
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?
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
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
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
December 31, 2013
February 2, 2015
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
Gracias!!!
[email protected]