onco-inmunologÍa cáncer de pulmón enriqueta felip, hospital vall d’hebron, barcelona xvii...
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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
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.
Lung Cancer
BreastCancer
ColorectalCancer
Prostate Cancer
0
500
1000
1500
2000 IncidenceMortality
GLOBOCAN 2012 (worldwide, both sexes)1
1.59 million1
(1 in 5) estimated deaths worldwide
1.82 million1
estimated new cases 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
ONCO-INMUNOLOGÍA: cáncer de pulmónOutline
• Rationale for PD1 and PDL1 blockade
• PD1 and PDL1 inhibitors in advanced NSCLC
Rationale for PD1 and PDL1 blockadeHow 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 NSCLCTarget Antibody N (NSCLC) Efficacy (ORR)
Overall%
According to PDL1 status
N for PDL status
PDL1 +%
PDL1-%
PD1 BMS-936558
MK-3475
12952 (1st line)
21745 (1st line, all
PDL1+)
24 (3 mg/kg)21 (3 mg/kg)
2026
6817
194-
13-15 31
2326
17-1410
9-
PD-L1 MPDL3280AMEDI-4736
53 47
2313
5332
83 39
315
Brahmer ASCO 14; Gettinger ASCO 14; Garon ASCO 14; Rizvi ASCO 14, Herbst Nature 14, Brahmer NEJM 12
Primary endpoints• DLTs• AEs• Response rate (primary RECIST, secondary irRC)• Biomarker expression
Locally-advanced or metastatic disease
Any carcinoma, melanoma, NSCLC
ECOG PS 0–1
MK-3475 in chemo-naïve
NSCLC pts with PD-L1+ (n=84)
MK-3475 in previously treated
NSCLC pts with PD-L1+ or PD-L1-
(n=217)
10mg/kg q2w
10mg/kg q3w
≥2L 10mg/kg q2w; PD-L1+ (n=58)
≥2L 10mg/kg q3w; PD-L1+ (n=86)
≥3L 10mg/kg q2w; PD-L1– (n=40)
≥3L 10mg/kg q3w; PD-L1+ (n=33)
MK-3475 (NCT01295827)treated/untreated NSCLC p. Phase I
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
• 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%)
RECIST v1.1 per independent
central review
Immune-related response criteria per investigator
assessmentORR, % 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)
Rizvi J Clin Oncol 2014; 32 (suppl 5; abstr 8007)
- 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
Activity of MK-3475 and correlation with PDL1 expression in a pooled analysis of advanced NSCLC p
PFS (RECIST v1.1, Central Review)
0 8 16 24 32 40 48
100
80
60
40
20
0Prog
ress
ion-
free
sur
viva
l, %
Time, weeksn at riskStrongWeakNegative
445349
284330
181715
17127
961
600
300
Ove
rall
surv
ival
, %
StrongWeakNegative
0 2 4 6 8 10
100
80
60
40
20
0
Time, months
445349
435142
343429
272214
21188
18116
550
12
872
984
302621
323126
384838
384034
550
14
440
OS
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]
HistologyNon-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-L1Score ≥ potential cut point 57 (4/7) [18, 90]Score < potential cut point 9 (2/22) [1, 29]SmokingCurrent/former smokers 26 (NR/129) [19, 35]Never smokers 8 (NR/60) [3, 18]
Garon et al. Ann Oncol 2014
NSCLC responders by histology
Time (Week)0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160
Squa
mou
sN
on-s
quam
ous
Duration of response up to discontinuation of therapyOngoing responseTime to responseResponse duration following discontinuation of therapy
Brahmer ASCO 14, poster, abstr 8112
• 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)
BMS-936558 in advanced NSCLC p:
OS and clinical activity by subgroup analysis (n=129)
ORR 17% (24% in 3mg/kg)OS by BMS-936558 dose in NSCLC
OS by histology in NSCLC
OS 1 year 56%
OS 2 year 45%
1st-line BMS-936558 monotherapy (3mg/kg q 2 wks):Safety, efficacy, and correlation with PDL1 status (n=52)
• Key results– PDL1 expression status correlate with RR (31% in PDL1+; 10% PDL1-)– Grade 3–4 treatment-related AEs 20%
Rizvi, Chicago 2014
Responders by histology Responders by PDL1
RR 21%: 15% SCC, 23% Non-SCC
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)
Phase II study of BMS-936558 in p with advanced, refractory squamous NSCLC (N=117)
Ramalingam, Chicago 14
MPDL3280A phase I: efficacy
Single Agent RECIST 1.1 Response Rate
(ORRa)
SD of 24 Weeks or
Longer24-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
Diagnostic Population(n = 53)
ORR% (n/n)
PD Rate% (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)
MPDL3280A phase I: RR by PDL1 IHC status
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
Agent Assay Analysis Definition of positivityBMS-936558 Dako automated IHC
assay (28-8 rabbit Ab)Analytically validated
• Archival FFPE •1% and 5% cut-off among >100 evaluable tumour cells
MK-3475 Dako automated IHC assay (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
• Archival FFPE • 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 • Not reported
PD-L1 analysis: differences in evaluation and interpretation
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
• 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?
PD1 and PDL1 inhibitors: questions to answer
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!!!