Inmunoterapia en tumores digestivos no colorrectales
Santander, 13 de Julio del 2017
Maria Alsina, MD PhD
Hospital Universitari Vall d’Hebron
Outline
• Introduction
• Hepatocarcinoma
• Pancreatic Cancer
• Gastric Cancer
• Conclusions
Outline
• Introduction
• Hepatocarcinoma
• Pancreatic Cancer
• Gastric Cancer
• Conclusions
Introduction Tumors are complex systems
•Successful growth of tumors and metastasis is not determined solely by genetic alterations in tumor cells, but also by the advantage that such mutations confer in the environment
• Tumor formation involves the co-evolution of neoplastic cells together with extracellular matrix, tumor vasculature and immune cells.
Tumor Antigen Transport
Lymphocyte trafficking
Junttila Nature 2013
Introduction: Therapeutic approaches to target the cancer immunity cycle
Chen & Mellman Immunity 2013, Moehler Eur J Can 2016
Tumor
Lymph node
Blood vessel
Introduction Frequency of genetic somatic mutations in cancer
Altered proteins contain new epitopes for immune recognition, providing a common denominator for cancer immunotherapy
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Lawrence Nature 2013
No at Risk
Outline
• Introduction
• Hepatocarcinoma
• Gastric Cancer
• Pancreatic Cancer
• Conclusions
HCC: microenvironment and immune landscape
Koontongkaew, 2013
• HCC is an immunogenic cancer which express tumor-associated antigens and neo-antigens arising from gene mutations
• The 90% of the HCC are associated with prolonged hepatitis the immune microvenvironment has pivotal role in its pathogenesis
• The presence of immune infiltrates is asssociated with a better prognosis
• Antitumor immune responses are subverted by a variety of stromal cells and multiple immunoinhibitory molecules
• Chronic HBV and HCV infection are associated with PD-1 and PD-L1 upregulation
Nivolumab in HCC
Melero GI ASCO 2017, El-Khoureiy Lancet 2017
Nivolumab in HCC
Melero GI ASCO 2017, El-Khoureiy Lancet 2017
Nivolumab in HCC
Melero GI ASCO 2017
Checkpoint Blockade in advanced HCC
1. Sangro Hepatology 2013
2. El Khouelry Lancet 2017
3. Wainberg ASCO 2017 # 4071
4. Kelley ASCO 2017 # 4074
Future in HCC
Outline
• Introduction
• Hepatocarcinoma
• Pancreatic Cancer
• Gastric Cancer
• Conclusions
Immunotherapy for pancreatic cancer
• The microenvironment of PC is unique
Immunotherapy for pancreatic cancer
• PC is non-immunogenic secondary to immunosuppressive elements, low mutational burden, and paucity of T cells
• Single agent therapeutic approaches with immune checkpoint inhibitors or vaccines have not been encouraging
• Combinatorial approaches appear key • Overcome T-cell immunologic endpoints
Royal J Immunother 2010; Topalian NEJM 2012
Immunotherapy for pancreatic cancer
Targeting tumor infiltrating macrophages (TAMs) and myeloid derived suppressor cells • Targeting macrophage signaling (CCR2) will block myeloid monocyte/macrophage
recruitment to tumor microenvironment, which would improve cytotoxic efficacy and increase antitumor T-cell response.
Sideras Can Treat Reviews 2013; Lesokhin Cancer Res 2011, Mitchem Cancer Res 2013
Nywering Lancet Oncol 2016
Outline
• Introduction
• Hepatocarcinoma
• Pancreatic Cancer
• Gastric Cancer
• Conclusions
50%
20%
22%
9%
TCGA Nature 2014
TILs are predictive of overall survival in GC
Lee Br J Cancer 2008
Pooled OS data for 220 patients with gastric cancer surgically resected
PDL1 expression and T cells infiltration in GC
• 1014 GC pts
• CD3+ High and CD8+ High → Better OS
• PD-L1High (TC and IC) → Better OS
• Close relationship between CD3+, CD8+ cell density and PDL1 expression (TC and IC)
Xing ASCO GI 2017
Immune cells (IC) Tumor cells (TC)
PD-L1 74.9% 37.8%
Patients with higher CD8 and CD3 T cell densities also have higher PD-L1 expression, indicating an adaptive immune resistance
mechanism may be occurring
Anti-CTLA-4 therapy in GC
• Tremelimumab • Ph 2 in 2nd Line, not randomized
• Ipilimumab • Ph 2 for maintenance after 1st Line, randomized
• Stopped after interim analysis
Ralph Clin Cancer Res 2012; Moehler ASCO & World GI 2016
Anti-PD1 & anti-PD-L1 therapies in GC
• Anti-PD1 • Pembrolizumab: KEYNOTE 012, KEYNOTE 059
• Nivolumab: Checkmate 032, ATTRACTION-2 (ONO-4538/BMS-936558)
• Anti-PDL1 • Avelumab: JAVELIN Japanese
• Atezolizumab1
• Durvalumab2 Only old activity reported, from Ph 1 basket trials
Herbst JCO 2013; Segal Ann Oncol 2014
KEYNOTE 012 Pembrolizumab in GC
Bang 2015 ASCO Annual Meeting
53.1% of patients experienced a decrease from
baseline
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Bang YJ et al. Proc ESMO GI 2015
KEYNOTE 012 Pembrolizumab in GC
• OS (ITT)
• 6-months OS rate: 66%
• mOS: 11m
Fuchs ASCO 2017
• ORR • All patients: 11.6% • PD-L1 pos: 15.5% (vs 6.4% in PD-L1 neg) • 3rd Line: 16.4% (vs 6.4% in > 3rd L) • MSI-H: 57.1% (vs 9% in non MSI-H)
KEYNOTE 059 Pembrolizumab in GC
Yoon-Koo Kang ESMO World Congress on Gastrointestinal Cancer 2017
• 31 pts, all PD-L1 positive • ORR (1ary End Point): 25.8%
• 1 pt with complete response • mPFS: 3,3m (95% CI 2.0-6.0) • mOS: not reached
KEYNOTE 059 Pembrolizumab in GC
KEYNOTE 059 Pembrolizumab in GC
Janjigian ASCO 2016 & ASCO 2017
Checkmate 032 Nivolumab in GC
ATTRACTION-2 Nivolumab in ≥ 3rd Line
Kang ASCO GI 2017
Nivolumab 3 mg/kg (n = 268)
Placebo (n = 131)
ORR, n (%) [95% CI] P value
30 (11.2) [7.7–15.6] < 0.0001
0 [0–2.8]
—
BOR, n (%) Complete response Partial response Stable disease Progressive disease
0
30 (11.2) 78 (29.1) 124 (46.3)
0 0
33 (25.2) 79 (60.3)
DCR, n (%) [95% CI] P value
108 (40.3) [34.4–46.4]
0.0036
33 (25.2) [18.0–33.5]
—
Median TTR (range), months 1.61 (1.4–7.0) —
Median DOR, months [95% CI]
9.53 [6.14–9.82]
—
Overall Survival
Avelumab in GC
• Ph 1b in GC/GEJ pts • Irrespectively of PD-L1 status
Chung ASCO 2016
2L (n = 22) Mn (n = 52)
PD-L1+ (n = 11) PD-L1− (n = 11) PD-L1+ (n = 20) PD-L1− (n = 32)
ORR % (95% CI) 18.2
(2.3, 51.8)
9.1
(0.2, 41.3)
10.0
(1.2, 31.7)
3.1
(0.1, 16.2)
mPFS w (95% CI) 6.3
(5.4, 18.0)
10.4
(4.1, 21.9)
17.6
(6.0, 24.1)
11.6
(5.7, 14.1)
Which biomarker?
• PD-L1 IHC • Different positivity rate (57.1% in KEYNOTE 059, 31% in Checkmate 032)
• IHC test not standardized
• Different Ab, different positivity criteria
• Other issues: sampling time, simple type (heterogeneity)
• Trend of higher activity in PDL1+
• Gene expression signature • IFN-γ signature (18 gene) as a predictor for inefficacy
• Usefulness not evident: much overlap
Shankaran V et al. Abstract 3026. Presented at the 2015 ASCO
Which biomarker?
• MSI • MSI-High rate is quite low (≈5% in incidence)
• Very high activity in MSI-high (KEYNOTE 059)
• Useful for clinical practice
Seruca Int J Can 1995 Hye Seung Lee Mod Pathol 2002
P = .046
Combined strategies
Anti-angiogenic agents Immune response
• Vasculature normalization • ↓ Interstitial pressure • ↑ Perfusion • ↑ Adhesion molecules • Preserve endothelial cell anergy
• Availability of glucose, amino acids and oxygen • ↑ Lymphocyte infiltration • ↑ T-cell access and function
Manning Clin Ca Res 2007
Hodi Cancer Immunol Res 2014
Sznol J Clin Oncol 2015 (suppl)
Combined strategies
• Immunotherapy + anti-angiogenesis
• Pembrolizumab + Ramucirumab1
• Immunotherapy + radiotherapy (Abscopal Effect)
• Pembrolizumab + palliative radiotherapy (30 Gy on 1ary tumor or single metastasis) → Pembrolizumab until PD2
• Immunotherapy + targeted agents • With anti-HER2 agents (margetuximab)3
• With anti-MMP9 agents (GS-5745)4
• With PARP-inhibitors (Olaparib) 5
1. Chau ASCO GI 2017; 2. Chao ASCO GI 2017;3, Catenacci ASCO GI 2017; 4. NCT02864381; 5. NCT02734004
The future in GC
Outline
• Introduction
• Hepatocarcinoma
• Pancreatic Cancer
• Gastric Cancer
• Conclusions
Conclusions
• Pancreatic Cancer • PC is an immune privileged tumor
• Still too early for immunotherapy, but many opportunities using rational combinations
• HCC • Activity for anti-CTLA-4 and anti-PD1
• Efficacy observed irrespective of HCV, HBV or PDL1 status
Conclusions
• Esophago-Gastric Cancer • Single agent anti-CTLA4 – no activity
• Very interesting activity with single agent anti-PD1 and anti-PD-L1
• Dual PD-1/CTLA-4 (nivo/ipi) may be more active, but with higher toxicity
• Biomarkers • PD-L1 IHC: multiple technical factors, response in PDL1 negative patients
• Gene expression profiles, MSI/EBV status, mutational load
• Combinatorial strategies
Take home messages
• Activity in subset of patients, particularly in esophago-gastric tumors
• ≈ 25% long term survivors
• Pembrolizumab as a standard in MSI+ patients
• Combination strategies may improve the efficacy
• Biomarkers beyond MSI are crucial
• Need to further understand the immune-pattern of response and how to manage related adverse events
¡Muchas gracias!
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