Curigliano - Immunotherapy for breast cancer€¦ · Immunotherapy for Breast Cancer Giuseppe...
Transcript of Curigliano - Immunotherapy for breast cancer€¦ · Immunotherapy for Breast Cancer Giuseppe...
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Immunotherapy for Breast Cancer
Giuseppe Curigliano MD, PhDBreast Cancer ProgramBreast Cancer Program
Division of Early Drug DevelopmentIstituto Europeo di Oncologia, Milano, IT
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Lymphocytic infiltration assessed by HES andoutcome in breast cancer
Loi S, ASCO, 2012
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Lymphocytic infiltration assessed by HES andoutcome in breast cancer
reference n trial endpoint Subclass analyzed result
Denkert
(J Clin Oncol, 2010)
840 GBG
(G-3)
pCR all pCR:41% in TIL+ BC
Validated in G-5
Loi
(J Clin Oncol, 2013)
2009 BIG
(2-98)
DFS Preplanned analysisof molecular subtypes
Prognostic impactin TNBC (n=256):(J Clin Oncol, 2013) (2-98) of molecular subtypes in TNBC (n=256):
HR:0.31 (0.11-0.84)
Loi
(ASCO 2012)
935 FinnHer DFS Preplanned analysisof molecular subtypes
Prognostic impactin TNBC (n=134):
HR:0.31 (0.12-0.8)
Predictive value fortrastuzumab
efficacy: p=0.02
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TIL as risk stratification for TNBC
FinnHer BIG2-98
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N tot=308
N=291IT and/or ST evaluable
N=17IT and ST non evaluable
IT and/or ST evaluable
Included in the analysisN=289
IT and ST evaluable
N=2Only IT or ST evaluable
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AnthraAnthraAnthra+taxOthertax
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DFS: IT and/or ST >60% vs >=60%
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OS: IT and/or ST >60% vs >=60%
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Extensively infiltrated tumors
Gu-Trantien et al, JCI 2013
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Higher levels of TILS Lower levels of TILS
Correlations between TILs and immune genesin HER2+ BC
Anti-tumor effector immunity Pro-tumor/immunosuppressive
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Higher levels of TILS Lower levels of TILS
Correlations between TILs and immune genes
Tumor microenvironment is immunosuppressive, high levels of Teffectors and T regs
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High levels of lymphocytic infiltrate is associatedwith benefit from trastuzumab in HER2+ disease
HR 0.16 (0.031-0.81) P=0.013 HR 1.0 (0.55-1.75) P=0.99
Significant interaction test p=0.02For every 10% increase in TILs, there was increasing benefit to trastuzumab
Loi et al, Annals Oncol 2014
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Treatment with Trastuzumab relievesimmunosuppression in some way
CTLA4 low CTLA4 high
CTLA4
Loi et al, SABCS 2013
PD-1
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Augmenting T cell responses with trastuzumab
Background BALB/c MMTV/neu miceSABCS 2013
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A Phase Ib/II study of an anti-PD-1 monoclonAl aNtibody inadvAnCed, trastuzumab-resistant, ERBB2-overexpressing breAst
cancer: PANACEA
Screening: Locally advanced or metastatic breast cancer overexpressing HER2 at diagnosis Submit an FFPE block from core biopsy for central testing
Central Testing:
HER2 by IHC
HER2 neg:not eligible
HER2 pos:Central PD-L1 testing
Phase Ib: dose f inding for lambrolizumab in 3+3 design ─ Phase II at RP2D
Treatment in 3 week cycles: 1 2 3 4 5……………..… PD
T : trastuzumab 6mg/kg T T T T TL : lambrolizumab at RP2D L L L L L
PD-L1 neg:not eligible
PD-L1 positive: enrol
Blood samples: whole bloodplasma&serum prior to cycles 1, 2, 3, 4, 5 and then every 3 cycles
and 6 months post end of tx
Tissue at enrolment: re-biopsy at PD:Samples: FFPE block FFPE Block
Fresh f rozen block Fresh f rozen block
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Challenges for Therapeutic vaccination
• Endogenous immunity: Features leading to diseaseeradication versus tolerance
• Stromal elements influencing local immunity• Stromal elements influencing local immunity
• Therapeutic vaccination: Challenges to achievingsterile immunity versus resetting equilibrium andrescuing a failed host response
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Therapeutic vaccination in BC
• Drive setting of clinical trial according to theexpression of the antigens in cancer subtype
• Select patients with no or minimal tumor burden• Select patients with no or minimal tumor burden
• Perform correlation studies of immunological/clinicalresponse
• Evaluate genetic/immunological profile ofresponders
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Phase I open-label dose-escalation vaccine trial of dHER2protein with AS15 adjuvant in HER2-overexpressing patients
with high-risk breast cancer
• Breast cancer (stage II > 1 N+ or stage III)
• Adjuvant setting after standard treatment
• Herceptest 3+ or FISH positive
• No recurrence
• Adequate LVEF (MUGA scan)
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Phase I open-label dose-escalation vaccine trial of dHER2protein with AS15 adjuvant in HER2-overexpressing patients
with high-risk breast cancer
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Endpoints
• Primary:
Safety
• Secondary:• Secondary:
Humoral immunogenicity
Cell-mediated immunogenicity
Impact of escalating doses of HER2
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Study design
Cohorts N Dose (Route: IM) Timing
Cohort 1 15 20 µg dHER2/AS15 D 0, 14, 28, 42
(70 & 98)
Cohort 2 15 100 µg dHER2/AS15 D 0, 14, 28, 42
(70 & 98)
Cohort 3 15 500 µg dHER2/AS15 D 0, 14, 28, 42
(70 & 98)
Cohort 4 16 500 µg W 0, 4, 14, 34, 38
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Study design: Treatment
2 weeks 4 weeks
screening
weekanalysis
0 2 4 6 10 14
PBMC
Ab
MUGA
X
X
X
X X X X X
X X
X X X X
X X
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Results
• 304 administrations in 61 patients
• The incidence and intensity of symptoms reportedThe incidence and intensity of symptoms reportedwas similar across the study cohorts, whichindicates that increasing doses of the dHER2protein or a different schedule of treatmentadministration did not lead to a different safetyprofile
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Safety
• No dose relationship toxicity
• 5 patients withdrawn from study for safety reason
• 1 Grade 2 cardiotoxicity (sinus tachycardia)
• 1 Grade 2 fatigue
• 1 patient with Grade 2 headache + myalgia +fatigue
• 2 Grade 1 / 2 asymptomatic decrease in LVEF (12-13%)
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Immunogenicity
• For all the antigens investigated, the proportion ofseropositive patients and of patients developing anantigen-specific Ab response increased with thedose of the recombinant dHER2 protein.dose of the recombinant dHER2 protein.
• At the higher dose level (500 g), the majority ofthe patients developed a response to HER2, ECDand ICD after just a few doses of the dHER2 + AS15.
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Immunogenicity
1000
GM
T(E
U/m
l) Cohort 3 (500 µg)
10
100
0 28 56 84 112 140 168 196 224 252 280
GM
T(E
U/m
l)
Cohort 2 (100 µg)
Cohort 1 (20 µg)
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Responders anti ECD and anti ICD
% anti-ECD antibody responders
%o
fre
sp
on
der
pa
tie
nts
80
100
% anti-ICD antibody responders
of
resp
on
de
rp
ati
en
ts
80
100
60
88
61
8694
88
Cohort 1 Cohort 2 Cohort 3 Cohort 4
%o
fre
sp
on
der
pa
tie
nts
0
20
40
60
Cohort 1 Cohort 2 Cohort 3 Cohort 4%
of
resp
on
de
rp
ati
en
ts0
20
40
60
16
33
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d-HER2 induces antibodies that specificallybind the native HER2 receptor
• The ECD binding ratio seems to increase with thedose of HER2 protein when assessed after theadministration of four dHER2 + AS15 doses.
Day 0Day 56
SKBR3
Day 0Day 56
BT474
Cohort 1 Cohort 2 Cohort 3 Cohort 4
%
0
20
40
60
80
100
A B C
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Immunogenicity
• No ADCC activity was detected.
• The HER2 specific CD4+ T-cell responses wereassessed by an approach allowing detection of T-cells at frequencies as low as 10-5 (1 positive cell incells at frequencies as low as 10-5 (1 positive cell in105 T-cells). This method consists of a two-weekrepeated stimulation of blood lymphocytes witheither a pool of overlapping ECD or ICD peptides.This is followed by intracytoplasmic staining forIFNγ and TNFα and analysis by flow cytometry.
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Immunogenicity
Patientcode
Anti-ECDCD4+
Anti-ECDCD8+
Anti-ICDCD4+
Anti-ICDCD8+
Cohort 3A - + + -B + - + -C + + + +D + - + -EE - - - -F - - - -G - - - -
Cohort 4H + - - -I + + - -J + - + +K - - - +L - - - -M + - + -
Responders 7/13 3/13 6/13 3/13
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Five-year follow-up phase
• Forty-five (92%) of the 49 patients were still alive atthe time of the data base freeze (DBF, 6 October2013).
• Four patients were dead.• Four patients were dead.
• Three of the four deceased patients died of breastcancer, for one patient the cause of death wasunknown.
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Five-year follow-up phase
• Twenty-eight (62%) of the 45 patients with knownbreast cancer status at the end of the five-yearfollow-up period were disease-free at the time ofDBFDBF
• 17 (32%) had relapsed and two patients had a newtumor of another histology than breast cancer.
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Conclusions
• The dHER2 + AS15 was safe and well tolerated.
• The incidence and intensity of AEs was similaracross the study cohorts.
• The dHER2 + AS15 administration schedule withthe highest dose of dHER2 protein investigatedgave the highest Ab concentrations and the highestrate of responding patients for all the antigensassessed.
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Conclusions
• Three patients reported cardiac AEs during thefollow-up period. One of these (mitral valveincompetence) was assessed to be possibly relatedto the study treatment.to the study treatment.
• No other SAE was reported during the follow-upperiod.
• There was a trend for better DFS for patientsreceiving the highest dose of the dHER2 protein.
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Open-label Phase I/II trial of the safety and efficacy of the dHER2recombinant protein combined with immunological adjuvant AS15 in
patients with HER2+ metastatic breast cancer
• Cohort 1: patients receiving the dHER2 + AS15 asfirst-line therapy of metastatic disease.
• Cohort 2: patients receiving the dHER2 + AS15 assecond-line therapy after having received first-linetherapy of metastatic disease with trastuzumab,either alone or combined with chemotherapy.
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Inclusion Criteria
• A tumor lesion biopsied during or before screeningshowing either: overexpression of the HER2 proteinas determined by IHC or amplification of the HER2gene as determined by FISH test
• Eastern Cooperative Oncology Group (ECOG)• Eastern Cooperative Oncology Group (ECOG)performance status of 0 or 1 and adequate organfunction (bone marrow reserve, renal and hepaticfunction).
• Baseline left ventricular ejection fraction (LVEF)equal to or greater than the lower limit of normal.
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Endpoints
• Safety
• Clinical activity: response according to modifiedRECIST criteria and TTP
• Immunological response:
The proportion of patients being anti-dHER2, anti-The proportion of patients being anti-dHER2, anti-HER2 ECD and anti-HER2 ICD Ab seropositive.
Functional activity in vitro, assessed by growthinhibition of HER2-over-expressing breast tumorcells.
Frequency of cellular immune response in vitro todHER2, HER2 ECD and HER2 ICD.
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Study treatment
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Results
• Forty patients (17 in Cohort 1, 23 in Cohort 2) wereenrolled and received at least Dose 1.
• The patients’ mean age was 57 with a range from34 to 76.34 to 76.
• Thirty-five of the women were Caucasians and fivehad another ethnic background.
• Fourteen study centers in five countries (Belgium,Colombia, France, Italy, and Peru) enrolled patients.
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Safety
• The Grade 1 and 2 unsolicited AEs reported bymost patients were: back pain, myalgia, arthralgia,pain in extremity, chest pain, injection site pain,asthenia, diarrhea, chills.asthenia, diarrhea, chills.
• Six Grade 3 AEs were reported and this was themost severe grade observed.
• No cardiac event was reported.
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Activity
• One patient in Cohort 1 achieved a CR with aduration of 11 months and one patient in Cohort 2achieved a PR which lasted for three months.
• Twelve patients had SD as their overall best• Twelve patients had SD as their overall bestresponse to the treatment.
• The duration of the SDs achieved ranged from 18weeks to 47 weeks.
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Activity
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Activity
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Activity
• Thirty-four patients were withdrawn from thedHER2 + AS15 because of disease progression. Themedian time to progression was 2.8 months inCohort 1 and 3.4 months in Cohort 2.Cohort 1 and 3.4 months in Cohort 2.
• Four patients died during the study, three of breastcancer progression and one of an unrelated SAE(pulmonary embolism).
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Activity
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Immunogenicity
• All the patients in Cohort 1 receiving the dHER2 +AS15 as first-line therapy mounted a humoralimmune response against dHER2, HER2 ECD andHER2 ICD.
• The patients in Cohort 2 receiving the dHER2 +AS15 as second-line therapy all showed a humoralimmune response against HER2 ICD, while the rateof responders against HER2 ECD was one out ofseven, both after Dose 4.
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Immunogenicity
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Immunogenicity
• There are too few data available to make anassessment of the cell mediated immune responseto the dHER2 + AS15 and the impact of theto the dHER2 + AS15 and the impact of thehumoral response on tumor cell growth.
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Conclusions
• The study met the protocol specified criterion foracceptable safety, namely < 10% of the patients ineach cohort reporting a Grade 3 or higher AE,assessed by the investigator to be possiblytreatment related.
• The study met the protocol specified criterion foracceptable clinical activity, namely to achieve atleast one objective clinical response (CR or PR) ineach cohort.
• The immunogenic character of the dHER2 + AS15was demonstrated.
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Antigens in BC subtypes
Highly endocrine-
responsive
Lobular
0 1 2 3 4 5 6 7 8
number of cases
Triple Negative
Moderately endocrine-
responsive
HER2 positiveWT1/NY-ESO-1
WT1/PRAME
NY-ESO-1/PRAME
WT1/NY-ESO-1/PRAME
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Post neoadjuvant clinical setting
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IMPULSE trial
no pCR
pCR
60%
NeoadjChemoR/
35%
40%
ChemoR/ * (max 6q3week)
Surgery
R
1 Placebo(5q3week – 8q3months)
RadiationTNBC
65%
ChemoR/ * (max 6q3week)
N-
N+
Y%
X%
Surgery
R
2ASCI
(5q3week – 8q3months)
* Chemotherapy- SoC for “Adjuvant Cohort”- Authorized for no pCR cohort
Radiation
Chemotherapy & ASCI
Chemotherapy alone
ASCI alone
3 w
3 m
PI’s Peter Dubsky and Giuseppe Curigliano
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Summary
• Complexity of cancer, tumor heterogeneity andimmune escape
• Lack of definitive biomarker(s) for assessment ofclinical efficacy of cancer immunotherapiesclinical efficacy of cancer immunotherapies
• Conventional clinical response criteria do not takeinto consideration differences between responsepatterns to cytotoxic agents and immunotherapies
• Desperately need for clinical trials
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Thank you
Curigliano GroupCarmen CriscitielloAngela EspositoMarzia LocatelliIda Minchella
Research Nurses HeadAlessandra Milani
LabsLuisa LanfranconeSaverio MinucciMaria RescignoLuca MazzarellaAngelo CicaleseDaniela Bossi
Alessandra Milani
Data ManagerLaura AdamoliSabrina BoselliValeria BianchiValeria Bertolotti
My mentorAron Goldhirsch