“Immunoterapia e carcinoma della mammella”Maria Vittoria Dieci
Università di Padova
IOV - IRCCS
Alexandrov, Nature 2013
Mutational load across tumor types
Luen S et al, Breast 2016
QUALITY and not (only) QUANTITY of neoantigens is important for response to immunotherapy (reviewed by McArthur HL, ASCO 2018)
Median %
N None/absent Intermediate/present High
All 4161 16 89 11
TN 1640 15 80 20
HER2+ 929 9 84 16
HR+ 2410 20 94 6
2016
OS
HR 0.84 0.77-0.92
Loi S, SABCS 2015
Pooled individual patient data analysis of tumor infiltrating lymphocytes (TILs) in primary triple negative breast cancer (TNBC) treated with
anthracycline-based chemotherapySherene Loi, Damien Drubay, Sylvia Adams, Prudence A Francis, Heikki Joensuu, Maria Vittoria Dieci, Sunil Badve, Sandra Demaria, Robert Gray, Martine J Piccart, Pirkko-Liisa Kellokumpu-Lehtinen, Fabrice Andre, Carsten Denkert, Roberto Salgado, Stefan Michiels.
Adams S, ASCO 2017; Schmid P, AACR 2017; Dirix L, BCRT 2018
Pembrolizumab Atezolizumab Avelumab
Phase II I I
N 222 115 58
ORR
ORR 1L
ORR 2L+
---
23.1%*
4.7%
10%
26%
11%
5.2%**
---
---
Immune checkpoint inhibitors in
metastatic TNBC PDL1+/-
*All PD-L1+
**50% received > 2 previous lines of anticancer treatment
Activity of immunotherapy after Pseudo-progression
Adams S, ASCO 2017
Pembrolizumab single agent in
TNBC PD-L1+, untreated for MBC
Pembrolizumab single agent in TNBC
PD-L1+/-, >2L
KEYNOTE-086
Cohort A
KEYNOTE-086
Cohort B
Immune checkpoint inhibitors in metastatic TNBC:
durable responses
Adams S, ASCO 2017
Median OS follow-up (range) was 15.2 mo (0.4+ to 36.7) in all patients, 17.0 mo (0.43+ to 36.7) in IC2/3 patients and 12.8 mo (0.8+ to 16.9) in IC0/1 patients.
No. At Risk: CR/PR 15 15 14 14 12 10 6 6 6 4 3 2 1
SD 19 18 17 10 6 5 1PD 55 40 30 28 11 3
3y OS: 100%
1-y OS: 33%
1-y OS: 51%
2y OS: 100%1y OS: 100%
Ove
rall S
urv
iva
l
Time (months)
Response
■ CR/PR■ SD ■ PD
Atezolizumab
single agent in
mTNBC ≥1L,
PDL1+/-
Schmid P, et al. AACR 2017
OS according to response
- Optimize patients selection
- Combinations
- Chemotherapy
- PARP inhibitors
- Move to the early setting
How to move forward in TNBC
Schmid P, et al. AACR 2017; Adams S, et al ASCO 2017; Loi, ESMO 2017
17%
8%
PDL1-PDL1+
Ob
ject
ive
Res
po
nse
Rat
e (%
)
10%
20%
30%
0%
4.8% 4.7%
Pembrolizumab(Cohort A)
Atezolizumab
Anti-PD-L1/PD-1 single agent in mTNBC ≥1L, PDL1+/-
PDL1-PDL1+
PD-L1 expression and response to single agent immune
checkpoint inhibitor
Loi S, ESMO 2017
KEYNOTE-086: TILs and ORR
Schmid P, et al. AACR 2017 Phase Ia
Atezolizumab in TNBC
11
≤ 10% TILs (n = 53)
> 10% TILs(n = 56)
mOS(95% CI)
6.6 mo (4.9, 10.2)
12.6 mo (10.5, NA)
OS by TILs - atezolizumab
Dieci MV, et al. Ann Oncol. 2014 Bracci L, et al. Cell Death Differ 2014
Chemotherapy as a trigger for immune activation
1L
n=13
2L+
n=20
IC1/2/3
n=12
IC0
n=12
Unknown
n=9
Confirmed ORR
(95% CI)
54%
(25-81)
30%
(12–54)
42%
(15-72)
33%
(10-65)
44%
(14-79)
CR 1 (8%) 0 1 (8%) 0 0
PR 6 (46%) 6 (30%) 4 (33%) 4 (33%) 4 (44%)
SD 4 (31%) 9 (45%) 6 (50%) 5 (42%) 2 (22%)
PD 2 (15%) 4 (20%) 1 (8%) 3 (25%) 1 (11%)
CT + immune checkpoint inhibitor for mTNBC PD-L1+/-
Pohlmann PR, AACR 2018
ORR 39%, mPFS 5.5 months, mOS 14.7 months
ORR 26%, mPFS 4.2 months, mOS 17.7 months
Atezolizumab + nab-paclitaxel, n=33
Pembrolizumab + eribulin, n=107
Tolaney S, SABCS 2017
PD-L1+
PD-L1-
PD-L1 NA
PD-L1+
PD-L1-
PD-L1 NA
1st line: ORR 29.2%
2nd-3rd line: ORR 22%
Results expected at ESMO 2018
Kok M, ASCO 2018
TONIC phase II studyInduction→ Nivolumab (n=66 mTNBC)
The doxorubicin cohort as an «immune induction» will be expanded in the stage II of the trial.
ORR%Max 3
lines
MBC
Rationale for Parp + Checkpoint Inhibitors
Jiao et al, Clin Cancer Res 2017
Rationale for combining PARP inhibitors+ immune checkpoint inhibitors
MEDIOLA, phase II basket studyof olaparib and durvalumab: gBRCAmut HER2- MBC (n=25)
Domcheck et al, SABCS 2017
TOPACIO: Niraparib + Pembrolizumab (n=46)
ORR: 28% all; 60% tBRCAmut, 36% PD-L1+
Stratum A: AdjuvantHigh-risk TNBC pts (>4 metastatic axillary lymph nodes)
who received curative intent surgery and completed adjuvant chemotherapy
Stratum B: Post-neoadjuvantTNBC pts treated with neoadjuvant chemotherapy and
with residual invasive breast cancer in the breast and/or in the axilla at surgery (except from ypT1micN0,
ypT1micN0i+, ypT0N0i+)
R
Avelumab for 1 year
Observation
Co-primary endpoints: 1. DFS in all-comers; 2. DFS in PD-L1+ patientsSecondary endpoints: OS, Safety, Biomarkers
n=335 (for the 1st co-primary endpoint)
Randomization 1:1 (after RT, if indicated) balanced for adjuvant and post-neoadjuvant patients.
Sponsor: DiSCOG - UNIPDPI: P. Conte
Amendment 2, v3.0: post-neoadjuvant CT for up to 6 months allowedprior to randomization
Dieci MV, Ann Oncol 2016
Immune markers and pCR (CherLOB)TILs and DFS in N9831 (n=1581)
Kim RS, ASCO 2018
Immune-related markers are associated with pCRand long term outcome in early HER2+ BC patients
PANACEA study: Pembrolizumab + Trastuzumab in
trastuzumab-resistant HER2+ ABC
Patients
Loi S et al, SABCS 2017
PANACEA study: patients characteristics
Loi S et al, SABCS 2017
PANACEA study: results overall and by PD-L1
Primary endpoint: ORR
PD-L1+ cohort: disease controlMedian duration of disease control: 11.1 months
Loi S et al, SABCS 2017
PD-L1+ cohort
PANACEA study: results overall and by PD-L1
and TILs
Loi S et al, SABCS 2017
Luen S, Lancet Oncol 2017 Dieci MV, Breast Cancer Res 2018
Heterogeneity of immune microenvironment in
HER2+ BC
CD8+ T cells
2016
Rugo H, Clin Cancer Res 2018
Pembrolizumab HR+/HER2-% PD-L1+/screened 19%
PD-L1 cut-off >1% tumor cells or any stromal staining
Evaluable pts 25 (PD-L1+)
ORR 3 (12%)
CR 0
PR 3 (12%)
SD 4 (16%)
PD 15 (60%)
Median duration of response 12 months
Median time to response 8 w
No assessment/Unavailable data 3 (12%)
Available data on immune checkpoint inhibitor
for HR+/HER2- mBC
STUDY DESIGN
ENGAGING THE IMMUNE SYSTEM TO IMPROVE THE EFFICACY OF
NEOADJUVANT CHEMO-ENDOCRINE THERAPY FOR PREMENOPAUSAL LUMINAL B BREAST CANCER PATIENTS.
Frozen tumorFFPE tumor
Plasma
FFPE (biopsy) Plasma
FFPE (surgery) Plasma
Sponsor: University of PadovaPI: P.Conte
Financial Support: BMS
Population: n=48 Primary endpoint: pCRSecondary endpoints: OR, molecular response (Ki67), PEPI score, conservative surgery rate, safety, biomarkers
Luminal B (HR+/HER2-, G3 or Ki67 >20%) premenopausalstage II-IIIA BC patients
Conclusions• TNBC:
• promising results from immune check point inhibitors + CT, especially for 1° line mTNBC (pending IMPASSION130 data)
• Combination with PARPi deserves further evaluation in BRCAmut HER2-
• Ongoing phase III neoadjuvant and adjuvant studies
• HER2+ BC:
• complex biologic interactions
• crowded landscape
• role of CT? T-DM1?
• earlier lines in advanced disease?
• HR+ BC:• crowded landscape• more results needed• combination with CDK4/6 inhibitors?
• Biomarkers:• TILs++• PD-L1+• TMB?• Host-related?→which role in CT+immunotherapy combos? →Need to develop non-invasive dynamic markers
• Other drugs/combinations on the horizon:• New compounds (new immune checkpoint inhibitors, new anti-HER2 moAbs, i.e. margetuximab)• Immune attractants/agonists• Combination with radiotherapy
Conclusions
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