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immune checkpoint inhibitors&
potentiele biomarkersbij
(triple negatief) mammacarcinoom
Pathologendagen, 21 Nov 2019
Marleen Kok MD PhD
Netherlands Cancer Institute, Amsterdam
Medical Oncology & Immunology
outline
• immunotherapy for metastatic TNBC
• IMPASSION-130 study
• potential biomarkers
• immunotherapy for ER+ and HER2+ MBC
• immunotherapy for early TNBC
HER2+~15%
what is triple negative breast cancer?
• no targeted treatments available
• women frequently under 50 at diagnosis
• metastatic disease: median survival only 8-13 months
BREAST CANCER
ER/PR+~70%
TNBC~15%
ER = estrogen receptor, PR = progesterone receptor, HR = hormone receptor.
more tumor-infiltrating lymphocytes (TIL) in TNBC
Adapted from: Sobral-Leite, …, Kok, de Visser, Schmidt. Oncoimmunology 2018
TIL= tumor infiltrating lymphocytes
(H&E staining)
Loi et al. JCO 2019
TILs are prognostic in TNBC
PD-1 blockade in TNBC
1. Dirix et al. BCRT 2017, 2. Adams et al. Annals Oncol 2018, 3. Emens et al. JAMA Onc. 2018, 4. Nanda et al. JCO 2016, 5. Adams et al. Ann. Oncol 2018, 6. Voorwerk et al. Nat Med 2019
Phase
Study Drug n Patient selection ORR
Ib Javelin 1 avelumab 58 - 5%
II Keynote-86A 2 pembrolizumab 170 - 5%
I Emens et al. 3 atezolizumab 116 (in part) PD-L1 positive 13%
I Keynote-12 4 pembrolizumab 27 PD-L1 positive 19%
II Keynote-86B 5 pembrolizumab 84 PD-L1 positive, first line 21%
II TONIC6 nivolumab 70 low LDH 20%
OS in PD-L1+ Population
PD-L1 IHC with clone SP142 (Ventana), scored on immune cells, cut-off 1%
Recent op ESMO: PD-L1 in IMpassion-130
Rugo et al. LBA20, ESMO 2019
Recent op ESMO: PD-L1 in IMpassion-130
Rugo et al. LBA20, ESMO 2019
Conclusions IMpassion130, anti-PDL1+nab-paclitaxel
• Interim (not pre-planned): significant OS benefit of 7 months
• Toxicity managable
• Relatively ‘good’ patient population(only 60% neoadjuvant chemo, DFI<12m excluded)
• ESMO 2019: SP142 (Ventana) has ’better’ predictive capacitycompared to 22C3 (CPS, DAKO) and SP263 (Ventana)
• NVMO (cie-BOM) advies volgt
introductie anti-PDL1 bij TNBC in NL
• PD-L1 IHC: • Gebruik SP142 IHC• Cut-off 1%• Pathologen uit 17 centra reeds getraind
• Registratie om data en weefsel te verzamelen wordt opgezet(Carolien van Deurzen-Erasmus MC)
triple B – first line mTNBC
Advanced TNBCFirst lineBRCA-like yes/no
Stratification(Neo-)adj treatment yes/no(Neo-)adj taxanes yes/noInstitution
n= 304
Dutch Breast Cancer GroupProf dr Sabine Linn
Rianne OosterkampDr Marleen Kok
outline
• immunotherapy for metastatic TNBC
• IMPASSION-130 study
• potential biomarkers
• immunotherapy for ER+ and HER2+ MBC
• immunotherapy for early TNBC
Design TONIC trial
nivolumab 3mg/kg, every 2 weeks
• metastatic TNBC (ER<10%, HER2 negative)
• max 3 lines of chemotherapy for metastatic disease
• accessible lesion for biopsy and radiation
• LDH < 2x ULN
• n=70 in stage I
‘Established’ predictors of response to anti-PD-1
Leonie Voorwerk (pathology: Hugo Horlings, Koen vd Vijver, Roberto Salgado) & Maarten Slagter
PD
-L1
imm
un
e c
ells
(IH
C)
CD
8 (
IHC
)TI
L (H
&E)
p<0.05
p<0.01
p<0.01
MSI
Le et al. Science et al. June 8, 2017
Le et al. Science et al. June 8, 2017
ORR 53%!Clinical benefit 77%48% Lynch syndrome
Kok et al.J Clin Oncol PO, accepted for publication
MSI in breast cancer is very rare, however…
Before start anti-PD1 After 12 cycles anti-PD1
2013 TNBC, pT1cN02016 metastases in stomach, lung and lymph nodesExtensive revision of biopsies: confirmed BC and MSI
TMB and PD1-blockade in TNBC
Molinero et al. SABCS 2017,. In line with: Samstein et al. Nat Gen 2019
Voorwerk et al. Nat Med 2019, Emens et al. SABCS 2018
BRCA1/2-mutated of BRCA-like tumors more sensitive to ICI?
outline
• immunotherapy for metastatic TNBC
• IMPASSION-130 study
• potential biomarkers
• immunotherapy for ER+ and HER2+ MBC
• immunotherapy for early TNBC
1. Rugo et al. CCR 2018, 2. Dirix et al. BCRT 2017, 3. Dirix et al. BCRT 2017, 4. Loi et al. Lancet Oncol 2019, 5. Chia et al. ASCO 2018
study agent n selection ORR
1 KEYNOTE-28 pembrolizumab 25 PD-L1+ 12%
2 Javelin avelumab 72 - 2.8%
ER+
HER2+study agent n selection ORR
3 Javelin avelumab 26 - 0%
4 PANACEA pembro+trastuzumab 46 PDL1+ 15%
5 durvalumab+tras 15 3+ lines 0%
anti-PD1/anti-PDL1 ER+ and HER2+ MBC
3 lobular breast cancers2/3 with partial response
anti-PDL1 for metastatic lobular breast cancer: GELATO-trial
• In metastatic ILC: relative high TMB (Foundation Medicine)
• Gene expression studies: immune-related subtype within ILC1,2
• Preclinical data: synergy platinum and anti-PDL11,3
• Phase II trial at NKI, UMCG, MUMC+ (and EMC)
1. Michaut et al. Sc Rep 2016, 2. Ciriello et al. Cell 2017, 3. Kersten et al. (de Visser lab, confidential)
outline
• immunotherapy for metastatic TNBC
• IMPASSION-130 study
• potential biomarkers
• immunotherapy for ER+ and HER2+ MBC
• immunotherapy for early TNBC
Immune system metastatic vs primary disease
Szekely et al. Ann Oncol 2018also in: Luen et al. Lancet Oncol 2017
anti-PD1 in I-SPY
Nanda et al. ASCO 2017
Recent ESMO: KEYNOTE-522
Schmid et al. ESMO 2019
Recent op ESMO: KEYNOTE-522
Schmid et al. ESMO 2019
Primary breast cancer, start with anti-PD1 monotherapy (BELLINI-trial in AvL)
• Nivolumab pre-operative or before neoadjuvant chemotherapy• For patients with >5% TILs (medullair, BRCA-mutated, MSI etc)• TNBC and luminal B
Can we identify a highly immunogenic subset of BCs that
respond sufficiently well to anti-PD1 to avoid standard toxic
chemotherapy?
studie-coordinator: Iris Nederlof
Conclusions
• Expected indication for anti-PDL1 for PD-L1-positive advanced TNBC
• PD-L1 is not an ideal biomarker and has some technical challengesWith upcoming indication, important that pathologists’ get trained(expert group per region?)
• TIL, CD8 also have predictive capacity in TNBC, TMB probably not
• Patients should be treated in the context of a clinical trial toenable more research: optimal combination, optimal biomarker etc
• Neoadjuvant anti-PD1 for early TNBC promising, worth referringpatients for trials especially tumors with high TIL/PDL1 or MSI
