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Checkpoint Inhibitors in MSI+ Malignancies in Children & Adults
Dr Lynley MarshallMB BCh, DCH, MRCPCH, PhD
The Royal Marsden & The Institute of Cancer Research
1
Targeting the immune checkpoints for cancer immunotherapy
PD-1/PD-L1 pathway thus plays a critical role in tumour evasion and is an
attractive target for therapeutic intervention – ‘recognising tumour as
foreign’.
• PD-1 and CTLA-4 are immune
checkpoints which are
upregulated and present on the
surface of T cells in certain
cancers, dampening T-cell
activation & immune response to
tumour; contributing to the
tumour’s ability to evade the
immune system.
• Inhibiting a checkpoint
(“releasing the brakes”) on the
immune system may enhance
the anti-tumour T-cell immune
response.
Modified from Sharma et al
Immune checkpoint inhibitors & stages of development
Wagner, Oncotargets & Therapy 2017
Challenges for Paediatrics
• Multiple PD-(L1) inhibitors in clinical development:
- no overview of the whole class of drugs in advance
- how do we identify the best in class overall/for a given disease?
• Paediatric cancers as a group are rare; relatively small (& finite)
number of relapsed/refractory patients available for early phase
trials
• How do we identify the best in class agents rapidly?
• How do we optimise design & efficiency of studies?
Preclinical Early phase Front line combinations
• How do we achieve mechanism-of-action based drug
development incorporating robust predictive &/or
pharmacodynamic biomarkers (where possible)?
Targeting the immune checkpoints for cancer immunotherapy: PD-L1 expression as a biomarker
Pembrolizumab oncology indications in adults: studies in melanoma,,
NSCLC, breast cancer, head and neck cancer, bladder cancer, prostate cancer,
GI cancers, malignant glioma, multiple myeloma, renal cancer, sarcomas, and
Hodgkin lymphoma – single agent & combinations
• Attractive as paediatric agents
• Paediatric tumours have lower mutational burden compared to adult
cancers
• Efficacy of anti-PD-1 in pre-clinical neuroblastoma models
• High levels of PD-L1 in (some) paediatric tumours
Are PD-1 & PD-L1 relevant targets in paediatric cancers?
Courtesy of Dr Juliet Gray
7
Non-randomized, open-label, multicentre,
phase 1/2 study
–– Phase 1: dose-finding and dose-
confirmation cohorts
–– Phase 2: tumor expansion cohort
8
Results
Geoerger, ASCO 2017PD-L1+ in 32.1% of samples tested
9
Results
Geoerger, ASCO 2017ORR 8% in PD-L1+ patient group
iMATRIX- atezo: Tumour cohort overview
Cohort Name Cohort Disease
01 Ewing Sarcoma
02 Hodgkin Lymphoma
03 Neuroblastoma
04 Non-Hodgkin Lymphoma
05Non-rhabdomyosarcoma soft tissue
tumor
06 Osteosarcoma
07Rhabdomyosarcoma
08 Wilms' Tumor
09
Other tumor types with documented expression of PD-L1 pathway either on tumor cells or
immune cells (Tumors not included in the list above)
10
Other tumor types without known or expected PD-L1 pathway
involvement (Tumors not included in the list above)
11 Rhabdoid tumour
12 ATRT
11
Results
Geoerger, ASCO 2017ORR 4.8% in unselected patient group
12
Better Biomarkers?
Immune checkpoint inhibitors in hypermutant GBM
Mutational burden of paediatric tumours
Mutational burden
Number of somatic non-synonymous coding mutations per sample are plotted on a log scale for a variety of
paediatric and adult cancer types, and ordered by increasing median (red bar).
From data analysed in Jones et al, Nature Reviews Cancer, 2014
Paediatric Studies of PD1/PD-L1 inhibitors
Study &
Sponsor
Compound Indication Ages Start/End Status
NCT02304458
ADVL1412
NCI
Nivolumab+/-
Ipilimumab
Recurrent or Refractory
Solid Tumours or
Sarcomas
1-18yrs (30) Feb 2015-
Oct 2010
Recruiting
(ASC0 2017)
NCT02332668
KEYNOTE-051
Merck
Pembrolizumab Advanced Melanoma or
Advanced, Relapsed, or
Refractory PD-L1-Positive
Solid Tumours or
Lymphoma; Hodgkin’s and
MSI-High tumour
cohorts added
6months to
< 18 years
Mar 2015-
Sep 2022
Recruiting
(ASCO 2017)
NCT02359565
NCI
Pembrolizumab Recurrent, Progressive, or
Refractory High-Grade
Gliomas, Diffuse Intrinsic
Pontine Gliomas, or
Hypermutated Brain
Tumours
1-29 years May 2015-
April 2018
Recruiting
NCT02541604
iMATRIX
Hoffman-La
Roche
Atezolizumab Relapsed/refractory solid
tumours
<30 years Nov 2015-
Jan 2022
Recruiting
(ASCO 2017)
NCT02813135
ESMART
Gustave
Roussy
Nivolumab +
Cyclophosphamide
+/- Radiotherapy
Relapsed/refractory solid
tumours
<18 years June 2016-
Dec 2020
Recruiting
(arm G
completed)
Study &
Sponsor
Compound Indication Ages Start/End Status
NCT02793466
Children’s
Hospital LA
Durvulumab Relapsed or Refractory
Solid Tumours,
Lymphoma, and CNS
Tumours
1-<18 years Jul 2016 –
Dec 2018
Recruiting
NCT02901145
Hadassah
Medical Org,
Israel
Nivolumab Progressive/Relapsed
Solid Tumours
1-21 years Nov 2016-
Nov 2019
Recruiting
NCT03006848 Avelumab Progressive Osteosarcoma 12-29 years Feb 2017 –
May 2021
Recruiting
NCT02927769
(CheckMate-
744)
BMS
Nivolumab +
Brentuximab
Vedotinin
Hodgkin’s Lymphoma at 1st
relapse
5-30 years Mar 2017-
Mar 2021
Recruiting
PENGUIN
(UMIN0000264
97)
BMS
Nivolumab Malignant solid tumours or
Hodgkin lymphoma
1-18 years;
1-24 years
April 2017 –
?
Recruiting
NCT02992964
The Hospital
for Sick
Children,
Toronto
Nivolumab Hypermutant Cancers 1-18 years Apr 2017 –
Sep 2021
Recruiting
NCT03130959
(CheckMate-
908)
BMS
Nivolumab +/-
Ipilimumab
High Grade Primary CNS
Malignancies
June 2017
6 months-
21 years
Jun 2017-
Jun 2021
Recruiting
Conclusions:
• Multiple PD-(L1) inhibitors in clinical development
• PIPs ongoing for several
• Safe & well-tolerated in children
• Activity in paediatrics disappointing in unselected patient groups,
but optimal (biomarker-based) selection of patients is expected to
change this.
• We need to extrapolate from the adult experience: focus on MSI-
high tumours and those with high mutational burden
• In paediatrics this is likely to include gliomas, osteosarcomas, soft
tissue sarcomas, others….
• Combinations….
For Children & Adolescents?