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?