Targeting the PD-1 pathway in pediatric solid tumors and brain tumors

Figures & data

Figure 1 Immune response to tumors.

Notes: (A) Dying tumor cells are taken up by antigen-presenting cells (eg, dendritic cells) and presented to T-cells (commonly in the lymph system) where they then undergo clonal expansion and trafficking into the tumor. (B) Activated cytotoxic T-cells proliferate, participate in generation of inflammatory and toxic cytokines, including fatal secretion of perforin and granzyme; following chronic stimulation checkpoint receptors on the T-cells are bound by their ligands and the T-cell response is terminated. Blocking the PD-1 and/or CTLA4 checkpoints with antibodies leads to activation/reactivation of T-cells so they generate an antitumor response.
Abbreviations: MHC, major histocompatibility complex; PD-1, programmed cell death-1; PD-L1, programmed death-ligand 1.

Figure 2 Escaping immune surveillance.

Notes: T-cells in the immune system recognize and eliminate immunogenic transformed cells. However, some cells do not express enough neoantigens to be recognized by the immune system, while others express ligands for checkpoint receptors on T-cells to terminate the immune response.

Table 1 Checkpoint inhibitors available in the USA and select inhibitors in advanced studies

Drug	Target	Indication	Stage of development
Ipilimumab	CTLA4	Melanoma	FDA approved
Tremulimumab	CTLA4	Head and neck	Phase III – NCT02369874
		Mesothelioma	Phase III – NCT01843374
		Non-small-cell lung cancer	Phase III – NCT02542293
Pembrolizumab	PD-1	Non-small-cell lung cancer	FDA approved
		Melanoma
		Head and neck cancer
Nivolumab	PD-1	Non-small-cell lung cancer	FDA approved
		Melanoma
		Renal cell cancer
		Head and neck cancer
		Hodgkin lymphoma
Pidilizumab	PD-1	Diffuse large B-cell lymphoma	Phase II – NCT02530125
		Multiple myeloma	Phase I/II – NCT02077959
PDR001	PD-1	Neuroendocrine tumors	Phase II – NCT02955069
Atezolizumab	PD-L1	Non-small-cell lung cancer	FDA approved
		Bladder cancer
Durvalumab	PD-L1	Head and neck cancer	Phase III – NCT02369874
		Non-small-cell lung cancer	Phase III – NCT02453282
Avelumab	PD-L1	Non-small-cell lung cancer	Phase III – NCT02576574
		Breast cancer	Phase III – NCT02926196
		Ovarian cancer	Phase III – NCT02580058

Abbreviations: FDA, Food and Drug Administration; PD-1, programmed cell death-1; PD-L1, programmed death-ligand 1.

Table 2 Review of select biomarker studies and their ability to enrich responding patient populations

Biomarker	Drug	Disease/setting	Cutoff	Outcome	Comment
Tumor PD-L1	Pembrolizumab^Citation59	NSCLC	1%–24%	OS – 10 mo	Automated IHC assay with antibody 22C3
		Mostly second line	25%–49%	OS – 10 mo	Food and Drug Administration-approved test – positive = TPS 50%+
			50%–74%	OS – 16 mo
			75%+	OS – 17 mo
	Nivolumab^Citation60	NSCLC second line	<5%	OS – 10 mo	IHC assay with antibody 28-8
		(nonsquamous histology)	5%+	OS – 19 mo
	Atezolizumab^Citation61	NSCLC	<1%	OS – 13 mo	SP142 assay
		Second line	>1%	OS – 16 mo
			>5%	OS – 16 mo
			>50%	OS – 21 mo
	Nivolumab^Citation62	Melanoma	<5%	PFS – 5 mo	IHC assay with antibody 28-8
		First line	>5%	PFS – 22 mo	From pooled analysis
	Pembrolizumab^Citation63	Melanoma	<1%	PFS – 3 mo	IHC assay with antibody 22C3
		Prior treatment	1%+	PFS – 12 mo
Inflammatory gene	Pembrolizumab^Citation64	Head and neck cancer	Positive predictive value	40%	Interferon gamma genes: CXCL9, CXCL10
Signature		Second line	Negative predictive value	95%	IDO1, INF gamma, HLA-DRA, and STAT1
	Atezolizumab^Citation65	NSCLC	Teff/INF high	OS – NR median follow-up ~15 mo	Teff/INF gamma gene signature
		Second line	Teff/INF low	OS ~10 mo	Determined by gene expression of CD8A GZMA, GZMB, INF gamma, EOMES, CXCL9 CXCL10 and TBX21
Mutational burden	Pembrolizumab^Citation66	NSCLC	High (above median)	ORR – 59%	Nonsynonymous
		Prior treatment	Low (below median)	ORR – 12	Exom sequencing with 9049 nonsynonymous, coding point mutations considered
	Pembrolizumab^Citation66	NSCLC	High (above median)	PFS – 14.5 mo	Total exonic mutations
		Prior treatment	Low (below median)	PFS – 4.1 mo
	Pembrolizumab^Citation24	Colorectal cancer	Mismatch repair deficient	ORR – 40%	Microsatellite instability analysis using an assay from Promega
		Second line	Mismatch repair proficient	ORR – 0%
Angiopoietin 2	PD-1 inhibitor^Citation25	Melanoma	Low baseline with small increase w/tx	OS =34.6 mo	Serum-based assay
		Second line	High baseline with high increase w/tx	OS =7.9 mo	Monitored serially – association with vascular endothelial growth factor

Abbreviations: INF, interferon; IHC, immunohistochemistry; mo, months; NSCLC, non-small-cell lung cancer; OS, overall survival; PD-1, programmed cell death-1; PD-L1, programmed death-ligand 1; PFS, progression-free survival.

Table 3 Ongoing trials of agents targeting the PD-1 or PD-L1 pathway for treatment of pediatric cancer

ClinicalTrials.gov identifier	Population	Agent	Other drugs	Design	Sponsor/comments
NCT02304458	Relapsed solid tumors	Nivolumab	+/−Ipilimumab	Phase I/II	COG
NCT02332668	Melanoma, PD-L1 positive solid tumors or lymphoma	Pembrolizumab	–	Phase I/II	35 institutions
NCT02359565	Recurrent high-grade glioma	Pembrolizumab	–	Phase I/II	PBTC
NCT02813135	Recurrent solid tumors	Nivolumab	Cyclophosphamide	Basket trial	European study
NCT02541604	Recurrent solid tumors	Atezolizumab	–	Phase I/II	Hoffmann-LaRoche
NCT03006848	Recurrent osteosarcoma	Avelumab	–	Phase II	St Jude

Abbreviations: COG, Children’s Oncology Group; PBTC, Pediatric Brain Tumor Consortium; PD-L1, programmed death-ligand 1; PD-1, programmed cell death-1.

BaasPGaronEBHerbstRSRelationship between level of PD-L1 expression and outcomes in the KEYNOTE-010 study of pembrolizumab versus docetaxel for previously treated, PD-L1-positive NSCLCJ Clin Oncol201634 Suppl; abstr 9015

 Google Scholar

BorghaeiHBrahmerJNivolumab in nonsquamous non-small-cell lung cancerN Engl J Med20163745493494

 PubMed Web of Science ®Google Scholar

RittmeyerABarlesiFWaterkampDAtezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trialLancet201738610066255265

 Google Scholar

LongGVLarkinJAsciertoPAPD-L1 expression as a biomarker for nivolumab (NIVO) plus ipilimumab (IPI) and NIVO alone in advanced melanoma (MEL): a pooled analysisESMO 2016 Congress in Copenhagen, Denmark2016 Suppl; Abstr 1112PD

 Google Scholar

KeffordRRibasAHamidOClinical efficacy and correlation with tumor PD-L1 expression in patients (pts) with melanoma (MEL) treated with the anti-PD-1 monoclonal antibody MK-3475J Clin Oncol201432 Suppl; abstr 3005

 Google Scholar

SeiwertTYBurtnessBMehraRSafety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trialLancet Oncol201617795696527247226

 PubMed Web of Science ®Google Scholar

FehrenbacherLSpiraABallingerMAtezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trialLancet2016387100301837184626970723

 PubMed Web of Science ®Google Scholar

RizviNAHellmannMDSnyderACancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancerScience2015348623012412825765070

 PubMed Web of Science ®Google Scholar

LeDTUramJNWangHPD-1 blockade in tumors with mismatch-repair deficiencyN Engl J Med2015372262509252026028255

 PubMed Web of Science ®Google Scholar

WuXGiobbie-HurderALiaoXAngiopoietin-2 as a biomarker and target for immune checkpoint therapyCancer Immunol Res201751172828003187

 PubMedGoogle Scholar