Reference Detail

Ref Type

Journal Article

PMID

(29902298)

Authors

Goodman AM, Piccioni D, Kato S, Boichard A, Wang HY, Frampton G, Lippman SM, Connelly C, Fabrizio D, Miller V, Sicklick JK, Kurzrock R

Title

Prevalence of PDL1 Amplification and Preliminary Response to Immune Checkpoint Blockade in Solid Tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
JAMA oncology			2018 Jun 14	1237-1244	JAMA Oncol

URL

Abstract Text

Copy number alterations in programmed cell death ligand 1 (PDL1 or CD274), programmed cell death 1 ligand 2 (PDCD1LG2 or PDL2), and Janus kinase 2 (JAK2) genes (chromosome 9p24.1) characterize Hodgkin lymphoma, resulting in high response rates to programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade. The prevalence and utility of PDL1 amplification as a response biomarker to PD-1/PD-L1 blockade are unknown in other tumors.To examine the prevalence of PDL1 amplification and its utility as a response biomarker to PD-1/PD-L1 blockade in solid tumors.This retrospective study (October 1, 2012, to October 1, 2017) used a deidentified tumor database from a commercial company and annotated clinical records from a subset of patients treated at a university tertiary referral center. The study analyzed 118 187 tumors from the deidentified database, including a clinically annotated subgroup of 2039 malignant tumors.Comprehensive genomic profiling was performed on all samples to determine PDL1 amplification, microsatellite instability, and tumor mutational burden (TMB). A subset of patients was treated with PD-1/PD-L1 blockade.The prevalence of PDL1 amplification was determined among 118 187 patient samples that underwent next-generation sequencing. Solid tumors treated with checkpoint blockade were evaluated for response and progression-free survival (PFS).Of the 118 187 deidentified tumor samples, PDL1 amplifications were identified in 843 (0.7%), including more than 100 types of solid tumors. Most PDL1-amplified tumors (84.8%) had a low to intermediate TMB. PDL1 amplification did not always correlate with high-positive PD-L1 expression by immunohistochemical analysis. Six of 9 patients (66.7%) from 1 center with PDL1-amplified solid tumors had objective responses after checkpoint blockade administration. The median PFS among all treated patients was 15.2 months. Responders included 1 patient with glioblastoma (PFS, ≥5.2 months), 2 patients with head and neck squamous cell cancer (PFS, ≥9 and 15.2 months), 2 patients with metastatic basal cell cancer (PFS, 3.8 and ≥24.1 months), and 1 patient with urothelial cancer (PFS, ≥17.8 months).The results of this study suggest that PDL1 amplification occurs in a small subset of malignant tumors. Additional large-scale, prospective studies of PDL1-amplified cancers are warranted to confirm the responses to checkpoint blockade described herein, even in the absence of microsatellite instability, high PD-L1 expression, and a high TMB.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CD274 amp	Advanced Solid Tumor	predicted - sensitive	unspecified PD-1 antibody	Case Reports/Case Series	Actionable	In a clinical study, 66.7% (6/9) of advanced solid tumor patients harboring CD274 amplification demonstrated an objective response when treated with a PD-1/PD-L1 monotherapy (5 patients), a PD-1/PD-L1 therapy combined with an investigational drug (3 patients), or a combination of an anti-PD-1 and anti-CTLA4 therapy (1 patient) (PMID: 29902298).	29902298
CD274 amp	Advanced Solid Tumor	predicted - sensitive	unspecified PD-L1 antibody	Clinical Study	Actionable	In a clinical study, 66.7% (6/9) of advanced solid tumor patients harboring CD274 amplification demonstrated an objective response when treated with a PD-1/PD-L1 monotherapy (5 patients), a PD-1/PD-L1 therapy combined with an investigational drug (3 patients), or a combination of an anti-PD-1 and anti-CTLA4 therapy (1 patient) (PMID: 29902298).	29902298