PDCD1 Polymorphisms May Predict Response to Anti-PD-1 Blockade in Patients With Metastatic Melanoma

被引：14

作者：

Parakh, Sagun ^{[1
,2
,3
]}

Musafer, Ashan ^{[2
,3
]}

Paessler, Sabrina ^{[2
]}

Witkowski, Tom ^{[2
,3
]}

Suen, Connie S. N. Li Wai ^{[4
]}

Tutuka, Candani S. A. ^{[2
]}

Carlino, Matteo S. ^{[5
,6
,7
]}

Menzies, Alexander M. ^{[7
,8
,9
]}

Scolyer, Richard A. ^{[7
,10
,11
,12
]}

Cebon, Jonathan ^{[1
,2
,3
]}

Dobrovic, Alexander ^{[2
,3
]}

Long, Georgina V. ^{[7
,8
,9
,13
]}

Klein, Oliver ^{[1
,2
]}

Behren, Andreas ^{[2
,3
,14
]}

机构：

[1] Austin Hlth, Med Oncol Unit, Melbourne, Vic, Australia

[2] Olivia Newton John Canc Res Inst, Melbourne, Vic, Australia

[3] La Trobe Univ, Sch Canc Med, Melbourne, Vic, Australia

[4] La Trobe Univ, Dept Math & Stat, Melbourne, Vic, Australia

[5] Westmead Hosp, Dept Med Oncol, Sydney, NSW, Australia

[6] Blacktown Hosp, Dept Med Oncol, Sydney, NSW, Australia

[7] Univ Sydney, Melanoma Inst Australia, North Sydney, NSW, Australia

[8] Royal North Shore Hosp, Dept Med Oncol, Sydney, NSW, Australia

[9] Mater Hosp, Dept Med Oncol, Sydney, NSW, Australia

[10] Royal Prince Alfred Hosp, Tissue Pathol & Diagnost Oncol, Sydney, NSW, Australia

[11] NSW Hlth Pathol, Sydney, NSW, Australia

[12] Univ Sydney, Fac Med & Hlth, Sydney, NSW, Australia

[13] Macquarie Univ, Dept Clin Med, Sydney, NSW, Australia

[14] Univ Melbourne, Dept Med, Melbourne, Vic, Australia

来源：

FRONTIERS IN IMMUNOLOGY | 2021年 / 12卷

基金：

英国医学研究理事会;

关键词：

metastatic melanoma; PD1; polymorphism; predictive biomarker; immunotherapy; CELL LUNG-CANCER; SINGLE NUCLEOTIDE POLYMORPHISM; CHECKPOINT BLOCKADE; PD-L1; EXPRESSION; T-CELLS; ASSOCIATION; NIVOLUMAB; SURVIVAL; THERAPY; PEMBROLIZUMAB;

D O I：

10.3389/fimmu.2021.672521

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

A significant number of patients (pts) with metastatic melanoma do not respond to anti-programmed cell death 1 (PD1) therapies. Identifying predictive biomarkers therefore remains an urgent need. We retrospectively analyzed plasma DNA of pts with advanced melanoma treated with PD-1 antibodies, nivolumab or pembrolizumab, for five PD-1 genotype single nucleotide polymorphisms (SNPs): PD1.1 (rs36084323, G>A), PD1.3 (rs11568821, G>A), PD1.5 (rs2227981, C>T) PD1.6 (rs10204225, G>A) and PD1.9 (rs2227982, C>T). Clinico-pathological and treatment parameters were collected, and presence of SNPs correlated with response, progression free survival (PFS) and overall survival (OS). 115 patients were identified with a median follow up of 18.7 months (range 0.26 - 52.0 months). All were Caucasian; 27% BRAF V600 mutation positive. At PD-1 antibody commencement, 36% were treatment-naive and 52% had prior ipilimumab. The overall response rate was 43%, 19% achieving a complete response. Overall median PFS was 11.0 months (95% CI 5.4 - 17.3) and median OS was 31.1 months (95% CI 23.2 - NA). Patients with the G/G genotype had more complete responses than with A/G genotype (16.5% vs. 2.6% respectively) and the G allele of PD1.3 rs11568821 was significantly associated with a longer median PFS than the AG allele, 14.1 vs. 7.0 months compared to the A allele (p=0.04; 95% CI 0.14 - 0.94). No significant association between the remaining SNPs and responses, PFS or OS were observed. Despite limitations in sample size, this is the first study to demonstrate an association of a germline PD-1 polymorphism and PFS in response to anti-PD-1 therapy in pts with metastatic melanoma. Extrinsic factors like host germline polymorphisms should be considered with tumor intrinsic factors as predictive biomarkers for immune checkpoint regulators.

引用

页数：7