PO.CT01.04 · 临床试验
An ensemble multi-omics framework for chemo de-escaltion NSCLC patients with PD-L1-low/negative disease in the PEOPLE phase II trial (NCT03447678)
作者与单位
摘要 Abstract
Advanced non-small cell lung cancer (NSCLC) patients with PD-L1-low/negative expression face uncertainty regarding optimal treatment selection, as some derive meaningful benefit from pembrolizumab monotherapy while others require chemotherapy escalation. This study leverages multi-omic profiling from the PEOPLE Phase II trial (NCT03447678) to discover immune biomarkers that identify patients likely to benefit from immunotherapy alone, supporting precision-guided chemo de-escalation strategies for fragile patients.Among 87 patients treated with front-line pembrolizumab, circulating immune profiling (CIP), tumor gene expression panels (GEP), and gut metagenomics were collected and log₂-normalized. Compared to previously published work on the PEOPLE dataset, a novel population of atypical monocytes (CD14+CD33+CD56+CD16− HLA-DR) was identified thought an unsupervised analysis and included in the analysis. Immune profiling data, including this population, alongside transcriptomic and microbial data, was integrated using an ensemble analytical framework comprising three complementary methods: unsupervised multi-omic factorization (MOFA2), supervised multi-block classification (DIABLO in mixOmics), and patient-level similarity network fusion (SNF) for molecular subtype discovery. Remarkable concordance emerged across all three methods. Long survivors consistently demonstrated enrichment for NK cells (CD56dim CD16+), myeloid dendritic cells (CD1C+), T cell activation markers (CD3D, CD6, CD69), B-cell signatures (CD79A, BLK), cytotoxic markers (GZMK), and health-promoting gut bacteria (Phocaeicola massiliensis with short-chain fatty acid production). Conversely, short survivors exhibited elevated atypical monocytes (CD14+CD33+CD56+), pmn-MDSCs, neutrophils/granulocytes, IL1A expression, and dysbiotic microbial profiles (Lactobacilli, R. timonensis, S. mutans). SNF successfully identified a discrete poor-prognosis cluster characterized by this myeloid-driven inflammatory signature. This ensemble multi-omic approach reveals biologically meaningful patient stratification that transcends PD-L1 status alone, identifying a subpopulation with superior immunotherapy response despite low PD-L1 expression. The novel CD14+CD33+CD56+ atypical monocyte population represents a promising immunosuppressive biomarker warranting independent validation. These findings support precision-guided chemo de-escalation in PD-L1-low/negative advanced NSCLC, with prospective validation and predictive modeling as immediate next steps for clinical deployment.
利益披露 Disclosure
L. M. Invernizzi, None..
G. Farhikhteh, None..
A. Rigamonti, None..
S. P. Abu, None..
D. Cosi, None..
C. Silvestri, None..
L. Agnelli, None..
T. Triulzi, None.
M. Brambilla,
MSD ).
Johnson & Johnson Travel.
Leo Pharma Travel.
Bristol Myers Squibb (BMS) Travel.
M. Francesconi, None..
F. Sgambelluri, None.
M. Occhipinti,
Astra Zeneca Other, Honoraria.
BMS Other, Honoraria.
MSD Other, Honoraria.
Astra Zeneca Other, Consulting.
BMS Other, Consulting.
MSD Other, Consulting.
Pfizer Other, Consulting.
Johnson & Johnson Other, Consulting.
Eli Lilly Travel.
Johnson & Johnson Travel.
M. C. Garassino,
Merck ), Travel.
AstraZeneca Travel, Other, Honoraria, consulting, data safety monitoring or advisory board participation.
MSD International GmbH Travel, Other, Honoraria, consulting.
Bristol Myers Squibb (BMS) Travel, Other, Honoraria, consulting.
Boehringer Ingelheim Italia S.p.A Travel, Other, Honoraria, consulting.
Celgene Travel, Other, Honoraria, consulting.
Eli Lilly Travel, Other, Honoraria, consulting, data safety monitoring or advisory board participation.
Ignyta Travel, Other, Honoraria, consulting.
Incyte Travel, Other, Honoraria, consulting.
Inivata Travel, Other, Honoraria, consulting.
MedImmune Travel, Other, Honoraria, consulting.
Novartis Travel, Other, Honoraria, consulting.
Roche Travel, Other, Honoraria, consulting.
Seattle Genetics Travel, Other, Honoraria, consulting.
Pfizer (MISP) Travel, Other, Honoraria, consulting, data safety monitoring or advisory board participation.
Foundation Medicine Travel, Other, Honoraria, consulting.
GSK Travel, Other, Consulting.
Spectrum Pharmaceuticals Other, Honoraria.
Mirati Other, Honoraria.
R. Mortarini, None.
F. De Braud,
AstraZeneca ), Other, Honoraria.
BoehringerIngelheim Travel, Other, Honoraria.
BMS ), Other, Honoraria.
Eli Lilly ), Other, Honoraria.
F. Hoffmann-La Roche ), Other, Honoraria.
Ignyta ), Other, Honoraria.
Merck Sharp and Dohme ), Other, Honoraria.
Merck Serono ), Other, Honoraria.
Novartis ), Other, Honoraria.
Pfizer ), Other, Honoraria.
C. Proto,
Italfarmaco Other.
AstraZeneca Travel, Other, Honoraria, advisory board.
BMS ), Travel.
Merck Sharp and Dohme Other, Honporaria, advisory board.
Janssen Travel, Other, Advisory board.
Roche ), Travel, Other, Honoraria, advisory board.
F. Trovò, None..
M. Ganzinelli, None.
G. Lo Russo,
Merck Sharp and Dohme ), Other, Honoraria.
Takeda ), Other, Honoraria.
Amgen ), Other, Honoraria.
Eli Lilly ), Other, Honoraria.
BMS ), Other, Honoraria.
Roche ), Other, Honoraria.
Italfarmaco ), Other, Honoraria.
Novartis ), Other, Honoraria.
Sanofi ), Other, Honoraria.
Pfizer ), Other, Honoraria.
AstraZeneca ), Other, Honoraria.
A. Prelaj,
Amgen Other, Advisory board, personal interest.
AstraZeneca ), Other, Advisory board, personal interest.
Bayer ), Other, Advisory board, personal interest.
Bristol Myers Squibb (BMS) ), Other, Advisory board, personal interest.
Daiichii Sankyo Other, Advisory board, personal interest.
Gilead Invited speaker, personal.
IQUVIA Other, Invited speaker, personal.
Italfarma Personnel training, personal interest.
Janssen Travel, Other, Advisory board, personal interest.
Lilly ), Other, Invited speaker.
MEDSIR Other, Invited speaker.
MSD ), Other, Advisory board, personal interest.
Novartis Other, Invited speaker.
Pfizer Other, Advisory board, invited speaker.
Roche Other, Invited speaker.