1478P - Circulating pre-treatment T-Cell receptor repertoire as a predictive biomarker in non-small cell lung cancer patients treated with pembrolizumab

Background

The circulating T-cell receptor (TCR) repertoire is a dynamic representation of overall immune responses in an individual.

Methods

We prospectively collected baseline blood from patients treated with first-line pembrolizumab monotherapy (N=48) or in combination with chemotherapy (N=65), and sequenced the Complementarity Determining Region 3 (CDR3) of the TCR beta chain from whole blood-derived DNA. TCR repertoire metrics were correlated with clinical benefit (objective response or stable disease ≥ 6 months), progression-free survival (PFS), overall survival (OS) and immune-related adverse events (irAEs). We built a logistic regression model combining all four TCR-β repertoire metrics to predict clinical benefit. Receiver operating characteristic (ROC) analysis of the resulting logistic regression model probabilities was used to identify the best cut-off values to maximise sensitivity and predict clinical benefit.

Results

We observed an association between a reduced number of unique TCR clones and clinical benefit among patients treated with pembrolizumab monotherapy (RR=2.86, 95%CI 1.04-8.73, P=0.039). For patients treated with pembrolizumab plus chemotherapy, increased number of unique clones (HR=2.96, 95%CI 1.28-6.88, P=0.012) and Shannon Diversity (HR=2.73, 95%CI 1.08-6.87, P=0.033), and reduced evenness (HR=0.43, 95%CI 0.21-0.90, P= 0.025) and convergence (HR= 0.41, 95%CI 0.19-0.90, P=0.027) were associated with improved PFS, while only increased number of unique clones (HR= 4.62, 95%CI 1.52-14.02, P=0.007) was associated with improved OS. Logistic regression models combining the TCR repertoire metrics improved the prediction of clinical benefit and was strongly associated with OS (HR=0.20, 95%CI 0.05-0.76, P<0.0001). Reduced TCR conversion was associated with increased irAEs needing systemic steroid treatment (P=0.04).

Conclusions

Pre-treatment circulating TCR repertoire might serve as a predictive biomarker for clinical outcomes among patients with advanced NSCLC treated with pembrolizumab alone or combined with chemotherapy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Edith Cowan University.

Funding

This work was supported by an Oncomine Clinical Research Grant from Thermo Fisher Scientific; a grant from the clinical trial unit at Fiona Stanley Hospital; a research grant from the Lung Foundation Australia – Ellen Yates Memorial Grant in Aid for Lung Cancer Research; a fellowship to A.A. from the International Lung Cancer Foundation; and a fellowship to E.S.G. from the Cancer Council of Western Australia.

Disclosure

E.S. Gray: Financial Interests, Personal and Institutional, Funding, also Invited Speaker: Thermo Fisher Scientific; Financial Interests, Personal, Funding, also Invited Speaker: MSD. M. Millward: Financial Interests, Personal, Advisory Board: BeiGene Australia Pty Ltd, Bristol Myers Squibb Australia Pty Ltd, AstraZeneca Australia Pty Ltd, The Limbic, Eli Lilly Australia Pty Ltd, IQVIA Australia Pty Ltd, Amgen Australia Pty Ltd, Merck Pte Ltd, Pfizer Australia Pty Ltd, Guardant Health, Roche Products Pty Ltd; Financial Interests, Personal, Full or part-time Employment, Employee: University of Western Australia; Financial Interests, Personal, Other, Consultant: Linear Clinical Research; Financial Interests, Institutional, Local PI, Trial payments to Institution: Bristol Myers Squibb, Genentech/Roche, BeiGene, Eli Lilly, Albion Laboratories, Akeso Biopharma, AbbVie, Five Prime Therapeutics, Dizal Pharma, Maxinovel, Amgen, Atridia, INXMED, Alpine Immune Sciences, Turning Point Therapeutics, Impact Therapeutics, Kinnate Biopharma, Rely Therapeutics, GenFleet Therapeutics, Vivace Therapeutics, Eucure Biopahrma, InventisBio, Cullinan Oncology, Tyra Biosciences, Axelia Oncology; Non-Financial Interests, Other, Scientific Advisory Committee member: Thoracic Oncology Group Australasia. All other authors have declared no conflicts of interest.