LBA57 - MHC-II antigen presentation pathway as a predictive biomarker for sintilimab plus chemotherapy in first-line treatment of locally advanced or metastatic non-squamous non-small cell lung cancer (nsq-NSCLC)

Background

Immunotherapy plus chemotherapy is a promising treatment for first-line nsq-NSCLC. However, predictive biomarkers for this immuno-combination remain to be elucidated.

Methods

In a randomized, double-blind, phase III study evaluating the efficacy of sintilimab, an anti-PD-1 antibody, plus pemetrexed and platinum (Chemo) as first-line treatment (ORIENT-11), 397 patients with locally advanced or metastatic nsq-NSCLC were randomized (2:1 ratio) to receive either sintilimab plus Chemo (Combo) or placebo plus Chemo. The primary endpoint was progression-free survival (PFS). RNA sequencing was conducted on 248 baseline tumor biopsies (168 in Combo and 80 in Chemo).

Results

Combo group showed superiority to Chemo group in PFS (HR=0.48, 95%CI: 0.36-0.64, p<0.0001). Survival analysis showed that top 20 genes (Ranked by P-value) including ITGB2, ADAP2, MPP1, PIK3AP1, GBGT1, RAB27A, CD180, NEK6, RLN3, CD84, CASP8, DRAM1, HLA-DMB, OTULIN, HELZ, VDR, HLA-DPA1, MX2, FUCA1, MKRN1 were significantly associated with good efficacy of Combo treatment (mean HR 0.26, P<0.0001) but not Chemo treatment except for NEK6 (HR, 0.38; 95% CI, 0.14−0.50; P=0.0047). In line with this, we found that the entire signature score of MHC-II antigen presentation pathway was more significantly associated with clinical efficacy of Combo (HR, 0.51; 95% CI, 0.28-0.91; P=0.0230) than that of MHC-I (HR, 0.70; 95% CI, 0.39−1.25; P=0.2230). It was further validated that cells with MHC-II presentation capability also contributed to the longer PFS in the Combo group, e.g. macrophage (HR, 0.48; P=0.0120), activated dendritic cell (HR, 0.46; P=0.0114), immature dendritic cell (HR, 0.47; P=0.0134), or immature B cell (HR, 0.51; P=0.0245). Finally, multiplex immunohistochemistry data from 57 patients demonstrated concordance between RNA and protein expression and that higher level of CD68 protein was associated with good outcome (HR, 0.42; 95% CI, 0.12-1.54; P=0.1930).

Conclusions

Signature of MHC-II antigen presentation was significantly associated with longer PFS in patients receiving immune-combination therapy and could be served as a predictive biomarker.

Clinical trial identification

NCT03607539.

Editorial acknowledgement

Legal entity responsible for the study

Innovent Biologics, Inc.

Funding

Innovent Biologics Inc. and Eli Lilly and Company.

Disclosure

J. Sun, H. Zhou, S. Wang, W. Xu, B. Peng: Full/Part-time employment: Innovent Biologics Inc. L. Zhang: Research grant/Funding (self): Eli Lilly and Company; Research grant/Funding (self): Pfizer. All other authors have declared no conflicts of interest.