Assessment of TMB, PD-L1, and lymphocyte to monocyte ratio as predictive potential in a phase Ib study of sintilimab in patients with advanced solid tumors

Abstract

Background: Sintilimab is a humanized monoclonal antibody against the programmed cell death 1 (PD-L1). We aimed to assess the safety and activity of sintilimab monotherapy or in combination with chemotherapy in advanced solid tumors.

Methods: This phase Ib study included six cohorts. Cohort A-C were sintilimab monotherapy settings, and enrolled pretreated patients (2/3 L cohorts). Cohort D-F were treatment-naïve patients (1 L cohorts), and received sintilimab plus different chemotherapies. The primary endpoints were safety and objective response rate (ORR). Exploratory endpoints were potential biomarkers for the prognosis after treatment, such as tumor mutation burden scores (TMB), PD-L1 and lymphocyte-to-monocyte ratio (LMR).

Results: The ORR was 14.6% in the 2/3 L cohorts (n=146), and 73.2% in the 1 L cohorts (n=61). The incidence of grade 3-4 adverse events occurred in 55 patients (37.7%) in 2/3 L cohorts, and in 38 (62.3%) in 1 L cohorts. 157 patients had available TMB scores, and in 2/3 L cohorts, patients in the high TMB groups (TMB≥10) showed a longer progression-free survival (PFS) and overall survival (OS) than those in the low TMB groups (TMB<10). No significant differences in PFS and OS were observed across different PD-L1 groups in both 1 L and 2/3 L cohorts. A high LMR was significantly associated with an improved PFS in 1 L cohorts (P=0.022).

Conclusion: Sintilimab alone or combined with chemotherapy had a tolerable safety profile in solid tumors. The combination therapy showed a favorable activity with advanced non-small cell lung cancer and gastric or esophagogastric junction adenocarcinoma. LMR might be a prognostic factor for the combination regimen in these patients.

Trial registration: ClinicalTrials.gov, number NCT02937116. Registered 18 October 2016.

Keywords: Phase I; Sintilimab; lymphocyte-to-monocyte ratio; programmed cell death 1; solid tumors; tumor mutation burden.

Conflict of interest statement

None.

AJCR Copyright © 2021.

Figures

Figure 1

Flowchart of the study.

Figure 2

Outcomes of the patients (A) Progression-free survival in the cohort A, B and C (≥2 L), the cohort D, E and F (1 L). (B) Overall survival in the cohort A, B and C (≥2 L), the cohort D, E and F (1 L). (C-E) TMB analysis of the cohort A, B and C. Between TMB high (≥10) and low (

Figure 3

Shrinkage of tumor size.

Figure 4

PD-L1 analysis of the cohort A, B and C and cohort D, E and F. Between PD-L1 positive (≥1) and negative (

Figure 5

TMB analysis of the cohort D, E and F. Between TMB high (≥10) and low (

Figure 6

Pathway mutation analysis of the cohort A, B and C. Differential mutated pathways between two groups split by mPFS (A) or mOS (B) were shown. The leftmost P-value represents the significance of differential pathways (Fisher’s exact test).

Figure 7

Pathway mutation analysis of the cohort D, E and F. Differential mutated pathways between two groups split by mPFS were shown. The leftmost P-value represents the significance of differential pathways (Fisher’s exact test).

Figure 8

LMR results (A) Overall survival for all participants with low and high LMR. (B) Overall survival in the group of first line participants with low and high LMR. (C) Overall survival in the group of second line participants with low and high LMR. (D) Progression-free survival for all participants with low and high LMR. (E) Progression-free survival in the group of first line participants with low and high LMR. (F) Progression-free survival in the group of second line participants with low and high LMR.