Genomic profiling of advanced cervical cancer to predict response to programmed death-1 inhibitor combination therapy: a secondary analysis of the CLAP trial

Abstract

Background: The Camrelizumab Plus Apatinib in Patients with Advanced Cervical Cancer trial was a single-arm, phase II study that showed promising activity of the programmed death-1 (PD-1) inhibitor camrelizumab plus the vascular endothelial growth factor receptor-2 inhibitor apatinib in patients with advanced cervical cancer. However, the predictive biomarkers for treatment outcomes are unknown. In this study, we aimed to identify potential predictors of treatment response in PD-1 inhibitor combination therapy.

Methods: Genomic profiling was performed on patients with available biopsy or surgical samples by targeted next-generation sequencing of 425 cancer-related genes in this preplanned, secondary analysis. Somatic alterations, including all non-synonymous mutations, and tumor mutational burden (TMB) were assessed for their predictive values in objective response rate, progression-free survival (PFS), and overall survival (OS).

Results: A subset of 32 patients was included in this analysis. Top altered genes included PIK3CA (43.8%), STK11 (25%), FBXW7 (15.6%), and PTEN (15.6%). The PI3K/AKT pathway was among the most frequently dysregulated pathways, and its genetic alterations were identified in 68.8% of patients. PIK3CA (PFS HR 0.33, p=0.05; OS HR 0.23, p=0.04) and PTEN (PFS HR 3.71e-09, p=0.05; OS HR 3.64e-09, p=0.08) alterations were associated with improved outcomes. PI3K/AKT pathway genetic alterations showed improved predictive power compared with either PIK3CA or PTEN alterations alone (PFS HR 0.33, p=0.03; OS HR 0.25, p=0.02), while ERBB3 mutations (PFS HR 34.9, p<0.001; OS HR 19.8, p<0.001) correlated with poor survival. TMB-high (≥5 mut/Mb) was associated with prolonged PFS (HR 0.26, p<0.01) and OS (HR 0.31, p=0.05). Multivariate analysis showed ERBB3 mutations (PFS p=0.01, OS p<0.001), PD-L1 positive (PFS p=0.01, OS p=0.05), and high TMB (PFS p=0.01, OS p=0.05) remained significantly associated with survival.

Conclusions: We uncovered that genetic alterations in PIK3CA, PTEN, ERBB3, and PI3K/AKT pathway, as well as TMB, could be novel predictive biomarkers in patients with cervical cancer treated with PD-1 inhibitor combination therapy.

Trial registration number: NCT03816553.

Keywords: combination; drug therapy; gene expression profiling; genetic markers; immunotherapy.

Conflict of interest statement

Competing interests: YS, DZ, JZ and JCY are employees of Nanjing Geneseeq Technology Inc. All the other authors have declared no conflicts of interest.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

Distribution of genetic alterations with regard to clinical characteristics, response to treatment, and TMB (A). Association between genetic alterations and histological subtypes (B). CNV, copy number variation; irAE, immune-related adverse event; AC, adenocarcinoma; SCC, squamous cell carcinoma; TMB, tumor mutational burden; *

Figure 2

Kaplan-Meier curves of progression-free survival in patients with PIK3CA mutations and wild type (A), PTEN alteration and wild type (C), and ERBB3 mutations and wild type (E). Kaplan-Meier curves of overall survival in patients with PIK3CA mutations and wild type (B), PTEN alteration and wild type (D), and ErbB3 mutations and wild type (F).

Figure 3

Cut-off selection of TMB associated with PFS (A). Association between TMB levels and ORR (B). Kaplan-Meier curves of PFS (C) and overall survival (D) in patients with high TMB and low TMB. ORR, objective response rate; PFS, progression-free survival; TMB, tumor mutational burden. *

Figure 4

Distribution of genetic alterations with regard to the occurrence of immune-related adverse events. CNV, copy number variation.