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

Abstract

BackgroundThe 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.MethodsGenomic 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).ResultsA 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.ConclusionsWe 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 numberNCT03816553.

Efficacy and Safety of Sintilimab Plus Anlotinib for PD-L1–Positive Recurrent or Metastatic Cervical Cancer: A Multicenter, Single-Arm, Prospective Phase II Trial

“…Interestingly, genetic alterations in the PI3K/AKT pathway are more common in patients with SCC than in patients with adenocarcinoma (55.9% v 0%), which is similar to the CLAP study (80.9% v 45.5%; P = .05). 26 Furthermore, significantly more patients with altered PIK3CA responded to sintilimab plus anlotinib than their wild-type counterparts, with a better PFS, suggesting an intimate interplay between CA histology and aberrant PI3K-AKT signaling in shaping response to antiangiogenic therapy plus immunotherapy.…”

Genomic landscape, immune characteristics and prognostic mutation signature of cervical cancer in China

“…PIK3CA gene alterations were considerably higher in SCC (49%) than in AC (15%). The secondary analysis of CLAP trial also suggested that same result [ 20 ]. PIK3CA mutations occurred most frequently in the overall patient group, and the mutation rate in our study was higher than the rates in previous studies of cervical carcinoma from the Netherlands (20%), France (27%), Latin America (28–33%), the USA (31%) and Norway (15%) [ 3 , 21 – 24 ].…”

“…Nusrat and other researchers recently reported that microsatellite stable colorectal cancer patients with PIK3CA mutations benefited from immunotherapy [ 27 ]. Another study showed that PIK3CA mutations were associated with the response to immunotherapy in cervical cancer [ 7 ]. However, only 32 patients were included in this analysis.…”

Characterization of the Genomic Landscape in Cervical Cancer by Next Generation Sequencing

“…PIK3CA and MTOR were the most frequently mutated genes, demonstrating that the PI3K/Akt/mTOR signaling pathway is commonly activated in cervical cancer [ 16 ]. Previous studies revealed PIK3CA mutation is frequent in cervical cancer, and is associated with a poor OS and PFS [ 8 , 20 , 21 , 22 , 23 ]. PIK3CA was mutated in 14% cervical squamous cell carcinoma patients in the study by Ojesa et al, Genomic profiling of advanced cervical cancer in the CLAP trial also showed a higher PFS in women with mutated PIK3CA receiving second line or later camrelizumab plus apatinib [ 24 ].…”