학술논문
Pharmacometric modeling and machine learning analyses of prognostic and predictive factors in the JAVELIN Gastric 100 phase III trial of avelumab
Document Type
Report
Author
Source
CPT: Pharmacometrics & Systems Pharmacology. March 2022, Vol. 11 Issue 3, p333, 15 p.
Subject
Language
English
Abstract
Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Immune checkpoint inhibitors have limited antitumor activity in patients with gastric cancer or gastroesophageal junction cancer (GC/GEJC), but a subset [...]
: Avelumab (anti–PD‐L1) is an approved anticancer treatment for several indications. The JAVELIN Gastric 100 phase III trial did not meet its primary objective of demonstrating superior overall survival (OS) with avelumab maintenance versus continued chemotherapy in patients with advanced gastric cancer/gastroesophageal junction cancer; however, the OS rate was numerically higher with avelumab at timepoints after 12 months. Machine learning (random forests, SIDEScreen, and variable‐importance assessments) was used to build models to identify prognostic/predictive factors associated with long‐term OS and tumor growth dynamics (TGDs). Baseline, re‐baseline, and longitudinal variables were evaluated as covariates in a parametric time‐to‐event model for OS and Gompertzian population model for TGD. The final OS model incorporated a treatment effect on the log‐logistic shape parameter but did not identify a treatment effect on OS or TGD. Variables identified as prognostic for longer OS included older age; higher gamma‐glutamyl transferase (GGT) or albumin; absence of peritoneal carcinomatosis; lower neutrophil‐lymphocyte ratio, lactate dehydrogenase, or C‐reactive protein (CRP); response to induction chemotherapy; and Eastern Cooperative Oncology Group performance status of 0. Among baseline and time‐varying covariates, the largest effects were found for GGT and CRP, respectively. Liver metastasis at re‐baseline predicted higher tumor growth. Tumor size after induction chemotherapy was associated with number of metastatic sites and stable disease (vs. response). Asian region did not impact OS or TGD. Overall, an innovative workflow supporting pharmacometric modeling of OS and TGD was established. Consistent with the primary trial analysis, no treatment effect was identified. However, potential prognostic factors were identified.
: Avelumab (anti–PD‐L1) is an approved anticancer treatment for several indications. The JAVELIN Gastric 100 phase III trial did not meet its primary objective of demonstrating superior overall survival (OS) with avelumab maintenance versus continued chemotherapy in patients with advanced gastric cancer/gastroesophageal junction cancer; however, the OS rate was numerically higher with avelumab at timepoints after 12 months. Machine learning (random forests, SIDEScreen, and variable‐importance assessments) was used to build models to identify prognostic/predictive factors associated with long‐term OS and tumor growth dynamics (TGDs). Baseline, re‐baseline, and longitudinal variables were evaluated as covariates in a parametric time‐to‐event model for OS and Gompertzian population model for TGD. The final OS model incorporated a treatment effect on the log‐logistic shape parameter but did not identify a treatment effect on OS or TGD. Variables identified as prognostic for longer OS included older age; higher gamma‐glutamyl transferase (GGT) or albumin; absence of peritoneal carcinomatosis; lower neutrophil‐lymphocyte ratio, lactate dehydrogenase, or C‐reactive protein (CRP); response to induction chemotherapy; and Eastern Cooperative Oncology Group performance status of 0. Among baseline and time‐varying covariates, the largest effects were found for GGT and CRP, respectively. Liver metastasis at re‐baseline predicted higher tumor growth. Tumor size after induction chemotherapy was associated with number of metastatic sites and stable disease (vs. response). Asian region did not impact OS or TGD. Overall, an innovative workflow supporting pharmacometric modeling of OS and TGD was established. Consistent with the primary trial analysis, no treatment effect was identified. However, potential prognostic factors were identified.