Rilotumumab Exposure–Response Relationship in Patients with Advanced or Metastatic Gastric Cancer

Abstract

Purpose: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor. In a randomized phase II study, trends toward improved survival were observed with rilotumumab (7.5 or 15 mg/kg) plus epirubicin, cisplatin, and capecitabine (ECX) versus placebo plus ECX in gastric/gastroesophageal junction (GEJ) cancer patients, especially in MET-positive patients. Here, we quantitatively characterized the longitudinal exposure-response [tumor growth (TG) and overall survival (OS)] relationship for rilotumumab.Experimental Design: Rilotumumab concentrations, tumor sizes, and survival time from the phase II study were pooled to develop a longitudinal exposure versus TG model and parametric OS model that explored predictive/prognostic/treatment effects (MET expression, rilotumumab exposure, relative tumor size). Model evaluation included visual predictive checks, nonparametric bootstrap, and normalized prediction distribution errors.Simulations were undertaken to predict the relationship between rilotumumab dose and OS.Results: Rilotumumab exhibited linear time-independent pharmacokinetics not affected by MET expression. The TG model adequately described tumor size across arms. A Weibull distribution best described OS. Rilotumumab exposure and change in tumor size from baseline at week 24 were predictive of OS. METpositive patients showed shorter survival and responded better to rilotumumab than MET-negative patients. Simulations predicted a median (95% confidence interval) HR of 0.38 (0.18-0.60) in MET-positive patients treated with 15 mg/kg rilotumumab Q3W.Conclusions: Rilotumumab plus ECX demonstrated concentration-dependent effects on OS, influenced by MET expression, and tumor size in gastric/GEJ cancer patients. These findings support the phase II testing of rilotumumab 15 mg/ kg every 3 weeks in MET-positive gastric/GEJ cancer (RILOMET-1; NCT01697072).

Pembrolizumab Exposure–Response Assessments Challenged by Association of Cancer Cachexia and Catabolic Clearance

“…To date, several notable E-R analyses in different cancer types have considered a range of clinical endpoints, including overall survival (OS), progressionfree survival (PFS; refs. [2][3][4][5][6], and overall response rate (ORR)/ tumor kinetics (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). The registration of pembrolizumab for the treatment of melanoma and non-small cell lung cancer (NSCLC) at the dose of 2 mg/kg administered once every 3 weeks (Q3W) was supported by dose-response analyses and model-based E-R analyses of longitudinal tumor size (10,17) using techniques adapted from earlier work (7,18).…”

Personalized and precision medicine: integrating genomics into treatment decisions in gastrointestinal malignancies

“…In vitro studies have demonstrated that MET kinase inhibitor PHA-665752 causes arrest in cell proliferation and apoptosis in gastric cancer cells with constitutively activated MET whereas gastric cancer cells without constitutively activated MET were unaffected (109). Currently, AMG102 (rilotumumab) and MetMAb and PRO143966 (onartuzumab) are under active investigation as MET-targeting agents (56,(110)(111)(112). New results from a phase III study of AMG102 indicate that patients with advanced GEC treated with AMG102 adjunct to standard chemotherapy did not have improved OS compared to patients treated with chemotherapy alone.…”

Clinical Implications of Molecular Heterogeneity of Gastric Cancer

“…Rilomet-1 (NCT01697072) study attempted to evaluate the addition of rilotumumab to standard cisplatin and capecitabine chemotherapy as a first-line therapy for patients with advanced MET-positive GC or GEJ adenocarcinoma [73,74]. Rilotumumab is a human monoclonal antibody against c-MET (HGFR) factor.…”