Herceptin in HER2-positive Gastric Cancer: Evaluation of Exposure-Response with Two Dose Levels.
Matts Kågedal(1), Laurent Claret(1), Mathilde Marchand(2), Pascal Chanu(1), Rene Bruno(1), Amit Garg(1), Jin Jin(1)
1. Genentech INC 2. Certara
Objectives: Previous exposure response analyses of Herceptin treatment in patients (pts) with HER2+ metastatic gastric/GEJ Cancer (TOGA study), suggested an association between Herceptin exposure and overall survival (OS), where pts with low drug exposure had shorter OS. It was unclear whether the observed association represented a true causal relationship or if it resulted from confounding factors influencing both drug clearance (CL) and OS1,2. A new study (HELOISE) in HER2+ metastatic gastric/GEJ cancer has subsequently been performed including two treatment arms with different dose levels3. The objective of this exploratory analysis was to assess the exposure-response relationship for OS and the potential confounding effect of clinical factors based on results from the HELOISE phase III study.
Methods: HELOISE randomized pts with HER2-positive metastatic gastric cancer with poorer clinical factors to receive one of two Herceptin regimens. After an initial Herceptin dose of 8mg/kg in both arms, pts received either 6mg/kg (SoC) or 10 mg/kg (High) Herceptin every three weeks in combination with chemotherapy. Plasma clearance (CL) as well as AUC, Cmax and Cmin after the first dose (cycle 1) and at steady state were derived. Graphical exploration and multivariate Cox regression were performed to identify predictors of survival and any exposure-response relationship.
Results: Although higher Herceptin maintenance dosing is associated with higher concentrations in HELOISE, we observed no increased efficacy (OS)3. This finding was consistent across cycle 1 exposure levels, suggesting that increasing the dose/exposure did not improve survival even in the pts with the lowest exposure. Multivariate Cox regression across both arms including the covariates; number of metastatic sites, Albumin, Cmin,ss and CL suggested that CL was a predictor of OS (p=0.009), and that Cmin,ss may also contribute (p=0.02).
Conclusions: No improvement in efficacy was seen by increasing dose over SoC, irrespective of exposure level. The apparent exposure OS relationship based on the single dose TOGA study appears to be a confounding effect of CL along with poorer clinical factors, rather than a causal exposure-response relationship. Tumor growth inhibition metrics may be used to further address the confounding in exposure-response (OS)4.
References:
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[2] Jun Yang, Hong Zhao, et al. The Combination of Exposure-Response and Case-Control Analyses in Regulatory Decision Making. J Clin Pharmacol. 2013 Feb;53(2):160-6
[3] Manish A. Shah et al. HELOISE: Phase 3B randomized multicenter study comparing two trastuzumab (H) dose regimens combined with chemotherapy (CT) as first-line (1L) therapy in pts with HER2-positive metastatic gastric/gastroesophageal junction adenocarcinoma (mGC/GEJC). AACR Annual Meeting, April 16–20 2016, New Orleans, LA.
[4] Bruno R, Mercier F, Claret L. Evaluation of tumor-size response metrics to predict survival in oncology clinical trials. Clin Pharmacol Ther. 2014;95:386–93.