Population pharmacokinetics and exposure-response relationship of amatuximab, an anti-mesothelin monoclonal antibody, in patients with malignant pleural mesothelioma and its application in dose selection

Our plain-English summary of Population pharmacokinetics and exposure-response relationship of amatuximab, an anti-mesothelin monoclonal antibody, in patients with malignant pleural mesothelioma and its application in dose selection, by A. Gupta, Z. Hussein, R. Hassan, et al (Cancer Chemotherapy and Pharmacology, 2016).

The study

• Authors: A. Gupta, Z. Hussein, R. Hassan, J. Wustner, J.D. Maltzman, B.A. Wallin
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2016;77(4):733-43
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: To characterize amatuximab pharmacokinetics (PK) and the relationship of amatuximab exposure with response in patients with unresectable malignant pleural mesothelioma (MPM) receiving amatuximab with pemetrexed and cisplatin.

Methods: A nonlinear mixed effects PK model was built using data from all of the amatuximab studies conducted to date. Patients received amatuximab alone or in combination with chemotherapy. The influence of demographic, laboratory and disease characteristics on PK parameters was assessed. Exposure-response analyses explored relationships between amatuximab exposure and overall survival (OS), progression-free survival (PFS) and safety. Alternative amatuximab dosing regimens were explored with simulations using population PK and parametric survival models.

Results: Amatuximab PK was best described by a two-compartment model with parallel linear and nonlinear elimination pathways. Body weight and an antidrug antibodies reaction with the titer >64 affected volume of distribution and clearance, respectively. Exposure-response analyses demonstrated that the amatuximab exposure (C min) showed a significant effect on OS (log-rank test, P = 0.0202). For patients with amatuximab C min above the median (38.2 μg/mL), the median OS was 583 days (90 % CI 418 -NE). For patients with C min ≤ 38.2 μg/mL, the median OS was 375 days (90 % CI 325-486). The amatuximab exposure showed similar significant effect on PFS. Exposure-response analysis for adverse events did not reveal any relationship.

Conclusions: In patients with MPM, higher amatuximab exposure in combination with chemotherapy was shown to be associated with longer OS, supporting evaluation of more frequent dosing in future trials to achieve higher exposure and subsequently longer OS.

In plain English

This study looked at how the experimental antibody drug amatuximab, which targets mesothelin, behaves in the body. It also asked whether blood levels of the drug were linked to outcomes in patients with unresectable malignant pleural mesothelioma. It did not study asbestos exposure. The authors modeled drug levels in 199 patients from four Phase I and II trials. They then examined mesothelioma patients from one Phase II trial who received amatuximab with pemetrexed and cisplatin. Antidrug antibodies at a titer above 64 increased the drug's linear clearance (one of two elimination pathways in the model) 1.5-fold. Patients whose average pre-infusion drug level over their last three assessments (Cmin) was above the median of 38.2 μg/mL had a median overall survival of 583 days (90 % CI 418 to not estimable). Those at or below it had 375 days (90 % CI 325–486). Progression-free survival showed a similar pattern. Grade 3 or higher adverse events did not differ in frequency between patients whose highest pre-infusion level was at least 108 µg/mL and those below it. The authors concluded that higher exposure was associated with longer survival, supporting evaluation of more frequent dosing in future trials.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Population pharmacokinetic modeling and exploratory exposure–response analysis of pooled clinical trial data, with dosing simulations
• Who was studied: 199 patients from four trials made up the drug-level model: 24 in a US Phase I trial, 17 in a Japanese Phase I trial, 71 of 155 in a Phase II pancreatic cancer trial, and 87 in the Phase II mesothelioma trial. The exposure–response analysis used the international Phase II trial of 89 patients with unresectable malignant pleural mesothelioma. Dates are not given.
• Exposure: The exposure studied was the drug amatuximab, not asbestos. In the mesothelioma trial it was given at 5 mg/kg on Days 1 and 8 of each 21-day cycle with pemetrexed and cisplatin, then as maintenance therapy. Drug exposure was measured as Cmin (the observed average pre-infusion concentration over the last three assessments) and Cmax (the observed average post-infusion concentration over the last three assessments).
• Main results:
  • In the drug-level model for all 199 patients, antidrug antibodies with a titer above 64 increased amatuximab linear clearance by a factor of 1.5. The model also included a separate nonlinear elimination pathway.
  • In mesothelioma patients with survival data (86 patients), those with Cmin above the median (38.2 μg/mL) had a median overall survival of 583 days (90 % CI 418 to not estimable). Those below the median had 375 days (90 % CI 325–486). The log-rank P value was 0.0202.
  • In multivariate analysis of mesothelioma patients (N = 84), Cmin remained a significant predictor of overall survival after accounting for performance status (KPS) and histology. Longer survival went with better KPS, higher Cmin and epithelial histology.
  • In mesothelioma patients with progression data (76 patients), median progression-free survival was 238 days (90 % CI 193–322) for those with Cmin above 32.9 μg/mL.
  • Median progression-free survival was 115 days (90 % CI 94–165) for mesothelioma patients with Cmin at or below 32.9 μg/mL.
  • The authors compared the frequency of grade 3 or higher treatment-emergent adverse events between patients with maximum pre-infusion levels of at least 108 µg/mL and those below 108 µg/mL. They found no difference; the data were not shown.
  • When the analysis was limited to patients who completed at least four cycles, the same pattern of higher exposure with better outcome was seen, but it was less statistically significant.
  • Simulations predicted that about 80 % of patients would be above a Cmin of 38.2 µg/mL by 28 days with 5 mg/kg given weekly.
  • Simulations predicted that 7.5 mg/kg given weekly would raise this to about 90 % of patients.
• The authors' conclusion: The authors concluded that, in patients with malignant pleural mesothelioma, higher amatuximab exposure combined with chemotherapy was associated with longer overall survival. They wrote that this supports evaluating more frequent dosing in future trials.
• Limitations the authors state:
  • Patients who dropped out early affected the exposure–response relationship.
  • The smaller number of patients in the subset analysis may have reduced statistical power.
  • The higher simulated dose of 7.5 mg/kg had not been tested before and might raise safety concerns.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelin, Monoclonal Antibody, Pleural Mesothelioma, Unresectable, Pemetrexed (Alimta), Cisplatin, Chemotherapy, Overall Survival.

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