Pharmacokinetic and exposure-response analyses of pertuzumab in combination with trastuzumab and docetaxel during neoadjuvant treatment of HER2+ early breast cancer.

Autor: Quartino AL; Genentech, Inc., South San Francisco, CA, USA., Li H; Quantitative Solutions/Certara, Menlo Park, CA, USA., Jin JY; Genentech, Inc., South San Francisco, CA, USA., Wada DR; Quantitative Solutions/Certara, Menlo Park, CA, USA., Benyunes MC; Genentech, Inc., South San Francisco, CA, USA., McNally V; Roche Products Limited, Welwyn, UK., Viganò L; San Raffaele Hospital - Research Institute, Milan, Italy., Nijem I; Genentech, Inc., South San Francisco, CA, USA., Lum BL; Genentech, Inc., South San Francisco, CA, USA., Garg A; Genentech, Inc., South San Francisco, CA, USA. garg.amit@gene.com.
Jazyk: angličtina
Zdroj: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2017 Feb; Vol. 79 (2), pp. 353-361. Date of Electronic Publication: 2017 Jan 10.
DOI: 10.1007/s00280-016-3218-0
Abstrakt: Purpose: The NeoSphere trial evaluated pertuzumab in the neoadjuvant setting [early breast cancer (EBC)] with pathological complete response (pCR) as the primary efficacy end point. This analysis of pertuzumab aimed to (1) compare its pharmacokinetics (PK) in patients with EBC versus advanced cancers, (2) to further evaluate PK drug-drug interactions (DDIs) when given in combination with trastuzumab, and (3) to assess the relationship between exposure and efficacy to assess the clinical dosing regimen in the EBC patients.
Methods: Pertuzumab serum concentration data from 180 patients in NeoSphere were compared to historical observations and potential DDI was assessed, by applying simulation techniques using a population PK model. The impact of pertuzumab exposure on pCR rate was evaluated using a logit response model (n = 88).
Results: The observed PK matched the population PK model simulations, confirming that the PK in neoadjuvant EBC appear to be in agreement with the historical observations. No evidence of a DDI effect of trastuzumab or docetaxel on pertuzumab was observed supporting the doses when given in combination. In NeoSphere >90% of EBC patients achieved the non-clinical target serum concentration. There was no association between the pertuzumab serum concentration and pCR within the range observed in this study (20-100 μg/mL) supporting no dose adjustments needed for patients with lower exposure.
Conclusions: This analysis further supports the lack of DDI between the two therapeutic proteins and the appropriateness of the approved fixed non-body-weight-adjusted pertuzumab dose in the treatment of neoadjuvant EBC with pertuzumab in combination with trastuzumab and docetaxel.
Competing Interests: AQ is a salaried employee of Genentech, Inc., and owns stock in Roche Holding Ltd. HL was employed as consultant of Quantitative Solutions, who was contracted to conduct the PKPD analysis. JYJ is a salaried employee of Genentech, Inc. DRW was an employee of Quantitative Solutions, which received monies from many companies in the pharmaceutical industry for consulting services. MCB is a salaried employee of Genentech, Inc. VM is a salaried employee of, and owns stock in Roche. LV declares no conflict of interest. IN is a salaried employee of Genentech, Inc., and owns stock in Roche Holding Ltd. BL is a salaried employee of Genentech, Inc., and hold stock in Roche Holding Ltd. AG is a salaried employee of Genentech, Inc., and owns stock in Roche Holding Ltd. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of analysis, formal consent is not required. Informed consent Informed consent was obtained from all individual participants included in the study.
Databáze: MEDLINE
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