M Joerger1, J von Pawel2, S Kraff3, J R Fischer4, W Eberhardt5, T C Gauler6, L Mueller7, N Reinmuth8, M Reck8, M Kimmich9, F Mayer10, H-G Kopp11, D M Behringer12, Y-D Ko13, R A Hilger14, M Roessler15, C Kloft16, A Henrich16, B Moritz15, M C Miller17, S J Salamone17, U Jaehde3. 1. Department of Medical Oncology, Cantonal Hospital, St Gallen, Switzerland markus.joerger@kssg.ch. 2. Pneumology Clinic, Asklepios Fachkliniken, Gauting. 3. Institute of Pharmacy, Clinical Pharmacy, University of Bonn, Bonn. 4. Department of Medical Oncology, Klinik Löwenstein, Löwenstein. 5. Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen. 6. Department of Medical Oncology (Cancer Research), West German Cancer Center, University Hospital Essen of University Duisburg-Essen, Essen. 7. Oncological Practice, Praxis Leer, Leer. 8. Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf. 9. Pulmonology and Oncology, Klinik Schillerhöhe, Gerlingen. 10. Department of Oncology and Hematology, University Hospital, Medical Center II, Tübingen. 11. Department of Oncology and Hematology, Eberhard Karls University Medical Center, Tübingen. 12. Medical Oncology, Augusta-Kranken-Anstalt, Bochum. 13. Medical Oncology, Johanniter-Krankenhaus Bonn, Bonn. 14. Cancer Research, University Hospital Essen, Essen, Germany. 15. CESAR Central Office (CCO), Vienna CESAR Central European Society for Anticancer Drug Research-EWIV, Vienna, Austria. 16. Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Free University Berlin, Berlin, Germany. 17. Saladax Biomedical, Inc., Bethlehem, USA.
Abstract
BACKGROUND: Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS: Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION:PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION: NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).
RCT Entities:
BACKGROUND: Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS: Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION: PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION: NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).
Authors: Marie-Rose B S Crombag; Stijn L W Koolen; Sophie Wijngaard; Markus Joerger; Thomas P C Dorlo; Nielka P van Erp; Ron H J Mathijssen; Jos H Beijnen; Alwin D R Huitema Journal: Pharm Res Date: 2019-10-15 Impact factor: 4.200
Authors: Daniel L Hertz; Kelley M Kidwell; Kiran Vangipuram; Feng Li; Manjunath P Pai; Monika Burness; Jennifer J Griggs; Anne F Schott; Catherine Van Poznak; Daniel F Hayes; Ellen M Lavoie Smith; N Lynn Henry Journal: Clin Cancer Res Date: 2018-04-27 Impact factor: 12.531
Authors: Alexandre Chan; Daniel L Hertz; Manuel Morales; Elizabeth J Adams; Sharon Gordon; Chia Jie Tan; Nathan P Staff; Jayesh Kamath; Jeong Oh; Shivani Shinde; Doreen Pon; Niharkia Dixit; James D'Olimpio; Cristina Dumitrescu; Margherita Gobbo; Kord Kober; Samantha Mayo; Linda Pang; Ishwaria Subbiah; Andreas S Beutler; Katherine B Peters; Charles Loprinzi; Maryam B Lustberg Journal: Support Care Cancer Date: 2019-07-30 Impact factor: 3.603
Authors: Stefanie L Groenland; Ron H J Mathijssen; Jos H Beijnen; Alwin D R Huitema; Neeltje Steeghs Journal: Eur J Clin Pharmacol Date: 2019-06-07 Impact factor: 2.953
Authors: Yihan Sun; Jae Hyun Kim; Kiran Vangipuram; Daniel F Hayes; Ellen M L Smith; Larisa Yeomans; N Lynn Henry; Kathleen A Stringer; Daniel L Hertz Journal: Breast Cancer Res Treat Date: 2018-06-26 Impact factor: 4.872
Authors: Leonard J Appleman; Jan H Beumer; Yixing Jiang; Yan Lin; Fei Ding; Shannon Puhalla; Leigh Swartz; Taofeek K Owonikoko; R Donald Harvey; Ronald Stoller; Daniel P Petro; Hussein A Tawbi; Athanassios Argiris; Sandra Strychor; Marie Pouquet; Brian Kiesel; Alice P Chen; David Gandara; Chandra P Belani; Edward Chu; Suresh S Ramalingam Journal: Cancer Chemother Pharmacol Date: 2019-09-23 Impact factor: 3.333
Authors: Marie-Julie Nokin; Elodie Darbo; Camille Travert; Benjamin Drogat; Aurélie Lacouture; Sonia San José; Nuria Cabrera; Béatrice Turcq; Valérie Prouzet-Mauleon; Mattia Falcone; Alberto Villanueva; Haiyun Wang; Michael Herfs; Miguel Mosteiro; Pasi A Jänne; Jean-Louis Pujol; Antonio Maraver; Mariano Barbacid; Ernest Nadal; David Santamaría; Chiara Ambrogio Journal: JCI Insight Date: 2020-08-06