TY - JOUR
T1 - Phase 1b/2 Randomized Study of MEDI-575 in Combination With Carboplatin Plus Paclitaxel Versus Carboplatin Plus Paclitaxel Alone in Adult Patients With Previously Untreated Advanced Non–Small-Cell Lung Cancer
AU - Wheatley-Price, Paul
AU - Gadgeel, Shirish
AU - Takahashi, Toshiaki
AU - Li, Xia
AU - Dar, Mohammed
AU - Blumenschein, George R.
N1 - Funding Information:
P.W.-P. has participated in advisory boards for AstraZeneca. S.G. has participated in advisory boards for AstraZeneca/MedImmune. T.T. has received honoraria and study grants from AstraZeneca KK, Eli Lilly Japan KK, MSD K.K., ONO Pharmaceutical Co, Pfizer Japan, Taiho Pharmaceutical Co, honoraria from Boehringer Ingelheim Japan, and study grants from Takeda Pharmaceutical Co., Ltd. X.L. and M.D. are employees of MedImmune and own stock in AstraZeneca. G.B. has served as a consultant for Abbvie, Adicet, Amgen, Ariad, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Clovis, Genentech, Merck, Novartis, and Xcovery, and he or his institution has received study grants from Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Exelixis, Genentech, GlaxoSmithKline, Immatics, Incyte, Kite, MacroGenics, Merck, Novartis, Roche, Torque, and Xcovery.Supported by MedImmune, the global biologics R&D arm of AstraZeneca. Editorial support was provided by Amy Zannikos, PharmD, at Peloton Advantage, and was funded by MedImmune. We thank the patients and families who participated in the trial, the investigators and their teams at each study site, and the central data management and biostatistics teams.
Funding Information:
Supported by MedImmune , the global biologics R&D arm of AstraZeneca. Editorial support was provided by Amy Zannikos, PharmD, at Peloton Advantage, and was funded by MedImmune . We thank the patients and families who participated in the trial, the investigators and their teams at each study site, and the central data management and biostatistics teams.
Publisher Copyright:
© 2018
PY - 2019/5
Y1 - 2019/5
N2 - Introduction: Platinum doublet chemotherapy has represented the standard of care in advanced non–small-cell lung cancer for decades. Targeting platelet-derived growth factor receptors (PDGFR) is a potential mechanism to improve the efficacy of first-line therapy. This randomized phase 1b/2 trial investigated the addition of the anti-PDGFRα monoclonal antibody MEDI-575 to first-line carboplatin/paclitaxel (CP) chemotherapy. Patients and Methods: The phase 1b component was a dose-escalation study combining MEDI-575 with carboplatin area under the plasma concentration versus time curve 6 and paclitaxel 200 mg/m2 (CPM), with the end point of identifying a recommended phase 2 dose. The phase 2 component randomized patients to CPM or CP, with primary end point of progression-free survival. Secondary end points included overall survival, overall response rate, and adverse event rates. Results: Overall, 99 patients were enrolled and received either CPM (n = 53; 4 phase 1b, 49 phase 2) or CP (n = 46). Demographics were as follows: 63/36 male/female, 78/21 aged ≤ 70/> 70 years; 37/62 squamous/nonsquamous, 42/53 Eastern Cooperative Oncology Group performance status 0/1. The phase 2 portion of the trial did not meet its primary end point: progression-free survival was shorter with CPM (4.6 vs. 5.5 months) than CP. No significant difference was seen in overall response rate (31.7% vs. 22.5%) or median overall survival (10.0 vs. 11.8 months). More serious adverse events were observed in patients receiving CPM (47% vs. 40%); in particular, 9 patients in the CPM group had significant gastrointestinal or respiratory adverse events (including abscess, perforation, and pneumothorax). Conclusion: The addition of MEDI-575 to CP chemotherapy as first-line treatment of advanced non–small-cell lung cancer did not improve efficacy and resulted in increased toxicity. Platelet-derived growth factor receptor blockade was explored as a potential mechanism to improve the efficacy of first-line therapy in patients with advanced non–small-cell lung cancer (NSCLC). In this phase 1b/2 study, therapy with MEDI-575, carboplatin, and paclitaxel (n = 53) did not improve progression-free survival versus carboplatin and paclitaxel alone (n = 46), and resulted in a higher rate of adverse events in patients with treatment-naive advanced NSCLC.
AB - Introduction: Platinum doublet chemotherapy has represented the standard of care in advanced non–small-cell lung cancer for decades. Targeting platelet-derived growth factor receptors (PDGFR) is a potential mechanism to improve the efficacy of first-line therapy. This randomized phase 1b/2 trial investigated the addition of the anti-PDGFRα monoclonal antibody MEDI-575 to first-line carboplatin/paclitaxel (CP) chemotherapy. Patients and Methods: The phase 1b component was a dose-escalation study combining MEDI-575 with carboplatin area under the plasma concentration versus time curve 6 and paclitaxel 200 mg/m2 (CPM), with the end point of identifying a recommended phase 2 dose. The phase 2 component randomized patients to CPM or CP, with primary end point of progression-free survival. Secondary end points included overall survival, overall response rate, and adverse event rates. Results: Overall, 99 patients were enrolled and received either CPM (n = 53; 4 phase 1b, 49 phase 2) or CP (n = 46). Demographics were as follows: 63/36 male/female, 78/21 aged ≤ 70/> 70 years; 37/62 squamous/nonsquamous, 42/53 Eastern Cooperative Oncology Group performance status 0/1. The phase 2 portion of the trial did not meet its primary end point: progression-free survival was shorter with CPM (4.6 vs. 5.5 months) than CP. No significant difference was seen in overall response rate (31.7% vs. 22.5%) or median overall survival (10.0 vs. 11.8 months). More serious adverse events were observed in patients receiving CPM (47% vs. 40%); in particular, 9 patients in the CPM group had significant gastrointestinal or respiratory adverse events (including abscess, perforation, and pneumothorax). Conclusion: The addition of MEDI-575 to CP chemotherapy as first-line treatment of advanced non–small-cell lung cancer did not improve efficacy and resulted in increased toxicity. Platelet-derived growth factor receptor blockade was explored as a potential mechanism to improve the efficacy of first-line therapy in patients with advanced non–small-cell lung cancer (NSCLC). In this phase 1b/2 study, therapy with MEDI-575, carboplatin, and paclitaxel (n = 53) did not improve progression-free survival versus carboplatin and paclitaxel alone (n = 46), and resulted in a higher rate of adverse events in patients with treatment-naive advanced NSCLC.
KW - Chemotherapy
KW - NSCLC
KW - PDGFRα
KW - Receptor targeted therapies
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U2 - 10.1016/j.cllc.2018.11.012
DO - 10.1016/j.cllc.2018.11.012
M3 - Article
C2 - 30685114
AN - SCOPUS:85060334893
SN - 1525-7304
VL - 20
SP - e362-e368
JO - Clinical Lung Cancer
JF - Clinical Lung Cancer
IS - 3
ER -