Original StudyPhase 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
Introduction
Advanced non–small-cell lung cancer (NSCLC) remains the most common single cause of cancer deaths in the world.1 For select subgroups with actionable driver mutations or elevated programmed death ligand 1 expression, efficacious and well-tolerated options exist, including combinations of chemotherapy and immune checkpoint inhibitors; however, for those ineligible for targeted therapy, only systemic cytotoxic chemotherapy may offer improvements in overall survival (OS).2
Platelet-derived growth factors (PDGFs) are peptide growth factors that stimulate cellular growth, proliferation, and differentiation.3 They exert their cellular effects through transmembrane receptor tyrosine kinases PDGF receptors (PDGFR)-α and -β. PDGFRα plays an important role in human carcinogenesis, both as a direct target on tumor cells and as a mediator of stromal support for cancer cell growth. Expression of PDGFRα has been observed in multiple solid tumors, including lung cancer.4
MEDI-575 is a human immunoglobulin G subclass 2 kappa antibody that selectively binds to PDGFRα.5 MEDI-575 has demonstrated antitumor activity using preclinical NSCLC tumor models.5 Furthermore, combination treatment studies demonstrated that treatment of tumor-bearing mice with MEDI-575 plus carboplatin/paclitaxel (CP) chemotherapy was better tolerated and resulted in improved antitumor activity than either regimen alone.6
Therefore, the purpose of this study was to investigate the safety and efficacy of the addition of MEDI-575 to CP as first-line treatment for patients with advanced NSCLC.
Section snippets
Patients and Methods
This phase 1b/2, multicenter, open-label study of MEDI-575 evaluated the dose, antitumor activity, safety, and pharmacology (pharmacokinetics [PK], immunogenicity, and biomarkers) of MEDI-575 administered in combination with CP in patients with previously untreated advanced NSCLC. This study had 2 components: dose determination (phase 1b) and randomization (phase 2). This study was conducted in compliance with the principles of the Declaration of Helsinki, and each participating center received
Results
Ninety-nine patients were enrolled between December 2010 and July 2012: 4 in the phase 1b and 95 in the phase 2 trial parts. The NA/EU centers enrolled 85 patients; 14 were enrolled in Japan. In total, 53 patients were randomized to CPM (4 in phase 1b and 49 in phase 2) and 46 patients to CP (Figure 1). The treatment arms were well balanced for sex, ECOG PS, histology, and disease stage (Table 1). More elderly patients were included in the CPM group (28% vs. 11% aged ≥ 70 years).
Of the 99
Discussion
We here report a trial with negative findings. It failed to meet the primary end point of improved PFS in patients with NSCLC. Among 99 patients enrolled and 96 treated, the addition of MEDI-575 to standard CP chemotherapy did not improve PFS. Indeed, PFS was statistically significantly superior in the control (CP) arm. Further, there was an excess of toxicity in the CPM arm, so MEDI-575 is not being studied further for lung cancer or other malignancies.
Are there reasons for the failure of the
Conclusion
MEDI-575 treatment did not improve PFS when added to CP chemotherapy in patients with previously untreated advanced NSCLC, and the combination was not well tolerated.
Disclosure
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,
Acknowledgments
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.
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Targeting the PDGF/PDGFR signaling pathway for cancer therapy: A review
2022, International Journal of Biological MacromoleculesCitation Excerpt :However, in a phase II study, MEDI-575 showed a limited curative effect against recurrent glioblastoma. Furthermore, MEDI-575 treatment resulted in increased toxicity and had no add-on therapeutic effect when combined with carboplatin plus paclitaxel in previously untreated advanced NSCLC patients [65]. Gint4.T is a nuclease-resistant RNA-aptamer that specifically binds to human PDGFRβ (Fig. 6).
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