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Drugs Jan 2017Olaratumab (Lartruvo™) is a fully human IgG1 monoclonal antibody targeted against the human platelet-derived growth factor (PDGF) receptor α (PDGFRα). It was... (Review)
Review
Olaratumab (Lartruvo™) is a fully human IgG1 monoclonal antibody targeted against the human platelet-derived growth factor (PDGF) receptor α (PDGFRα). It was developed by Eli Lilly and Co. (previously ImClone Systems) after PDGFRα was identified as a potential therapeutic target in a variety of cancers. Olaratumab acts by selectively binding PDGFRα, thereby blocking PDGF ligand binding and inhibiting PDGFRα activation and downstream signalling. In October 2016, olaratumab received its first global approval, in the USA, for use in combination with doxorubicin for the treatment of adult patients with soft tissue sarcoma. The approval was granted by the US FDA under its Accelerated Approval Program based on the results of the JGDG phase II trial (NCT01185964). In addition, the EMA granted conditional approval for olaratumab in this indication in November 2016 following a review under the EMA's Accelerated Assessment Program. An international, confirmatory phase III trial in patients with soft tissue sarcoma is ongoing (ANNOUNCE; NCT02451943). Olaratumab has also been investigated in phase II trials in several other cancers. This article summarizes the milestones in the development of olaratumab leading to this first approval, for use in combination with doxorubicin for the treatment of soft tissue sarcoma in adults.
Topics: Adult; Antibodies, Monoclonal; Drug Approval; Humans; Receptor, Platelet-Derived Growth Factor alpha; Sarcoma; United States
PubMed: 27995580
DOI: 10.1007/s40265-016-0680-2 -
Future Oncology (London, England) Oct 2017The outcome for patients with unresectable/metastatic soft tissue sarcoma remains poor with few treatment options. In the first line setting, a number of randomized... (Review)
Review
The outcome for patients with unresectable/metastatic soft tissue sarcoma remains poor with few treatment options. In the first line setting, a number of randomized trials have shown no difference in overall survival between combination anthracycline schedules and single agent doxorubicin. A Phase Ib/randomized Phase II trial of doxorubicin with or without the monoclonal antibody to PDGFR-α, olaratumab, demonstrated a significant difference in median overall survival in favor of the olaratumab arm. The results of this trial led to approval of olaratumab in combination with doxorubicin in adult anthracycline-naive unresectable soft tissue sarcoma. In this review, we describe some of the preclinical and early clinical data of olaratumab in sarcomas, the Phase Ib/II trial and ongoing trials with olaratumab in sarcomas.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Molecular Targeted Therapy; Sarcoma; Treatment Outcome
PubMed: 28745071
DOI: 10.2217/fon-2017-0210 -
Journal of Oncology Pharmacy Practice :... Mar 2019Olaratumab, the first-in-class anti-PDGFRα monoclonal antibody, has been contingently approved in combination with doxorubicin to treat adult patients with advanced... (Review)
Review
Olaratumab, the first-in-class anti-PDGFRα monoclonal antibody, has been contingently approved in combination with doxorubicin to treat adult patients with advanced soft tissue sarcoma for improving progression-free and overall survival. Olaratumab-doxorubicin combination has tolerable safety profile, which mimics that of doxorubicin monotherapy, with the exception of infusion-related reactions. Survival data of an ongoing confirmatory phase 3 trial are forthcoming to ascertain the optimal role of this product in the management algorithm of advanced soft tissue sarcoma. Active research is ongoing to identify biomarkers predictive of clinical benefit to olaratumab, to expand its utility to the pediatric population, and to explore its safety and efficacy in combination with other active regimens.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Humans; Receptor, Platelet-Derived Growth Factor alpha; Sarcoma
PubMed: 30032714
DOI: 10.1177/1078155218788135 -
Expert Review of Anticancer Therapy Oct 2017Olaratumab, a human monoclonal antibody against platelet derived growth factor receptor alpha (PDGFR- α), is the first drug that in combination with doxorubicin for the... (Comparative Study)
Comparative Study Review
Olaratumab, a human monoclonal antibody against platelet derived growth factor receptor alpha (PDGFR- α), is the first drug that in combination with doxorubicin for the treatment of patients with advanced/metastatic soft tissue sarcoma (STS) that has showed an improved overall survival compared to doxorubicin alone. These initial results are exciting and have the potential to change the landscape of treatment for patients with STS. Areas covered: This article reviews the development of olaratumab for oncology use by reviewing articles in PubMed for 'platelet derived growth factor' and 'receptor' and 'soft tissue sarcoma'. We provide an overview of the published studies to date for olaratumab and specifically the use in soft tissue sarcoma. Expert commentary: Olaratumab is a well-tolerated drug that, when combined with doxorubicin, has shown an improved overall survival compared to doxorubicin alone and the phase III confirmatory study is eagerly awaited.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Humans; Receptor, Platelet-Derived Growth Factor alpha; Sarcoma; Survival Rate
PubMed: 28862476
DOI: 10.1080/14737140.2017.1374857 -
Expert Opinion on Biological Therapy Aug 2017Soft tissue sarcomas (STS) are rare malignant tumors. Unfortunately, the first-line doxorubicin-based treatment has not been improved since the 1970s. Platelet-derived... (Review)
Review
Soft tissue sarcomas (STS) are rare malignant tumors. Unfortunately, the first-line doxorubicin-based treatment has not been improved since the 1970s. Platelet-derived growth factor (PDGF) receptor alpha (PDGFR-α) and its ligands are co-expressed in many types of cancer, including sarcomas. They are involved in stimulating growth and regulating stromal-derived fibroblasts and angiogenesis. PDGFR-α and its ligand may play an important role in tumorigenesis and be a potential target in the treatment of sarcomas. Olaratumab is a fully human IgG1-type anti-PDGFR-α monoclonal antibody with a high affinity and a low 50% inhibitory concentration (IC50). Areas covered: The authors review the role of olaratumab in the treatment of STS by focusing on the recent, randomized Phase II JDGD trial that challenged patients with unresectable or metastatic STS with doxorubicin in the presence or absence of olaratumab. This trial showed a great improvement in overall survival (OS), with an increase in survival from 14.7 months to 26.5 months for patients in the experimental arm and showed acceptable toxicity. Expert opinion: Results seem promising. However, it must be qualified, as the study includes several uncertainties. These uncertainties should be addressed by the ongoing Phase 3 JGDJ confirmatory trial, for which the final efficacy analysis is expected by 2019.
Topics: Anemia; Antibodies, Monoclonal; Antineoplastic Agents; Clinical Trials as Topic; Humans; Neutropenia; Receptor, Platelet-Derived Growth Factor alpha; Sarcoma
PubMed: 28691538
DOI: 10.1080/14712598.2017.1339031 -
Expert Review of Clinical Pharmacology Jul 2017Olaratumab is a humanized IgG1 monoclonal antibody that blocks the platelet-derived growth factor receptor alpha (PDGFRα). Its antagonistic behavior inhibits the... (Comparative Study)
Comparative Study Review
Olaratumab is a humanized IgG1 monoclonal antibody that blocks the platelet-derived growth factor receptor alpha (PDGFRα). Its antagonistic behavior inhibits the receptor's tyrosine kinase activity, thereby, turning off the downstream signaling cascades responsible for soft tissue sarcoma tumorigenesis. In October 2016, olaratumab received Food and Drug Administration (FDA) approval for its use in combination with doxorubicin for treatment of advanced soft tissue sarcoma. Areas covered: This drug profile takes a comprehensive look at the clinical studies leading to FDA approval of olaratumab as well as its safety and efficacy as a front-line treatment option for sarcoma patients. The literature search was primarily conducted using PubMed. Expert commentary: The combination of olaratumab plus doxorubicin has provided a new front-line therapeutic option for soft tissue sarcoma patients. An open-label phase Ib and randomized phase II trial in patients with advanced soft tissue sarcoma demonstrated that the addition of olaratumab to doxorubicin prolonged progression-free survival by 2.5 months and overall survival by 11.8 months when compared to doxorubicin alone. Of importance, this clinically meaningful increase in overall survival did not come at the expense of a significantly greater number of toxicities. A phase III confirmatory trial (ClinicalTrials.gov Identifier NCT02451943) will be completed in 2020.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Doxorubicin; Humans; Randomized Controlled Trials as Topic; Receptor, Platelet-Derived Growth Factor alpha; Sarcoma; Survival Rate
PubMed: 28447475
DOI: 10.1080/17512433.2017.1324295 -
Clinical Pharmacology : Advances and... 2017The outcome of patients with unresectable or metastatic soft tissue sarcoma (STS) remains poor with few treatment options. A number of randomized trials in the... (Review)
Review
The outcome of patients with unresectable or metastatic soft tissue sarcoma (STS) remains poor with few treatment options. A number of randomized trials in the first-line setting have shown no difference in overall survival between combination anthracycline schedules and single-agent doxorubicin. A Phase Ib/randomized Phase II trial of doxorubicin with or without the platelet-derived growth factor receptor-α (PDGFRα)-blocking antibody, olaratumab, demonstrated a significant difference in median overall survival in favor of the olaratumab arm. The results of this trial led to the approval of olaratumab in combination with doxorubicin in adult anthracycline-naïve unresectable STS. In this review, we discuss the potential role of PDGFRα signaling, early clinical data with olaratumab in sarcomas, the Phase Ib/II trial and ongoing trials with olaratumab in sarcomas.
PubMed: 29270033
DOI: 10.2147/CPAA.S130178 -
European Journal of Cancer (Oxford,... Mar 2018Recent randomised phase II trial data have indicated that the addition of olaratumab, a novel monoclonal antibody against platelet-derived growth factor receptor alpha... (Review)
Review
Recent randomised phase II trial data have indicated that the addition of olaratumab, a novel monoclonal antibody against platelet-derived growth factor receptor alpha (PDGFRα), to doxorubicin confers an unprecedented improvement in overall survival to patients with anthracycline-naïve advanced soft tissue sarcoma. However, this result was disproportionate with progression-free survival and response rate, and consequently there are unanswered questions regarding the precise mechanism of action of olaratumab. While preclinical data show that olaratumab specifically inhibits PDGFRα-mediated oncogenic signalling with attendant anti-tumour effects, a lack of correlation between pharmacodynamics markers of PDGFRα inhibition and clinical benefit from olaratumab suggest other mechanisms beyond modulation of downstream PDGFRα molecular pathways. Proposed mechanisms of olaratumab activity include engagement of anti-tumour immune responses and alterations of the tumour stroma, but these require further evaluation. Meanwhile, the drug-specific contribution of cytotoxic agents to olaratumab-containing combinations has yet to be characterised. Ongoing and future preclinical and translational studies, coupled with the anticipated results of a phase III trial that has completed enrolment, should provide greater insight into the efficacy and mode of action of olaratumab in soft tissue sarcomas.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Biomarkers, Tumor; Disease Progression; Disease-Free Survival; Humans; Molecular Targeted Therapy; Receptor, Platelet-Derived Growth Factor alpha; Sarcoma; Signal Transduction; Soft Tissue Neoplasms; Treatment Outcome
PubMed: 29413687
DOI: 10.1016/j.ejca.2017.12.026