Olaratumab (trade name Lartruvo) is a monoclonal antibody developed by Eli Lilly and Company for the treatment of solid tumors. It is directed against the platelet-derived growth factor receptor alpha.
|Other names||IMC-3G3, LY-3012207|
|Elimination half-life||11 days|
|Chemical and physical data|
|Molar mass||147.2 kg/mol g·mol−1|
|(what is this?)|
It will be removed from the US and the European markets in the first half of 2019 due to insufficient proof of its medical advantage (see below "Medical uses").
Olaratumab is used in combination with doxorubicin for the treatment of adults with advanced soft-tissue sarcoma (STS) who cannot be cured by cancer surgery or radiation therapy, and who have not been previously treated with doxorubicin.
In a randomised controlled trial with 133 STS patients, olaratumab plus doxorubicin improved the median of progression-free survival from 4.1 to 6.6 months as compared to doxorubicin alone (p = 0.0615, narrowly missing statistical significance), and overall survival from 14.7 to 26.5 months (p = 0.0003, highly significant). However, the ANNOUNCE phase 3 trial did not find any advantage in adding olaratumab to doxorubicin. Therefore, in January 2019, FDA and EMA decided to recommend against starting olaratumab for soft tissue sarcoma. In April 2019 the European Medicines Agency explicitly requested the marketing authorisation of the medicine to be revoked. Shortly afterwards the German Physician's Medicines Commission reported that Olaratumab will be removed from the German market "in a few weeks" and asked doctors not to treat new patients with this drug outside of clinical trials.
In studies, the most serious side effects of the combination olaratumab/doxorubicin were neutropenia (low count of neutrophil white blood cells) with a severity of grade 3 or 4 in 55% of patients, and musculoskeletal pain grade 3 or 4 in 8% of patients. Common milder side effects were lymphopenia, headache, diarrhoea, nausea and vomiting, mucositis, and reactions at the infusion site; all typical effects of cancer therapies.
No pharmacokinetic interactions with doxorubicin were observed in studies. Being a monoclonal antibody, olaratumab is neither metabolised by cytochrome P450 liver enzymes nor transported by transmembrane pumps, and is thus not expected to interact relevantly with other drugs.
Mechanism of actionEdit
Olaratumab was originally developed by ImClone Systems, which was acquired by Eli Lilly in 2008. A Phase I clinical trial was conducted in Japanese patients in September 2010, followed by a Phase II trial in 133 patients, starting in October 2010.
In February 2015, the European Medicines Agency assigned olaratumab orphan drug status for the treatment of soft-tissue sarcoma. The European Commission granted a conditional marketing authorisation, based on the mentioned Phase II study, valid throughout the European Union on 9 November 2016.
Considered a promising drug, the FDA granted olaratumab fast track designation, breakthrough therapy designation and priority review status. In October 2016, the US FDA issued an accelerated approval notice for use of olaratumab with doxorubicin to treat adults with certain types of soft-tissue sarcoma, based on the same study.
- "Statement on a Nonproprietary name adopted by the USAN Council: Olaratumab" (PDF).
- "EPAR – Product information for Lartruvo" (PDF). European Medicines Agency. 23 November 2016.
- "FDA grants accelerated approval to new treatment for advanced soft tissue sarcoma". US FDA. 19 October 2016.
- Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias AD, Adkins D, et al. (July 2016). "Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial". Lancet. 388 (10043): 488–97. doi:10.1016/S0140-6736(16)30587-6. PMC 5647653. PMID 27291997.
- "FDA, EMA Recommend Against Starting Olaratumab for Soft Tissue Sarcoma". OncLive.
- "EMA recommends withdrawal of marketing authorisation for cancer medicine Lartruvo" (PDF).
- "Drug Safety Mail 2019-25 by Arzneimittelkommission der Deutschen Ärzteschaft (in German)". 7 May 2019.
- "Imclone legacy drug gains green light for Lilly in soft tissue sarcoma". BioWorld.
- Doi T, Ma Y, Dontabhaktuni A, Nippgen C, Nippgen J, Ohtsu A (July 2014). "Phase I study of olaratumab in Japanese patients with advanced solid tumors". Cancer Science. 105 (7): 862–9. doi:10.1111/cas.12444. PMC 4317910. PMID 24816152.
- Clinical trial number NCT01185964 for "A Study of IMC-3G3 in Soft Tissue Sarcoma" at ClinicalTrials.gov
- "Orphan Designation for olaratumab". European Medicines Agency. 9 April 2015.
- "EPAR summary for the public for Lartruvo" (PDF). European Medicines Agency. 23 November 2016.
- Shirley M (January 2017). "Olaratumab: First Global Approval". Drugs. 77 (1): 107–112. doi:10.1007/s40265-016-0680-2. PMID 27995580.
- Clinical trial number NCT02451943 for "A Study of Doxorubicin Plus Olaratumab (LY3012207) in Participants With Advanced or Metastatic Soft Tissue Sarcoma (ANNOUNCE)" at ClinicalTrials.gov