What is olaratumab?
Olaratumab is a first in class platelet-derived growth factor receptor alpha (PDGFR-[alpha]) blocking antibody.
How does olaratumab work?
PDGFR-[alpha] is a receptor expressed on the cell surface of mesenchymal, tumor, and stromal cells. When activated, it helps facilitate cancer cell proliferation, metastasis, and stabilization of the tumor microenvironment. When olaratumab binds to PDGFR-[alpha], PDGF ligands cannot bind to the receptor and activate downstream cell signaling cascades.
What is this approved for?
Olaratumab is approved for treatment of soft tissue sarcoma in combination with doxorubicin therapy for patients who do not have a curative option with surgery or radiation.
What is the basis for this approval?
Olaratumab was granted accelerated approval by the FDA based on an open-label phase Ib/randomized phase II trial where patients with unresectable or metastatic soft tissue sarcoma were randomized to either doxorubicin and olaratumab or doxorubicin alone. One hundred and thirty three patients were randomized and treated every 21 days for up to 8 cycles. The primary endpoint was progression-free survival (PFS) with a prespecified two-sided [alpha] of 0.2. Median PFS was 6.6 months with olaratumab/doxorubicin and 4.1 months with doxorubicin alone (HR 0.67, p=0.0615). Median overall survival was 26.5 months with olaratumab/doxorubicin and 14.7 months with doxorubicin (HR 0.46, p=0.0003). More patients in the combination arm had more frequent adverse events such as neutropenia, mucositis, nausea, and diarrhea (Lancet 2016;388:488-97).
How do you administer this drug?
Olaratumab is administered as a 15 mg/kg dose over 60 minutes on days 1 and 8 of a 21 day cycle until disease progression or toxicity. For the first 8 cycles, doxorubicin is administered on day 1 after the patient has received olaratumab.
Are there any premedications needed for olaratumab?
Due to the risk of infusion reactions, premedication is necessary for treatment with olaratumab. All patients should receive an antihistamine such as diphenhydramine 25-50 mg IV and coriticosteroid such as dexamethasone 10-20 mg IV 30 minutes prior.
What are the common side effects associated with olaratumab (> or =10%)?
Olaratumab and doxorubicin resulted in at least a 5 percent increase over doxorubicin alone for the following:
* GI: nausea, mucositis, vomiting, diarrhea abdominal pain, decreased appetite
* General: fatigue, infusion-related reactions, alopecia
* Musculoskeletal pain, neuropathy, dry eyes
* Laboratory: hyperglycemia, hypokalemia, hypophosphatemia, hypomagnesemia, lymphopenia, neutropenia, thrombocytopenia
What are the uncommon side effects associated with olaratumab (less than 10%)?
About 4 percent of all patients had IgG neutralizing antibodies develop after being treated with olaratumab. The clinical significance of this has not been determined.
Are there any important drug interactions?
No drug interactions are known with olaratumab at this time.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
There are no known renal or hepatic dose adjustments for olaratumab. Olaratumab has not been studied in severe renal or hepatic dysfunction; however, since olaratumab is not hepatically metabolized or renally excreted, drug exposure is not expected to be different in these populations.
Practical tips
Infusion reactions occur in up to 14 percent of patients despite premedications. Patients should be monitored for an hour after the first two cycles of chemotherapy to ensure that a delayed infusion reaction is not going to occur. If a patient does experience an infusion reaction, the infusion may be slowed down to 50 percent of the previous rate and/or additional premedications such as famotidine or albuterol nebulizers may be warranted.
What should my patients know about olaratumab?
All patients should be educated on the side effects of doxorubicin as well as those side effects that may get worse with the addition of olaratumab. Patients should contact their health care provider if they experience any of the following:
* Itching, shortness of breath or flushing during the infusion
* Fever
* Nausea or vomiting that is uncontrolled with medications at home
* Mouth sores that are painful or interfere with eating
* High blood sugars
What else should I know about olaratumab?
* Olaratumab may be continued after completion of therapy with doxorubicin if the patient is responding to therapy.
* Patients are at risk of infusion-related reactions despite premedications with antihistamines and steroids. Most patients were able to successfully receive olaratumab infusions again with increased premedications.
* Patients receiving olaratumab and doxorubicin have more side effects than patients receiving doxorubicin alone. These include nausea, mucositis, vomiting, diarrhea, pain, neuropathy, hyperglycemia, hypomagnesemia, and neutropenia.
What useful links are available?
* http://www.lartruvo.com
* http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm526087.htm
Any ongoing clinical trials related to olaratumumab?
Clinical trials with olaratumab are being conducted in several settings including those involving upfront therapy with doxorubicin and dexrazoxane, in combination with other chemotherapy agents such as gemcitabine, docetaxel, vincristine, irinotecan, and ifosfamide, and in the pediatric population. More information is available about the clinical trials at https://clinicaltrials.gov.
SARA K. BUTLER, PHARMD, BCPS, BCOP, is Clinical Oncology Pharmacy Supervisor, Barnes-Jewish Hospital, St. Louis, Mo, and also serves as the Pharmacy Forum column editor. Oncology Times Clinical Advisory Editor RAMASWAMY GOVINDAN, MD, Co-Director, Section of Medical Oncology, Professor of Medicine, Washington University School of Medicine, Alvin J. Siteman Cancer Center, serves as the Pharmacy Forum column physician advisor.