Soft-tissue sarcomas are malignant tumors that affect the mesodermal tissues, including the muscles, tendons, fat, blood vessels, nerves, and joint tissues.1 Approximately 50% of soft-tissue sarcomas occur in the extremities, 40% in the trunk and retroperitoneum, and 10% in the head and neck.1 In the United States, an estimated 12,310 individuals will be diagnosed with soft-tissue sarcoma in 2016, and 4990 will die of the disease.2
The 5-year survival rate for patients with localized soft-tissue sarcomas is 83%; it is 54% for patients with regional stage, and 16% for those with distant metastatic disease.2 The most common site of metastasis for this disease is the lungs.3 However, soft-tissue tumors that originate in the abdominal cavity often metastasize to the liver and the peritoneum.3
The risk factors for soft-tissue sarcomas include certain genetic syndromes, chemical exposure, and radiation treatment for other cancers.4 More than 50 subtypes of soft-tissue sarcomas are known, which makes the diagnosis and treatment particularly challenging.1,2 The most common subtypes of soft-tissue sarcomas include liposarcoma, undifferentiated pleomorphic sarcoma, leiomyosarcoma, gastrointestinal stromal tumors, synovial sarcoma, and malignant peripheral nerve sheath tumors.3
Treatment decisions are based on the type, location, and stage of the disease; the patient’s overall physical health; and the risks and side effects (ie, toxicities) of the anticancer agents used. The treatment may include surgery, radiation, chemotherapy, or targeted therapy.2,3
Doxorubicin, as monotherapy or in combination with other therapies, has been a cornerstone treatment for soft-tissue sarcoma.3,5 In January 2016, the US Food and Drug Administration (FDA) approved eribulin mesylate (Halaven), a microtubule dynamics inhibitor, for the treatment of patients with unresectable or metastatic liposarcoma who received treatment with an anthracycline-containing regimen.6 However, an unmet medical need remains for treatment options that improve outcomes for patients with advanced soft-tissue sarcoma.5
Lartruvo Receives FDA Approval for Soft-Tissue Sarcoma
On October 19, 2016, the FDA granted an accelerated approval to olaratumab (Lartruvo; Eli Lilly) for the treatment of adults with certain types of soft-tissue sarcoma.7 Olaratumab, a platelet-derived growth factor (PDGF) receptor-alpha–blocking monoclonal antibody is indicated, in combination with doxorubicin, for the treatment of adults with soft-tissue sarcoma of a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery.7
Olaratumab’s approval for this indication may be contingent on clinical benefit shown in a confirmatory clinical trial.8 In addition to its fast-track designation, olaratumab received a breakthrough therapy and was given a priority review based on preliminary clinical evidence showing that it may offer a substantial improvement in treating a serious or life-threatening disease.7 The FDA also granted olaratumab an orphan drug designation.7
“This is the first new therapy approved by the FDA for the initial treatment of soft tissue sarcoma since doxorubicin’s approval more than 40 years ago,” said Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products.7
According to William D. Tap, MD, Chief, Sarcoma Medical Oncology Services, Memorial Sloan Kettering Cancer Center, New York, and principal investigator of the pivotal phase 2 clinical trial for olaratumab, “Lartruvo represents an important step forward in soft tissue sarcoma treatment. We are pleased with this approval, which will provide patients with a treatment option that offers new hope in their battle against this difficult disease.”9
Bert E. Thomas IV, PhD, MBA, Chief Executive Officer of the Sarcoma Foundation of America, commented, “The entire sarcoma patient community is excited to have an innovative medicine approved for the treatment of advanced soft tissue sarcoma. We are confident that the approval of Lartruvo will help these patients live longer.”9
Mechanism of Action
Olaratumab, a human immunoglobulin G1 antibody, binds the PDGF receptor-alpha, a tyrosine kinase receptor that is expressed in mesenchymal cells. Signaling through the PDGF receptor-alpha plays a role in stem-cell growth, differentiation, and angiogenesis.5,8 This signaling pathway has also been implicated in some tumor and stromal cells, including sarcomas, where it can contribute to cancer-cell proliferation and metastasis.5,8 Olaratumab exhibits antitumor activity against specific sarcoma cell lines and disrupts the PDGF receptor-alpha signaling pathway.8
Dosing and Administration
Olaratumab is administered as an intravenous (IV) infusion at 15 mg/kg for 60 minutes on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity. For the first 8 cycles, olaratumab is administered with doxorubicin. Patients should receive premedication with diphenhydramine and dexamethasone on day 1 of cycle 1.8
Olaratumab is indicated for IV infusion only. It should not be administered as an IV push or bolus. Olaratumab is available as a 500-mg/50-mL (10-mg/mL) solution in a single-dose vial.8
Olaratumab is distributed through several distribution networks and specialty pharmacies, including AmerisourceBergen Specialty Group, CuraScript SD, Cardinal Health Specialty Pharmaceutical Distribution, McKesson Specialty Care Distribution Corporation, and Smith Medical Partners.
Pivotal Clinical Trial
The safety and efficacy of olaratumab were evaluated in the clinical trial known as JGDG, an open-label, randomized, active-controlled, phase 2 study in patients with metastatic soft-tissue sarcoma that was not amenable to curative treatment with surgery or radiotherapy with a histologic subtype for which an anthracycline-containing regimen is appropriate.5,8,9 This study included 133 patients (median age, 58 years) with more than 25 subtypes of metastatic soft-tissue sarcoma (Table 1). Of these patients, 65% received no chemotherapy, excluding adjuvant and neoadjuvant therapy.8
The patients were randomized in a 1:1 ratio to receive olaratumab in combination with doxorubicin or doxorubicin alone. Olaratumab 15 mg/kg was administered as an IV infusion on days 1 and 8 of each 21-day cycle until disease progression or until unacceptable toxicity. Doxorubicin 75 mg/m2 was administered as an IV infusion to all patients on day 1 of each 21-day cycle for up to 8 cycles. Patients who received single-agent doxorubicin also received dexrazoxane, a cardioprotective agent, before doxorubicin administration in cycles 5 to 8. At the time of disease progression, the patients in the single-agent doxorubicin group were offered olaratumab treatment; 30 (45%) of these patients received olaratumab as a single agent at the time of disease progression.8
The efficacy outcome measures included overall survival, progression-free survival, and objective response rate, as assessed by an investigator and by an independent review, according to the Response Evaluation Criteria in Solid Tumors guideline (version 1.1).8,10
Treatment with olaratumab plus doxorubicin demonstrated a significant improvement in overall survival; patients who received the combination lived a median of 11.8 months longer than those who received doxorubicin alone (Table 2).
In addition, the median progression-free survival was 4.8 months longer among patients who received the combination therapy than among patients who received doxorubicin alone. Furthermore, the objective response rate (ie, tumor shrinkage) was more than twice higher with olaratumab plus doxorubicin than with doxorubicin alone (Table 2).8
The most common (≥20% of patients) all-grade adverse reactions associated with olaratumab plus doxorubicin therapy, respectively, were nausea (73%), fatigue (69%), musculoskeletal pain (64%), mucositis (53%), alopecia (52%), vomiting (45%), diarrhea (34%), decreased appetite (31%), abdominal pain (23%), neuropathy (22%), and headache (20%).8
Of the 64 patients who were evaluated in the safety analysis, 5 (8%) patients permanently discontinued therapy with olaratumab because of adverse reactions. Infusion-related reactions, occurring in 3% of patients, were the most common adverse reactions that resulted in the permanent discontinuation of olaratumab.8
As with all therapeutic proteins, immunogenicity may occur with olaratumab. Based on the limited number of patients who had treatment-related anti-olaratumab antibodies, the effects of anti-olaratumab antibodies on the efficacy, safety, and exposure of olaratumab could not be evaluated.8 Olaratumab has no contraindications.8
Warnings and Precautions
Infusion-related reactions. Patients who receive olaratumab should be monitored for infusion-related reactions in a setting with available resuscitation equipment. Olaratumab should be permanently discontinued in patients with grade 3 or 4 infusion-related reactions.8
Embryo-fetal toxicity. Olaratumab can cause fetal harm when administered to a pregnant woman. Pregnant women should be advised of the potential risk to the fetus. Women of reproductive potential should use effective contraception during treatment with olaratumab and for 3 months after the last dose.8
Use in Specific Populations
Women should be advised not to breast-feed during treatment with olaratumab and for 3 months after the last dose.8
Current clinical trial data are insufficient to determine whether older patients (aged ≥65 years) respond to olaratumab different from younger patients.8
The accelerated FDA approval of olaratumab, for use in combination with doxorubicin, marks the availability of the first new frontline therapy for soft-tissue sarcoma since the approval of doxorubicin more than 4 decades ago. Olaratumab, a PDGF receptor-alpha–blocking antibody, is a new treatment option for patients with soft-tissue sarcoma, a complex disease with more than 50 subtypes and a poor prognosis, particularly in advanced stages.
In the pivotal clinical trial involving 133 patients with more than 25 subtypes of metastatic soft-tissue sarcoma, treatment with olaratumab plus doxorubicin demonstrated a significant improvement in overall survival, median progression-free survival, and objective response rate.
A phase 3 clinical trial (ANNOUNCE) evaluating olaratumab and doxorubicin in patients with advanced soft-tissue sarcoma is ongoing (it is no longer recruiting new patients).11
1. National Cancer Institute. Adult soft tissue sarcoma treatment (PDQ)—health professional version. Updated January 29, 2016. www.cancer.gov/types/soft-tissue-sarcoma/hp/adult-soft-tissue-treatment-pdq. Accessed October 25, 2016.
2. American Cancer Society. Sarcoma: adult soft tissue cancer. Revised October 21, 2016. www.cancer.org/acs/groups/cid/documents/webcontent/003138-pdf.pdf. Accessed October 26, 2016.
3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Soft Tissue Sarcoma. Version 2.2016. February 19, 2016. www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed October 26, 2016.
4. Mayo Clinic staff. Diseases and conditions: soft tissue sarcoma. July 1, 2015. www.mayoclinic.org/diseases-conditions/soft-tissue-sarcoma/basics/definition/con-20033386. Accessed October 26, 2016.
5. Tap WD, Jones RL, Van Tine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016;388:488-497. Erratum in: Lancet. 2016;388:464.
6. US Food and Drug Administration. FDA approves first drug to show survival benefit in liposarcoma. Press release. January 28, 2016. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm483714.htm. Accessed June 30, 2016.
7. US Food and Drug Administration. FDA grants accelerated approval to new treatment for advanced soft tissue sarcoma. Press release. October 19, 2016. www.fda.gov/newsevents/newsroom/pressannouncements/ucm525878.htm. Accessed October 21, 2016.
8. Lartruvo (olaratumab) injection [prescribing information]. Indianapolis, IN: Eli Lilly and Company; October 2016.
9. Lilly. FDA approves Lilly’s Lartruvo (olaratumab) in combination with doxorubicin for soft tissue sarcoma. Press release. October 19, 2016. https://investor.lilly.com/releasedetail.cfm?ReleaseID=994445. Accessed October 21, 2016.
10. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.
11. ClinicalTrials.gov. A study of doxorubicin plus olaratumab (LY3012207) in participants with advanced or metastatic soft tissue sarcoma (ANNOUNCE). https://clinicaltrials.gov/ct2/show/NCT02451943?term=NCT02451943&rank=1. Accessed October 25, 2016.