Drug Comparison: LartruvoTM (Olaratumab) for Soft Tissue Sarcoma By: Majd Abedrabbo, PharmD Candidate 2018 Fairleigh Dickinson University School of Pharmacy May 3, 2017 Introduction Soft Tissue Sarcoma (STS) is a rare type of cancer with multiple treatment options. There are approximately 12,390 new cases of STS diagnosed and 4,990 Americans are estimated to die each year in the United States. The standard of care for patients with metastatic STS is treatment with doxorubicin, an anthracycline that was approved in 1974 and is associated with significant toxicity, including myelosuppression, the development of secondary cancers, and dose-limiting cardiotoxicity. Other treatment options include targeted therapies, which interfere with mutated or over-active proteins that drive the cancer. In this article, we compare doxorubicin (Adriamycin), the standard of care, chemotherapeutic agent, with Olaratumab (Lartruvo), a new targeted therapy. Background STS is a collection of cancers of tissues that connect and support the body, like fat cells and blood vessels, which are of mesenchymal origin.1 Since sarcomas need not invade the basement membrane, they have a very high metastatic potential, capable of spreading throughout the body with relative ease. Risk factors of STS include specific genetic diseases, radiation treatments for other cancers, and exposure to chemicals.2 Although there are more than 50 types of STS, the most common types in adults are undifferentiated pleomorphic sarcoma, liposarcoma, and leiomyosarcoma.3 The risk and severity of STS depends on the type, which is dependent upon the location, specific cell of origin, stage of differentiation, and mutations. The standard of care for patients with metastatic STS is treatment with doxorubicin, which disrupts topoisomerase II by intercalating into the DNA, preventing DNA replication and transcription, thereby inducing apoptosis.4 It can be used as 1 monotherapy or in combination with other drugs. When used alone, response rates range from 20-30% with a median overall survival of 7.7 to 12 months. Doxorubicin follows a dose response relationship; therefore, response rates increase when given at higher doses.5 A study conducted by the Southwest Oncology Group (SWOG) included 79 patients who were categorized as good risk patients. They were randomly assigned to doxorubicin doses of 45, 60, or 75 mg/m2 and sarcoma response rates were 18, 20, and 37%, respectively.6 The optimal dose response ranges from 75 to 90 mg/m2.5 Olaratumab is a fully human IgG1 monoclonal antibody that binds to PDGFR-α (Platelet Derived Growth Factor Receptor), which is expressed on mesenchymal cells, including sarcomas. It is highly specific in its binding to PDGFR-α, which is a receptor tyrosine kinase that plays a significant role in cell growth, chemotaxis, and cell differentiation. PDGFR-α is located on tumor cells, stromal cells, and sarcomas, and provides signals that drive proliferation of cancer cells and metastases.8 The Food and Drug Administration (FDA) granted the olaratumab fast track designation, breakthrough therapy designation, and priority review status because Phase II trails suggested “evidence indicating substantial improvement in effectiveness in the treatment of a serious or life-threatening disease or condition.”7 On October 16, 2016, the FDA approved olaratumab in combination with doxorubicin for the treatment of STS. A two-part open-label, multicenter, randomized, active-controlled, phase 1b and phase 2 study compared the effectiveness of doxorubicin single agent and combination doxorubicin plus olaratumab in patients with STS that was unresectable, metastatic, or not amendable to radiotherapy. In the phase 2 segment, a total of 133 patients who were not previously treated with an anthracycline were included: ages 22 to 86 years (median 2 58 years), 44% were men, and the population was predominantly Caucasian. Eligible patients were not previously treated with an anthracycline-containing regimen. Olaratumab was administered at 15 mg/kg IV infusion on days 1 and 8 during each 21- day cycle until toxicity was seen or the disease had progressed. Both arms in the study received doxorubicin 75 mg/m2 IV infusion on day 1 during each 21-day cycle for a maximum of eight cycles. Patients treated with olaratumab plus doxorubicin had an overall survival of 26.5 months versus 14.7 months for doxorubicin, alone (p < 0.05).9 In this pivotal study, participants were permitted to receive dexrazoxane (a cardio- protective agent) before administration of doxorubicin in cycles 5 to 8 because doxorubicin has been associated with severe and life-threatening cardiotoxicity. The exact mechanism of cardiotoxicity is controversial, but one main theory relates to the formation of doxorubicin metabolites and iron-related free radicals. This mechanism is supported by evidence that the administration of dexrazoxane, an iron chelator, provides protection from doxorubicin toxicity.10 Cardiotoxicity can occur early (acute) or late (delayed). Acute cardiotoxicity consists of ECG abnormalities and sinus tachycardia. Symptoms of delayed cardiotoxicity can occur after months or even several years following completion of treatment and include tachycardia, dyspnea, and pulmonary edema, all of which indicate the development of irreversible congestive heart failure (CHF). The risk of developing CHF increases with higher doses, but doxorubicin-induced cardiotoxicity can also occur at lower doses in patients with risk factors, including pre- existing heart disease, exposure at an early age, advanced age, and concomitant use of other cardiotoxic agents. The potential damage seen begins at cumulative doses of doxorubicin of more than 300 mg/m2. Other severe adverse reactions caused by 3 doxorubicin are severe myelosuppression, occurrence of secondary leukemia (acute myeloid leukemia or myelodysplastic syndrome), and peripheral neurotoxicity.11 In olaratumab treated patients, adverse reactions that resulted in permanent discontinuation occurred in 8% of patients. The primary cause of discontinuation is infusion-related reactions, which is included as a warning in the label. The most common adverse reactions (> 20%) associated with the drug are nausea, fatigue, musculoskeletal pain, mucositis, alopecia, vomiting, diarrhea, decreased appetite, abdominal pain, neuropathy, and headache. The most common laboratory abnormalities (> 20%) seen with the use of olaratumab are lymphopenia, neutropenia, thrombocytopenia, hyperglycemia, elevated aPTT, hypokalemia, and hypophosphatemia. Although the combination of olaratumab plus doxorubicin increases the risk of gastrointestinal side effects, fatigue, and bone marrow suppression, all chemotherapies used in STS are associated with these toxicities.8 Currently, evidence demonstrates that both doxorubicin and olaratumab are effective for the treatment of STS. It is important to highlight that since olaratumab is indicated in combination with doxorubicin, the increased risk of gastrointestinal effects, fatigue, and bone marrow suppression are more likely attributed to doxorubicin rather than olaratumab. Doxorubicin toxicities are frequently responsible for discontinuation of therapy and dose reductions, both of which reduce the effectiveness of the drug. Olaratumab may be especially helpful in this regard: (1) improved response rates and durations of response could obviate the need for additional courses of therapy; and (2) olaratumab may maintain response rates when dose intensity of doxorubicin needs to be reduced to manage toxicity. 4 The Director of the FDA Office of Hematology and Oncology Products, Richard Pazdur said, “[Olaratumab] 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”.2 The Hematology-Oncology team lead at Northwestern Medicine, Marco Martino stated, “Approximately 12,310 new cases of STS will be diagnosed in 2016. Despite these setbacks, the 5-year overall survival of STS remains strong at 50% to 60%; thus, there is a significant need for developing treatment options that have good response rates and an acceptable adverse effect profile”.12 Olaratumab provides improved outcomes when used in combination with doxorubicin and may help to lessen the incidence and severity of doxorubicin-related toxicities in the acute and long-term treatment of STS. 5 References 1. Cancer Biology: Discussions of New Developments and Updates. Olaratumab Receives Priority Review for Soft Tissue Sarcoma. http://blogs.shu.edu/cancer/2016/05/11/olaratumab-receives-priority-review-for- soft-tissue-sarcoma/. Accessed April 5, 2017. 2. Fala L. Lartruvo (Olaratumab) a Novel First-Line Treatment Approved for Patients with Advanced Soft-Tissue Sarcoma. Oncology Practice Management. http://oncpracticemanagement.com/issue-archive/2017/january-2017-vol-7-no- 1/lartruvo-olaratumab-a-novel-first-line-treatment-approved-for-patients-with- advanced-soft-tissue-sarcoma/. Published January 2017. Accessed April 22, 2017. 3. American Cancer Society. About Soft Tissue Sarcoma. https://www.cancer.org/cancer/soft-tissue-sarcoma/about/key-statistics.html. Accessed April 8, 2017. 4. Thorn CF, Oshiro C, Marsh S, et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenetics and Genomics. 2011;21(7):440-446. doi:10.1097/FPC.0b013e32833ffb56. 5. Purohit S, Bhise R, Appachu S, Lakshmaiah KC, Govindbabu K. Systemic Therapy in Soft Tissue Sarcomas: Past, Present and Future. Indian Journal of Surgical