Introduction
Olaratumab (Lartruvo®) is a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody that specifically targets platelet-derived growth factor receptor alpha (PDGFR-α). It received accelerated FDA approval in 2016 for the treatment of advanced soft tissue sarcoma. Olaratumab represents a novel targeted therapeutic approach for this difficult-to-treat malignancy, though its clinical development has undergone significant evolution following post-marketing studies.
Mechanism of Action
Olaratumab binds specifically to human PDGFR-α with high affinity, blocking receptor activation by PDGF-AA, PDGF-BB, and PDGF-CC ligands. This binding inhibits PDGFR-α signaling pathways, which are implicated in tumor growth, metastasis, and stromal recruitment. PDGFR-α is overexpressed in various sarcomas and plays a role in promoting tumor proliferation, angiogenesis, and maintenance of the tumor microenvironment. By targeting this receptor, olaratumab disrupts these pro-tumorigenic processes.
Indications
FDA-approved indication:- Treatment of adult patients with soft tissue sarcoma with a histologic subtype for which anthracycline-containing chemotherapy is appropriate and which is not amenable to curative treatment with radiotherapy or surgery
Dosage and Administration
Initial cycle:- 15 mg/kg administered intravenously on days 1 and 8 of a 21-day cycle
- 15 mg/kg administered intravenously on day 1 of each subsequent 21-day cycle
- Administer prior to doxorubicin on day 1 of each cycle
- Infuse intravenously over 60 minutes through a 0.22 micron in-line filter
- Premedication with diphenhydramine (25-50 mg IV) and dexamethasone (10-20 mg IV) is recommended to prevent infusion-related reactions
- No dose reductions recommended for olaratumab
- For infusion reactions: interrupt infusion and manage symptoms
- May resume at 50% reduced rate when symptoms resolve
- Renal impairment: No dosage adjustment recommended
- Hepatic impairment: No dosage adjustment recommended
- Elderly: No dosage adjustment recommended
Pharmacokinetics
Absorption: Administered intravenously, resulting in complete bioavailability Distribution: Steady-state volume of distribution is approximately 7.3 L. PDGFR-α binding affects distribution characteristics Metabolism: Olaratumab is expected to be metabolized via proteolytic degradation pathways typical of monoclonal antibodies Elimination: Terminal half-life is approximately 11 days (range 6-24 days). Clearance is approximately 0.55 L/day and is influenced by body weight and PDGFR-α expression levels Special populations: No clinically significant differences based on age, gender, race, renal impairment, or mild to moderate hepatic impairmentContraindications
- Known severe hypersensitivity to olaratumab or any of its excipients
- No other absolute contraindications have been identified
Warnings and Precautions
Infusion-related reactions: Occurred in approximately 13% of patients. Manifestations include fever, chills, hypotension, and dyspnea. Premedication and close monitoring during infusion are essential Embryo-fetal toxicity: May cause fetal harm based on mechanism of action. Advise females of reproductive potential to use effective contraception during treatment and for 3 months after last dose Neutropenia: Increased incidence observed when combined with doxorubicin. Monitor blood counts regularly QT interval prolongation: Monitor electrolytes and ECGs in patients at risk Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicityDrug Interactions
Doxorubicin: Increased doxorubicin exposure observed (AUC increased by 22%). Monitor for doxorubicin-related toxicities Other PDGFR-α inhibitors: Potential for additive effects and toxicity Live vaccines: Avoid concurrent administration due to potential decreased immune responseAdverse Effects
Most common adverse reactions (≥20%):- Nausea (73%)
- Fatigue (69%)
- Musculoskeletal pain (64%)
- Mucosal inflammation (53%)
- Alopecia (52%)
- Vomiting (45%)
- Diarrhea (34%)
- Decreased appetite (33%)
- Abdominal pain (32%)
- Neuropathy (29%)
- Headache (26%)
- Neutropenia (12%)
- Febrile neutropenia (7%)
- Infusion-related reactions (4%)
- Hypersensitivity reactions
Monitoring Parameters
Prior to initiation:- Comprehensive metabolic panel
- Complete blood count with differential
- ECG in patients with risk factors for QT prolongation
- Pregnancy test in women of childbearing potential
- Vital signs during and following infusion
- CBC with differential prior to each cycle
- Liver function tests periodically
- Signs and symptoms of infusion reactions
- Monitor for mucositis, neuropathy, and other toxicities
- Assessment of tumor response per RECIST criteria
- Cardiac function (due to doxorubicin combination)
- Continued assessment for late-emerging toxicities
Patient Education
Treatment information:- Explain the targeted mechanism of action and treatment schedule
- Discuss the combination nature of therapy with doxorubicin
- Report any signs of infusion reactions during or after treatment
- Manage nausea with prescribed antiemetics and dietary modifications
- Maintain oral hygiene to prevent and manage mucositis
- Report fever or signs of infection immediately
- Use caution regarding fatigue and avoid hazardous activities
- Use effective contraception during treatment and for 3 months after
- Discuss fertility preservation options before treatment
- Arrange for transportation after infusion appointments
- Maintain adequate hydration and nutrition
- Keep all scheduled follow-up appointments
- Report any new or worsening symptoms promptly
References
1. FDA Package Insert: Lartruvo® (olaratumab). Revised April 2019. 2. 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(10043):488-497. 3. Tap WD, Wagner AJ, Schöffski P, et al. Effect of doxorubicin plus olaratumab vs doxorubicin plus placebo on survival in patients with advanced soft tissue sarcomas: The ANNOUNCE randomized clinical trial. JAMA. 2020;323(13):1266-1276. 4. National Comprehensive Cancer Network (NCCN) Guidelines: Soft Tissue Sarcoma. Version 2.2023. 5. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379(9829):1879-1886. 6. Schöffski P, Chawla S, Maki RG, et al. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. Lancet. 2016;387(10028):1629-1637.
This monograph is intended for educational purposes only. Clinical decisions should be based on comprehensive patient assessment and current practice guidelines.