Clinical Pharmacology Corner: FDA approves LARTRUVO (olaratumab)

FDA approves LARTRUVO (olaratumab), in combination with doxorubicin, for the treatment of adult patients with soft tissue sarcoma  

On 10/19/2016, the U.S. Food and Drug Administration (FDA) granted accelerated approval to LARTRUVO (olaratumab) injection, in combination with doxorubicin, for the treatment of adult patients with soft tissue sarcoma (STS) with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery. The approved recommended dosage of LARTRUVO is 15 mg/kg as an intravenous infusion over 60 minutes on Days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity. For the first 8 cycles, LARTRUVO is administered with doxorubicin. Refer to doxorubicin prescribing information for dosing and dose modifications.

Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) of Olaratumab 

MOA: Olaratumab is a human IgG1 antibody that binds platelet-derived growth factor receptor alpha (PDGFR-α).

Distribution: The mean volume of distribution (CV%) at steady-state (Vss) is 7.7 L (16%).

Elimination: The mean clearance (CV%) for olaratumab was 0.56 L/day (33%). The estimated elimination half-life was approximately 11 days (range 6 to 24 days).

Exposure-Response: Olaratumab exposure-response relationships and the time course of the pharmacodynamics response are unknown.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity with LARTRUVO. In clinical trials, 13/370 (3.5%) of evaluable LARTRUVO-treated patients tested positive for treatment-emergent anti-olaratumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in all patients who tested positive for treatment-emergent anti-olaratumab antibodies. The effects of anti-olaratumab antibodies on efficacy, safety, and exposure of olaratumab could not be assessed due to the limited number of patients with treatment-emergent anti-olaratumab antibodies.

Drug Interaction Potential

No clinically relevant changes in the exposure of either olaratumab or doxorubicin were observed when LARTRUVO 15 mg/kg and doxorubicin 75 mg/m² were co-administered in patients with solid tumors.

Use in Specific Populations

No dose adjustment is necessary for mild to moderate (calculated creatinine clearance (CLcr) 30-89 mL/min as estimated by the Cockcroft-Gault formula) renal impairment, and mild (total bilirubin within upper limit of normal (ULN) and AST greater than ULN or total bilirubin greater than 1.0 and up to 1.5 times ULN and any AST) to moderate (total bilirubin greater than 1.5 and up to 3.0 times ULN and any AST) hepatic impairment.

Safety and Efficacy

Clinical efficacy and safety of olaratumab were demonstrated at the approved recommended dosage in an open-label, randomized, active-controlled clinical trial in 133 adult patients with soft tissue sarcoma not amenable to curative treatment with surgery or radiotherapy and a histologic type of sarcoma for which an anthracycline-containing regimen was appropriate, but had not been administered. The median overall survival (OS) was 26.5 months in patients treated with olaratumab and doxorubicin compared with 14.7 months in those receiving doxorubicin alone (hazard ratio 0.52 [95% CI: 0.34, 0.79], p-value less than 0.05). The median progression-free survival (PFS) was 8.2 months in patients treated with olaratumab and doxorubicin compared with 4.4 months in those receiving doxorubicin alone (hazard ratio 0.74 [95% CI: 0.46, 1.19]).

The most common (greater than or equal to 20%) adverse reactions of LARTRUVO in combination with doxorubicin were nausea, fatigue, musculoskeletal pain, mucositis, alopecia, vomiting, diarrhea, decreased appetite, abdominal pain, neuropathy, and headache. The most common (greater than or equal to 20%) laboratory abnormalities were lymphopenia, neutropenia, thrombocytopenia, hyperglycemia, elevated activated thromboplastin time (aPTT), hypokalemia, and hypophosphatemia.

As a condition of the accelerated approval, Eli Lilly and Company is conducting a larger randomized, controlled trial to verify and further describe the clinical benefit of olaratumab given with doxorubicin in adult patients with soft tissue sarcoma.

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Full prescribing information for LARTRUVO is available at http://go.usa.gov/xkfRu.

Full prescribing information for Doxorubicin HCl is available at: http://go.usa.gov/xkfRM.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the Agency’s Drugs@FDA website (http://go.usa.gov/xktcs).

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This burst was prepared by the Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov