FDA grants accelerated approval to new treatment for advanced soft tissue sarcoma.

October 19, 2016

The U.S. Food and Drug Administration granted accelerated approval to Lartruvo (olaratumab) with doxorubicin to treat adults with certain types of soft tissue sarcoma (STS), which are cancers that develop in muscles, fat, tendons or other soft tissues.

Lartruvo is approved for use with the FDA-approved chemotherapy drug doxorubicin for the treatment of patients with STS who cannot be cured with radiation or surgery and who have a type of STS for which an anthracycline (chemotherapy) is an appropriate treatment.

pdgfr-signaling
http://www.lillyoncologypipeline.com/_assets/pdf/pdgfra_antibody.pdf

 

DESCRIPTION

Olaratumab is a recombinant human IgG1 monoclonal blocking antibody that binds specifically to human plateletederived growth factor receptor alpha (PDGFR-α).

LARTRUVO has an approximate molecular weight of 154 kDa. LARTRUVO is produced in genetically engineered mammalian NS0 cells.

CLINICAL PHARMACOLOGY

 Mechanism of Action

 

http://www.slideshare.net/coolesanum/olaratumab-imc-3-g3-ottobre-2010
http://www.slideshare.net/coolesanum/olaratumab-imc-3-g3-ottobre-2010
  • Olaratumab is a human IgG1 antibody that binds platelet-derived growth factor receptor alpha (PDGFR-α).
  • PDGFR-α is a receptor tyrosine kinase expressed on cells of mesenchymal origin.
  • Signaling through this receptor plays a role in cell growth, chemotaxis, and mesenchymal stem cell differentiation.
  • The receptor has also been detected on some tumor and stromal cells, including sarcomas, where signaling can contribute to cancer cell proliferation, metastasis, and maintenance of the tumor microenvironment.
  • The interaction between olaratumab and PDGFR-α prevents binding of the receptor by the PDGF-AA and -BB ligands as well as PDGF-AA, -BB, and -CC-induced receptor activation and downstream PDGFR-α pathway signaling.
  • Olaratumab exhibits in vitro and in vivo anti-tumor activity against selected sarcoma cell lines and disrupted the PDGFR-α signaling pathway in in vivo tumor implant models.

INDICATION

This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

DOSAGE AND ADMINISTRATION

• Administer LARTRUVO at 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.

• Premedicate with diphenhydramine and dexamethasone intravenously, prior to LARTRUVO on Day 1 of cycle 1.

 • For intravenous infusion only. Do not administer as an intravenous push or bolus.

SAFETY & EFFICACY

The safety and efficacy of Lartruvo were studied in a randomized clinical trial involving 133 patients with more than 25 different subtypes of metastatic STS. Patients received either Lartruvo with doxorubicin or doxorubicin alone. This trial measured the length of time patients lived after treatment (overall survival), the length of time tumors did not grow after treatment (progression-free survival) and the percentage of patients who experienced shrinkage of their tumors (overall response rate). Patients in this trial who received Lartruvo with doxorubicin had a statistically significant improvement in overall survival: the median survival was 26.5 months compared to 14.7 months for patients who received doxorubicin alone. Patients who received Lartruvo with doxorubicin had a median progression-free survival of 8.2 months compared to 4.4 months for patients who received doxorubicin alone. Tumor shrinkage was 18.2 percent for patients who received Lartruvo with doxorubicin and 7.5 percent for those who received doxorubicin alone.

WARNINGS AND PRECAUTIONS

• Infusion-Related Reactions: Monitor for signs and symptoms during and following infusion.Discontinue LARTRUVO for Grade 3 or 4 infusion-related reactions.

• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of potential risk to the fetus and to use effective contraception during treatment with LARTRUVO and for 3 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions of LARTRUVO plus doxorubicin are nausea, fatigue, musculoskeletal pain, mucositis, alopecia, vomiting, diarrhea, decreased appetite, abdominal pain, neuropathy, and headache.

The most common (≥20%) laboratory abnormalities were lymphopenia, neutropenia, thrombocytopenia, hyperglycemia, elevated aPTT, hypokalemia, and hypophosphatemia.

 

Reference:

  1. FDA News
  2. PIL