October 19, 2016
On October 19, 2016, the U.S. Food and Drug Administration granted accelerated approval to olaratumab (LARTRUVO, Eli Lilly and Company) for the treatment of patients with soft tissue sarcoma (STS) not amenable to curative treatment with radiotherapy or surgery and with a histologic subtype for which an anthracycline-containing regimen is appropriate.
Approval was based on data from a randomized, active-controlled, clinical trial involving 133 patients with metastatic STS. Patients were required to have STS 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.
Patients were randomized (1:1) to receive the combination of olaratumab plus doxorubicin or doxorubicin as a single agent. Olaratumab was administered at 15 mg/kg as an intravenous (IV) infusion on days 1 and 8 of each 21-day cycle. All patients received doxorubicin 75 mg/m2 as an IV infusion on day 1 of each 21-day cycle for maximum of eight cycles and were permitted to receive dexrazoxane on cycles 5 to 8. Single-agent olaratumab was offered to patients in the doxorubicin alone arm at the time of disease progression. Sixty-six patients were randomized to the combination treatment and 67 to doxorubicin alone. Sixty-five percent of patients had no prior chemotherapy (excluding adjuvant and neoadjuvant therapy), 38% had leiomyosarcoma, 1.5% had synovial sarcoma, and 61% had other histologies (over 25 different STS histologies). All patients had metastatic disease and were enrolled in the United States.
Patients who received the combination treatment had a statistically significant improvement in overall survival (OS) compared to those receiving doxorubicin alone. Patients receiving the combination treatment had a median OS of 26.5 months (95% CI: 20.9, 31.7) compared to 14.7 months (95% CI: 9.2, 17.1) for those receiving doxorubicin alone (HR=0.52 [95% CI: 0.34, 0.79]).
The median progression-free survival (independent review) was 8.2 months (95% CI: 5.5, 9.8) for patients who received the combination treatment and 4.4 months (95% CI: 3.1, 7.4) for those receiving doxorubicin alone (HR=0.74 [95% CI: 0.46, 1.19]). The overall response rate (independent review) was 18% (95% CI: 9.8, 29.6) in the combination arm and 8% (95% CI: 2.5, 16.6) in the doxorubicin alone arm.
The most common (greater than or equal to 20%) side effects of treatment with olaratumab are nausea, fatigue, neutropenia, musculoskeletal pain, mucositis, alopecia, vomiting, diarrhea, decreased appetite, abdominal pain, neuropathy, and headache. Infusion-related reactions were seen in 13% of patients.
The recommended dose and schedule of olaratumab is 15 mg/kg administered as an IV infusion over 60 minutes on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity. For the first eight cycles, olaratumab is administered with doxorubicin.
FDA granted olaratumab fast track and breakthrough therapy designation, priority review status, and accelerated approval for this indication. As a condition of the accelerated approval, Eli Lilly and Company is required to conduct a randomized, controlled trial to verify and further describe the clinical benefit of olaratumab given with doxorubicin in patients with STS. Olaratumab also received orphan drug designation. A description of these expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.
Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761038lbl.pdf
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 mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
Pharmacist's Application to Practice
Olaratumab for Advanced or Metastatic Soft-Tissue Sarcoma in Combination with Doxorubicin
Author: Rene Mani, PharmD BCOP BCPS
Clinical Pharmacy Specialist, Hematology-Oncology
Dallas VA Medical Center
What is the potential role for olaratumab in the management of soft-tissue sarcoma?
- As a first-in-class anti-PDGFRα monoclonal antibody, olaratumab could potentially represent a shift in the treatment paradigm for advanced or metastatic soft-tissue sarcoma. Doxorubicin, either as monotherapy or in combination with ifosfamide, has remained the standard of care for first-line treatment of most soft-tissue sarcomas for the last several decades, while other regimens have largely failed to improve survival. Olaratumab in combination with doxorubicin appears to be an exception, displaying a very impressive gain in overall survival of almost 1 year.1,2
- Significant concerns may limit the utility of this regimen until more robust data are available from the ongoing phase 3 ANNOUNCE trial. Those concerns include the following:1,2
- The primary end point of progression-free survival is not statistically significant, according to conventional statistical limits by either investigator assessment or independent review (α-level was set at 0.2).
- Discontinuation rates were higher in the monotherapy arm, in spite of the combination arm’s experiencing more toxicity, which was most likely influenced by the open-label nature of the trial and could possibly have affected the overall-survival outcome.
- No correlation was found between tumor PDGFRα positivity and outcomes, which calls into question the primary mechanism of action of olaratumab and the amount of additional benefit it is actually providing when combined with doxorubicin.
- The maximum number of 8 cycles of doxorubicin (600 mg/m2 cumulative exposure) is above the conventional limit of 450–500 mg/m2, thus raising long-term safety concerns and necessitating the addition of dexrazoxane for cardioprotection (which, incidentally, further increases the cost of therapy).
What role can the pharmacist play in the management of patients on olaratumab?
- Given the fairly large increase in both nausea (73% vs. 52%) and vomiting (45% vs. 18%) with the combination of olaratumab and doxorubicin compared to doxorubicin alone, antiemetic prophylaxis and treatment associated with this regimen can be optimized with the expertise of the oncology pharmacist; appropriate prophylaxis for highly emetogenic chemotherapy regimens as per multiple antiemesis guidelines should be instituted with this regimen.2
- Pharmacists can educate and advise providers regarding the necessity and frequency of cardiac monitoring on this regimen, especially given that the cumulative doxorubicin exposure can exceed 450–500 mg/m2. Although the prescribing information contains no specific monitoring requirement, the trial investigators evaluated cardiac function by echocardiogram or multiple gated acquisition scan at baseline and prior to cycles 5 and 7, so it would be prudent to adopt a similar routine in clinical practice.2
- Olaratumab is supplied as a 500 mg/50ml (10 mg/ml) single-dose vial, which may be taken into account for determining appropriate rounding of calculated doses.3
- Dexrazoxane was administered prior to doxorubicin in cycles 5 through 8 in an effort to prevent cardiotoxicity.2
- On the basis of animal data and its mechanism of action, olaratumab is likely to cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to use adequate contraception during treatment with olaratumab and for 3 months after the last dose.3
- Judson I, van der Graaf WT. Sarcoma: Olaratumab—really a breakthrough for soft-tissue sarcomas? Nat Rev Clin Oncol. 2016;13(9):534-36.
- 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):488-97.
- Lartruvo [package insert]. Indianapolis, IN: Eli Lilly and Co; 2016.