Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial.
BACKGROUND
Treatment with doxorubicin is a present standard of care for patients with metastatic soft-tissue sarcoma and median overall survival for those treated is 12-16 months, but few, if any, novel treatments or chemotherapy combinations have been able to improve these poor outcomes. Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumour activity in human sarcoma xenografts. We aimed to assess the efficacy of olaratumab plus doxorubicin in patients with advanced or metastatic soft-tissue sarcoma.


METHODS
We did an open-label phase 1b and randomised phase 2 study of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic soft-tissue sarcoma at 16 clinical sites in the USA. For both the phase 1b and phase 2 parts of the study, eligible patients were aged 18 years or older and had a histologically confirmed diagnosis of locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and available tumour tissue to determine PDGFRα expression by immunohistochemistry. In the phase 2 part of the study, patients were randomly assigned in a 1:1 ratio to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m(2)) or doxorubicin alone (75 mg/m(2)) on day 1 of each 21-day cycle for up to eight cycles. Randomisation was dynamic and used the minimisation randomisation technique. The phase 1b primary endpoint was safety and the phase 2 primary endpoint was progression-free survival using a two-sided α level of 0.2 and statistical power of 0.8. This study was registered with ClinicalTrials.gov, number NCT01185964.


RESULTS
15 patients were enrolled and treated with olaratumab plus doxorubicin in the phase 1b study, and 133 patients were randomised (66 to olaratumab plus doxorubicin; 67 to doxorubicin alone) in the phase 2 trial, 129 (97%) of whom received at least one dose of study treatment (64 received olaratumab plus doxorubicin, 65 received doxorubicin). Median progression-free survival in phase 2 was 6.6 months (95% CI 4.1-8.3) with olaratumab plus doxorubicin and 4.1 months (2.8-5.4) with doxorubicin (stratified hazard ratio [HR] 0.67; 0.44-1.02, p=0.0615). Median overall survival was 26.5 months (20.9-31.7) with olaratumab plus doxorubicin and 14.7 months (9.2-17.1) with doxorubicin (stratified HR 0.46, 0.30-0.71, p=0.0003). The objective response rate was 18.2% (9.8-29.6) with olaratumab plus doxorubicin and 11.9% (5.3-22.2) with doxorubicin (p=0.3421). Steady state olaratumab serum concentrations were reached during cycle 3 with mean maximum and trough concentrations ranging from 419 μg/mL (geometric coefficient of variation in percentage [CV%] 26.2) to 487 μg/mL (CV% 33.0) and from 123 μg/mL (CV% 31.2) to 156 μg/mL (CV% 38.0), respectively. Adverse events that were more frequent with olaratumab plus doxorubicin versus doxorubicin alone included neutropenia (37 [58%] vs 23 [35%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [18%]), and diarrhoea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade 3 or higher was similar in both groups (olaratumab plus doxorubicin: eight [13%] of 64 patients vs doxorubicin: nine [14%] of 65 patients).


CONCLUSIONS
This study of olaratumab with doxorubicin in patients with advanced soft-tissue sarcoma met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement of 11.8 months in median overall survival, suggesting a potential shift in the treatment of soft-tissue sarcoma.


BACKGROUND
Eli Lilly and Company.
Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. Electronic address: tapw@mskcc.org.
William D
WD
Tap
University Washington, Seattle, WA, USA; The Royal Marsden Hospital, London, UK.
Robin L
RL
Jones
Washington University in St Louis, St Louis, MO, USA.
Brian A
BA
Van Tine
UCLA Medical Center, Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA.
Bartosz
B
Chmielowski
University of Colorado Cancer Center, Aurora, CO, USA.
Anthony D
AD
Elias
Washington University in St Louis, St Louis, MO, USA.
Douglas
D
Adkins
Northwestern University, Chicago, IL, USA.
Mark
M
Agulnik
University Hospitals Case Medical Center, Seidman Cancer Center, Division of Hematology and Oncology, Cleveland, OH, USA.
Matthew M
MM
Cooney
Carolinas Healthcare System, The Charlotte-Mecklenburg Hospital Authority, Charlotte, NC, USA.
Michael B
MB
Livingston
Baptist MD Anderson Cancer Center, Jacksonville, FL, USA.
Gregory
G
Pennock
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Meera R
MR
Hameed
Novartis Pharmaceuticals, East Hanover, NJ, USA.
Gaurav D
GD
Shah
Eli Lilly and Company, Bridgewater, NJ, USA.
Amy
A
Qin
Eli Lilly and Company, Windlesham, Surrey, UK.
Ashwin
A
Shahir
Eli Lilly and Company, Windlesham, Surrey, UK.
Damien M
DM
Cronier
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
Robert
R
Ilaria
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
Ilaria
I
Conti
Eli Lilly and Company, Bridgewater, NJ, USA.
Jan
J
Cosaert
Columbia University School of Medicine, New York, NY, USA.
Gary K
GK
Schwartz
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D012509:Sarcoma / Q000188:drug therapy*; D016896:Treatment Outcome; D014481:United States
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D004317:Doxorubicin; C000589393:olaratumab