Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial

Abstract

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.

Findings: 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).

Interpretation: 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.

Funding: Eli Lilly and Company.

Conflict of interest statement

Declaration of interests

WDT reports personal fees from Eli Lilly and Company, Advaxis, Ariad, Boehringer Ingelheim, EMD Serono, Daiichi Sankyo, Morphotek, and Plexxikon. RLJ has received a grant(s) from ImClone. BAVT served on an advisory board for Eli Lilly and Company. BC reports personal fees from Eli Lilly and Company, Amgen, Astella, Genentech, and BMS. DA has received a grant(s) from Eli Lilly and Company. MA reports personal fees from EMD Serono, Janssen, and Novartis. GP reports personal fees from Bristol-Myers Squibb. GDS was an employee of Novartis during the conduct of the study. AQ, AS, DMC, RI, IC are employees of and stockholders in Eli Lilly and Company. JC was an employee of Eli Lilly and Company during the conduct of the study. ADE, MMC, MBL, MRH, and GKS declare no competing interests.

Copyright © 2016 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Enrollment and Outcomes in Phase 2

Control arm = doxorubicin; investigational arm = olaratumab + doxorubicin; olara = olaratumab Data cut-off date: 16 May 2015.

Figure 2. Survival Endpoints in Phase 2

Panels A and B show the Kaplan-Meier curves for the investigator assessment of progression-free survival and overall survival for the olaratumab + doxorubicin versus doxorubicin groups in the intention-to-treat population. CI denotes confidence interval, and HR denotes hazard ratio.*In Panel A the independent assessment of progression-free survival is included as an insert for comparison.

Figure 3. Forest Plot of Overall Survival Hazard Ratios for Potentially Prognostic Factors

Forest plot of overall survival with hazard ratios (HR) and 95% confidence intervals (CI) for several subgroups that could potentially influence the overall survival treatment effect (phase 2, intention-to-treat population). Duration of disease is the time from date of histology/pathology confirmation of soft tissue sarcoma to date of informed consent. ECOG denotes Eastern Cooperative Oncology Group, PDGFRα denotes platelet-derived growth factor receptor alpha, and WBC denotes white blood cell.