William D. Tap, MD

As reported by William D. Tap, MD, of Memorial Sloan Kettering Cancer Center, and colleagues in The Lancet, the addition of the anti-PDGFRα (platelet-derived growth factor receptor alpha) antibody olaratumab to doxorubicin resulted in prolonged progression-free and overall survival in phase II evaluation in patients with advanced soft-tissue sarcoma.¹

Study Details

In the phase II portion of an open-label phase Ib/II trial, 133 patients with advanced or metastatic disease and no previous anthracycline treatment from 16 U.S. sites were randomized between October 2010 and January 2013 to receive olaratumab at 15 mg/kg intravenously on days 1 and 8 plus doxorubicin at 75 mg/m² (n = 66) or doxorubicin alone (n = 67) on day 1 of each 21-day cycle for up to 8 cycles. After eight cycles of doxorubicin, patients in the olaratumab/doxorubicin group could receive olaratumab monotherapy until disease progression, and patients in the doxorubicin group could receive olaratumab monotherapy after disease progression.

Randomization was stratified for Eastern Cooperative Oncology Group (ECOG) performance status, histologic tumor type, immunohistochemical PDGFR expression, and number of previous treatments. The primary endpoint was investigator-assessed progression-free survival in the intent-to-treat population using a two-sided α level of 0.2 and statistical power of 0.8.

For the olaratumab/doxorubicin and doxorubicin groups, median age was 58.5 and 58.0 years; 61% and 51% were women; 83% and 90% were white; 94% in both groups had an ECOG performance status of 0 or 1; 64% and 60% had nonleiomyosarcoma histologic type (most common types = leiomyosarcoma in 36% and 40%, undifferentiated pleomorphic sarcoma in 15% and 21%, and liposarcoma in 12% and 22%); and 59% and 54% had received at least one prior treatment. The initial PDGFRα assay indicated that 88% of both groups were positive (higher staining); however, the assay was subsequently shown to detect both PDGFRα and PDGFRβ. Another exploratory assay was developed for post-hoc analysis; on this assay, 33% of those receiving olaratumab/doxorubicin and 34% of those receiving doxorubicin alone were considered positive for PDGFRα based on staining intensity. Two patients in each group did not begin study treatment.

Progression-Free Survival

Median progression-free survival was 6.6 months (95% confidence interval [CI] = 4.1–8.3 months) in the olaratumab/doxorubicin group vs 4.1 months (95% CI = 2.8–5.4 months) in the doxorubicin group (stratified hazard ratio [HR] = 0.67, P = .0615, meeting the protocol-defined significance level of .1999 for final progression-free survival). On blinded independent retrospective review of radiologic scans, the hazard ratio was 0.67 (P = .1208), with median progression-free survival of 8.2 vs 4.4 months. Objective response rates were 18.2% vs 11.9% (P = .3421).

Overall Survival

Median overall survival was 26.5 months (95% CI = 20.9–31.7 months) vs 14.7 months (95% CI = 9.2–17.1 months; stratified HR = 0.46, P = .0003). Benefit of olaratumab was consistent across subgroup stratification factors, including sex (HRs = 0.53 in women and 0.55 in men), histologic tumor type (HRs = 0.47 in leiomyosarcoma and 0.56 in others), number of lines of previous treatment (HRs = 0.47 for 0 and 0.55 for ≥ 1), and PDGFRα status (HRs = 0.64 for positive and 0.40 for negative on exploratory assay). Treatment after disease progression was received by more than 65% of patients in each group, including olaratumab in 46% of the doxorubicin group; a sensitivity analysis with censoring at the time of starting any new anticancer treatment yielded a similar hazard ratio of 0.425 (P = .0284). Olaratumab was continued as monotherapy for at least one cycle in 53% of the olaratumab group.

Adverse Events

The most common adverse events of any grade were nausea, fatigue, neutropenia, and mucositis in the olaratumab/doxorubicin group and fatigue, nausea, alopecia, and neutropenia in the doxorubicin group. Adverse events of any grade commonly associated with doxorubicin that were more common in the olaratumab/doxorubicin group included neutropenia (58% vs 35%; grade ≥ 3 in 53% vs 33%), mucositis (53% vs 35%), nausea (73% vs 52%), vomiting (45% vs 18%), and diarrhea (34% vs 23%). Grade ≥ 3 adverse events occurred in 80% vs 69% of patients, with the most common in the olaratumab/doxorubicin group being neutropenia, leukopenia (36% vs 17%), anemia (13% vs 9%), and febrile neutropenia (13% vs 14%).

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….

— William D. Tap, MD, and colleagues

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Serious adverse events occurred in 42% vs 38%. Treatment was discontinued due to adverse events in 13% vs 18%. The most common reason for discontinuation of olaratumab was infusion-related reaction (3%); the most common cause of discontinuation of doxorubicin was decreased ejection fraction (5% of the olaratumab/doxorubicin group and 6% of the doxorubicin group).

The investigators concluded: “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.” ■

Disclosure: The study was funded by Eli Lilly and Company. For full disclosures of the study authors, visit www.thelancet.com.

Reference

1. 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 388:488-497, 2016.