1923P - Combined analysis of phase III ANNOUNCE study and phase II study exploring olaratumab in advanced soft tissue sarcoma

Background

Doxorubicin remains the standard of care for most of advanced soft tissue sarcoma. However, survival for patients with advanced soft tissue sarcoma is unsatisfactory. Consequently, there is an urgent need for new treatments. Olaratumab is a monoclonal antibody directed against the platelet-derived growth factor receptor and has been studied in soft tissue sarcoma. In a phase II study, olaratumab in combination with doxorubicin showed an overall survival benefit over doxorubicin alone. However, a confirmatory phase III ANNOUNCE study failed to demonstrate the benefit of olaratumab. One possible explanation of the contradictory results is that the dose of doxorubicin used in each trial is significantly different. Therefore, we examined the effect of doxorubicin dose on survival using individual data from the phase II and phase III studies.

Methods

Individual patient data were retrieved from the Vivli platform (https://vivli.org/) after study proposal approval. Patient characteristics including clinicopathologic findings, progression-free and overall survival (OS) data, and doxorubicin dose were analyzed. Cox proportional hazard model was used to estimate the effect of doxorubicin dose on survival.

Results

A total of 632 patients (128 from phase II and 504 from phase III study) were included in the current study. Median age was 58 years, 267 (42.2%) were male, 375 (59.3%) were performance status 0, and 282 (44.6%) had leiomyosarcoma. Median cumulative doxorubicin dose was 449 mg/m² in all patients, 426 mg/m² (488 in phase II and 409 in phase III) for doxorubicin with olaratumab arm and 451 mg/m² (300 in phase II and 483 in phase III) for doxorubicin alone arm. In the combined analysis olaratumab showed marginal OS benefit (HR: 0.83, 95%CI: 0.69-1.01, p-value: 0.061). Cumulative doxorubicin dose had statistically significant impact on OS (HR for difference in dose of 75mg/m²: 0.80, 95%CI: 0.77-0.83, p-value: <0.001).

Conclusions

Cumulative doxorubicin dose had a significant impact on OS, with a HR of 0.80 for the difference by doxorubicin dose per cycle, which may explain the discrepancy between the phase II and phase III results. Our investigation reaffirms the importance of doxorubicin in advanced soft tissue sarcoma.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

Y. Naito: Financial Interests, Personal, Invited Speaker, Speakers Bureau: Chugai, Pfizer, Eli Lilly, Eisai, AstraZeneca, PDR pharma, Novartis, Gardant, Ono, Takeda, Taiho, Bayer, Nihon Kayaku, Daiichi Sankyo, BMS, MSD; Financial Interests, Personal, Funding: Roche; Financial Interests, Personal, Invited Speaker: AbbVie, Boehringer Ingelheim, Daiichi Sankyo, Ono, Chugai, Taiho, Pfizer, AstraZeneca, Gilead, Takeda; Non-Financial Interests, Principal Investigator, JCOG: Natera. T. Mukohara: Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo, Eisai, MSD, Pfizer, Novartis, Sanofi, Chugai, AstraZeneca, Ono; Financial Interests, Personal and Institutional, Research Grant: Sysmex; Financial Interests, Personal, Other, lecture fee: Eli Lilly, Kyowa Kirin, Taiho. All other authors have declared no conflicts of interest.