eUpdate – Soft Tissue Sarcoma Treatment Recommendations

Published: 5 May 2017. Authors: ESMO Guidelines Committee

Clinical Practice Guidelines

This update refers to the Soft tissue and visceral sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. ESMO/European Sarcoma Network Working Group. Ann Oncol 2014;25 (Suppl 3): iii102-iii12. Erratum in: Ann Oncol 2015;26 (Suppl 5): v174-v177.

Section

Management of advanced disease

Text update

In an open label, randomised phase Ib/II trial of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic soft tissue sarcoma, patients aged 18 years or older with a histologically confirmed diagnosis of locally advanced or metastatic soft tissue sarcoma not previously treated with an anthracycline and with a performance status of 0–2, 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/m2) or doxorubicin alone (75 mg/m2) on day 1 of each 21-day cycle for up to eight cycles in the phase II part of the study.

The phase 1b primary end point was safety and the phase 2 primary end point was progression-free survival (PFS) using a two-sided α level of 0.2 and statistical power of 0.8.133 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 PFS 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), thus meeting the idiosyncratic predefined primary end point for PFS of p<0·1999.

Median overall survival (OS), a secondary end point, 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).
Although this study of olaratumab with doxorubicin in patients with unresectable or metastatic soft tissue sarcoma did not achieve the usual standard of p<0.05 for its primary outcome of PFS, it did achieve its predefined primary end point with p=0.0615.  Furthermore, it achieved a highly significant improvement of 11.8 months in median OS, a secondary end point.

A double-blind placebo controlled phase III study comparing doxorubicin plus placebo versus doxorubicin plus olaratumab, with the same two arms as described for the phase II study, has completed accrual, and results are expected in 2019.

E-Alert

In patients with unresectable or metastatic soft tissue sarcoma, this small phase 1/II study of olaratumab with doxorubicin in patients with advanced soft tissue sarcoma met its predefined primary end point for PFS (p<0.1999) and achieved a highly significant improvement of 11.8 months in median OS, a secondary end point.

A double-blind placebo controlled phase III study comparing doxorubicin plus placebo versus doxorubicin plus olaratumab, with the same two arms as described for the phase II study, has completed accrual, and results are expected in 2019.

The observed PFS benefit is associated with an ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) score of 4, because of the magnitude of improvement on OS.

ESMO-Magnitude of Clinical Benefit Scale (MCBS) table for new therapies/indications in soft tissue and visceral sarcomas*

Therapy Disease setting Trial Control Absolute survival gain HR (95% CI) QoL/toxicity MCBS score**
Olaratumab with doxorubicin Unresectable or metastatic soft tissue sarcoma with a histologically confirmed diagnosis, PS of 0-2 and not previously treated with an anthracycline

Olaratumab and Doxorubicin versus Doxorubicin Alone for Treatment of Soft-Tissue Sarcoma: An Open-Label Phase 1b and Randomised Phase 2 Trial [1]

Phase Ib/II
 
NCT01185964

Doxorubicin
 
Median OS: 14.7 months
OS gain: 11.8 months OS HR: 0.46 (0.30–0.71) QoL not available
 
AEs similar (or slightly worse for leukopaenia and neutropaenia)
4 (Form 2a; secondary endpoint of OS in a small phase II randomised study)

*EMA approvals from January 2016 to end January 2017.

**ESMO-MCBS version 1.0 [2]

AE, adverse event; CI, confidence interval; EMA, European Medicines Agency; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PS, performance status; QoL, quality of life

References

  1. Tap WG, 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: 488-497.
  2. Cherny NI, Sullivan R, Dafni U et al. A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Ann Oncol 2015; 26: 1547–1573.