Olaratumab May Cause ‘Potential Paradigm Shift’ In Soft-Tissue Sarcoma Treatment

Soft-tissue sarcoma patients with locally advanced or metastatic disease derive a survival benefit with the combination of olaratumab and doxorubicin

medwireNews: The addition of olaratumab to doxorubicin improves survival in patients with locally advanced or metastatic soft-tissue sarcoma, find researchers.

Treatment with the antiplatelet-derived growth factor receptor α (PDGFRα) monoclonal antibody prolonged progression-free survival (PFS) and furthermore led to a “highly significant” improvement of 11.8 months in median overall survival (OS), “suggesting a potential paradigm shift in the treatment of soft-tissue sarcoma”, they write in the The Lancet.

In the phase II part of this trial, 133 patients not previously treated with an anthracycline were randomly assigned to receive doxorubicin 75 mg/m2 on day 1 of a 3-week cycle either alongside intravenous olaratumab 15 mg/kg on days 1 and 8 or alone for up to eight cycles. Participants in the dual therapy arm could continue with single-agent olaratumab after completing eight doxorubicin cycles, while those in the doxorubicin alone arm could receive olaratumab monotherapy after progression.

The primary endpoint of PFS was a median of 6.6 months for the 66 olaratumab-treated patients compared with 4.1 months for the 67 given doxorubicin alone. This equated to a hazard ratio (HR) of 0.672 in favour of olaratumab plus doxorubicin, which with a p value of 0.0615 met the protocol-defined significance level of 0.1999.

Of note, median OS was 26.5 months in the olaratumab arm and 14.7 months in the control arm, and corresponded to a significant HR of 0.46.And OS was improved by olaratumab across the predefined subgroups, including histological tumour type, number of previous lines of treatment, and PDGFR status, but the difference was not always significant, reports the team led by William Tap, from Memorial Sloan Kettering Cancer Center in New York, USA.

Patients given olaratumab plus doxorubicin had a higher incidence of side effects of grade 3 or worse than those treated with doxorubicin alone, with neutropenia (53 vs 32%) and fatigue (9 vs 3%) seen more often in the dual than the single therapy arm.But the researchers point out that the incidence of febrile neutropenia was comparable (13 vs 14%) and a smaller proportion of patients in the olaratumab arm discontinued treatment as a result of an adverse event (13 vs 18%).

Writing in an accompanying piece, Winette van der Graaf, from The Institute of Cancer Research in Sutton, UK, hails the findings as promising “[i]n view of the desperate need of patients with soft-tissue sarcomas for new active drugs”.

But she says that the OS difference of nearly a year beyond the PFS gain of 2.5 months is “as much promising as puzzling”. The commentator believes that “[t]he exact effect of various post-study treatments, including local treatments, is not easy to interpret.”

“Differences in the pace of progression before start of treatment might have affected the results because no specific time period in which progression should have occurred before patients entered the study was defined and only the group with shorter history of disease showed a significant increase in overall survival”, she continues.

Winette van der Graaf asks: “[W]hy does targeting PDGFRα and its combination with doxorubicin lead to this impressive gain in overall survival?” But she acknowledges that at present this is an open question as in-depth information about PDGFR receptors in sarcomas is lacking.

References

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 2016; Advance online publication 9 June. doi: http://dx.doi.org/10.1016/S0140-6736(16)30587-6van der Graaf WTA. Olaratumab in soft-tissue sarcomas. Lancet 2016; Advance online publication 9 June. doi: http://dx.doi.org/10.1016/S0140-6736(16)30788-7

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