Aldoxorubicin Shows PFS Promise for Unresectable Soft-Tissue Sarcoma

Aldoxorubicin may raise progression-free survival for patients with locally advanced soft-tissue sarcoma while reducing anthracycline-related cardiotoxicity

medwireNews: Phase IIb trial results suggest that an albumin-binding doxorubicin prodrug may offer better survival and less cardiotoxicity than conventional doxorubicin for patients with unresectable, locally advanced soft-tissue sarcoma.

Median progression-free survival (PFS) on independent review was 5.6 months for the 83 patients randomly assigned to receive up to six cycles of aldoxorubicin 350 mg/m2 once every 3 weeks, a doxorubicin equivalent dose of 260 mg/m2.

This was a significantly longer PFS than the 2.7 months achieved by the 40 patients who received doxorubicin 75 mg/m2 on the same schedule, report Sant Chawla, from the Sarcoma Oncology Center in Santa Monica, California, USA, and co-workers in JAMA Oncology.

There was also a trend towards improved median overall survival in the aldoxorubicin versus doxorubicin treatment groups, at 15.8 versus 14.3 months, but this difference did not reach significance.

And the RECIST tumour response was higher for the aldoxorubicin-treated patients than those given doxorubicin, with an overall response rate of 25% versus 0% on independent review.

Writing in an invited commentary, Rashmi Chugh and Scott Schuetze, from the University of Michigan in Ann Arbor, USA, suggest that these “provocative” results may be attributed to greater aldoxorubicin accumulation in sarcoma.

But they caution that the findings may be affected by imbalances in the treatment groups with regard to sarcoma subtypes, known to vary in sensitivity to chemotherapy, or in the proportions of patients with intermediate- versus high-grade disease.

Analysis showed that the aldoxorubicin group had an overall higher rate of grade 3 or 4 events than the doxorubicin group (80 vs 58%), with all types of events more common except for anaemia and febrile neutropenia.

Nevertheless, the commentators believe that the relative reduction in cardiac toxicity with aldoxorubicin offers a “clear advantage”, noting that 12% of patients given aldoxorubicin experienced a 10% or higher decline in left ventricular ejection fraction compared with 29% of doxorubicin-treated patients, while a decrease of up to 50% was reported in zero and three patients, respectively.

“The unique, relatively tumor-specific delivery of active doxorubicin via circulating albumin using aldoxorubicin may prevent the accumulation or release of the cardiotoxic agent(s) into the myocardium, preventing myocyte damage”, they explain, potentially allowing a higher cumulative dose.

“This hypothesis is under study in an ongoing phase III trial of aldoxorubicin (NCT02049905) in which patients who are deriving clinical benefit are permitted to continue treatment beyond 6 cycles”, say Rashmi Chugh and Scott Schuetze.

Sant Chawla et al agree, adding: “This result raises intriguing possibilities of further augmenting the efficacy of aldoxorubicin by combining it with doxorubicin hydrochloride (NCT01673438), ifosfamide (NCT02235701), or gemcitabine hydrochloride (NCT02235688), or enhancing the efficacy of combination regimens by allowing higher cumulative anthracycline doses.”

References

Chawla SP, Papai Z, Mukhametshina G, et al. First-line aldoxorubicin vs doxorubicin in metastatic or locally advanced unresectable soft-tissue sarcoma. A phase 2b randomized clinical trial. JAMA Oncol; Advance online publication 17 September 2015. doi:10.1001/jamaoncol.2015.3101

Chugh R, Schuetze SM. Aldoxorubicin in sarcoma. Teaching an old drug new tricks. JAMA Oncol; Advance online publication 17 September 2015. doi:10.1001/jamaoncol.2015.3221

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