Aldoxorubicin Improves PFS in Advanced Soft Tissue Sarcoma

Sant Chawla, MD

Aldoxorubicin was associated with superior progression-free survival (PFS) compared with standard chemotherapy regimens and may be a viable treatment alternative for some patients with relapsed or refractory soft tissue sarcomas, according to results from a phase III international study.

The overall median PFS was 4.11 months (95% CI, 2.79-5.06) for patients assigned to aldoxorubicin (n = 218) compared with 2.96 months (95% CI, 2.56-4.17) for patients assigned to the investigator’s choice of chemotherapy (n = 215). The hazard ratio (HR) was 0.81 (95% CI, 0.64-1.03; P = .0870).

For patients with liposarcoma and leiomyosarcoma (L-sarcomas), the median PFS was 5.32 months (95% CI, 3.45-7.16) compared with 2.96 months (95% CI, 2.10-4.37) for patients assigned to standard chemotherapy (HR, 0.62; 95% CI, 0.44-0.88; P = .0070).

“Aldoxorubicin is an active drug for relapsed and refractory sarcomas, especially L-sarcomas,” said lead author Sant Chawla, MD, director of the Sarcoma Oncology Center in Santa Monica, California. He presented the results at the 2017 ASCO Annual Meeting. “Outcomes favored aldoxorubicin in leiomyosarcoma, liposarcoma, synovial sarcoma, and all the demographics in North America. The only factors that favored the control arm were European region and other histologies.”

PFS at 4 and 6 months was superior with aldoxorubicin, a tumor-targeted doxorubicin, in the intent-to-treat population, patients with L-sarcomas, and patients who had undergone previous doxorubicin treatment.

Overall, 42.5% of patients had leiomyosarcoma, 15% had liposarcoma, and 9% had synovial sarcoma. Other sarcomas represented 33.5% of patients and L-sarcomas accounted for 57.5% of the cohort.

In the study, patients were assigned to 350 mg/m2 for 3 weeks (n = 218) or investigator’s choice of dacarbazine, doxorubicin, pazopanib, ifosfamide, or gemcitabine/docetaxel (n = 215). Roughly two-thirds of patients in both groups had received prior doxorubicin treatment.

Patients enrolled at centers in North America/Australia (72%), Western Europe (20.1%) and Eastern Europe (7.9%). The Western Europe group included Israel and Chile.

Aldoxorubicin was associated with significantly superior PFS in the North America/Australia arm (4.21 months vs 2.96 months; HR, 0.71; 95% CI, 0.53-0.96; P = .0225), but not in other regions (2.96 months vs 3.02 months; HR, 1.11; 95% CI, 0.71-1.73; P = .6439).

There was no significant difference in overall survival between the treatment arms, but objective response rate (ORR) was twice as high in the aldoxorubicin arm compared with standard chemotherapy (8.3% vs 4.2%; P = 0.1106) in the intent-to-treat population. For patients with L-sarcomas, ORR was 10.0 % in the experimental group compared with 4.0% for investigator’s choice (P = .0790).

In the intent-to-treat population, the disease control rate (DCR) was 33.5% with aldoxorubicin versus 25.1% with standard chemotherapy (P = .0583). DCR was 41.7% in patients with L-sarcomas assigned to aldoxorubicin compared with 27.0% for investigator’s choice (P = .0161).

Patients in the experimental arm received a median total cumulative dose of 1400 mg/m2 of aldoxorubicin, with a maximum cumulative dose of 14,700 mg/m2. Among patients in the investigator’s choice group treated with doxorubicin (n = 47), 8.5% had ≥20% decrease in left ventricle ejection fraction (LVEF) from baseline compared with 3.8% with aldoxorubicin. Similarly, patients assigned to doxorubicin were more likely to have LVEF below 50% from baseline at any point (19.1% vs 4.2%).

“Despite an unprecedented cumulative anthracycline dose administered, there was no clinical evidence of cardiac toxicity,” Chawala said. “Aldoxorubicin is the only anthracycline where there is no dose-limiting cardiac toxicity.”

Patients in the aldoxorubicin arm were more likely to experience grade ≥3 adverse events (AEs; 74.2% vs 64.3%), grade ≥3 treatment-related AEs (64.3% vs 46.9%), treatment-related AEs resulting in death (1.4% vs. 0.0%), serious AEs (42.7% vs 32.9%), and treatment-related serious AEs (28.6% vs 14.5%). However, Chawala noted that the investigator’s choice arm included less toxic treatments, such as pazopanib and dacarbazine, so a fairer comparison would be aldoxorubicin versus doxorubicin.

He said stomatitis was higher in the aldoxorubicin arm (15.5% vs 2.1% with doxorubicin) because patients received higher doses of medication.

“Hematological toxicity of neutropenia, anemia, febrile neutropenia, and sepsis are equal in both arms,” Chawla said. “Despite the 3 to 4 times higher single dose and cumulative dose, we did not find any unexpected toxicity.”

However, he said investigators were surprised to find no cases of alopecia in the aldoxorubicin group, including 1 patient who maintained her hair through 20 cycles of treatment.

Chawla SP, Ganjoo KN, Schuetze S, et al. Phase III study of aldoxorubicin vs investigators' choice as treatment for relapsed/refractory soft tissue sarcomas. J Clin Oncol. 35, 2017 (suppl; abstr 11000).