Apatinib Plus Chemotherapy Extends Progression-Free Survival in Advanced Osteosarcoma Phase II Trial

A multicenter randomized phase II trial has demonstrated that adding apatinib to standard chemotherapy significantly improves progression-free survival in patients with advanced osteosarcoma, offering new hope for this challenging malignancy that predominantly affects adolescents and young adults.

The OAIE/PKUPH-sarcoma 11 study, conducted across four centers in China under the Chinese Sarcoma Study Group, enrolled 81 patients with unresectable, recurrent, or refractory osteosarcoma. Participants were randomized 2:1 to receive either apatinib plus ifosfamide and etoposide (Apa+IE, n=53) or ifosfamide and etoposide alone (IE, n=28).

Primary Efficacy Results

The trial met its primary endpoint, showing a statistically significant improvement in median progression-free survival. Patients receiving the combination therapy achieved a median PFS of 5.5 months (95% CI: 3.9-6.4) compared to 3.4 months (95% CI: 1.4-4.6) in the chemotherapy-only group (hazard ratio 0.60; 95% CI: 0.37-0.98; P=0.0402).

The 4-month and 6-month PFS rates were notably higher in the combination group at 65.8% and 36.7% respectively, versus 41.6% and 15.9% in the control arm. The disease control rate reached 90.6% with apatinib plus chemotherapy compared to 60.7% with chemotherapy alone.

"The combination of apatinib with IE improved PFS relative to IE alone, particularly among patients with multiple metastatic sites and high tumor burden," the researchers noted in their Nature Communications publication.

Treatment Response and Duration

The objective response rate was 32.1% in the combination group versus 25.0% in the chemotherapy-only group. Notably, one patient achieved a complete response following Apa+IE treatment, demonstrating a partial response after one month, reaching complete response at four months, though subsequently experiencing disease progression at five months.

The median time to response was similar between groups (1.3 months vs 1.5 months), as was the duration of response (3.9 months vs 4.1 months), suggesting that while the combination therapy increased the likelihood of response, it did not substantially extend response duration.

Safety Profile and Tolerability

Treatment-related adverse events occurred in 98.1% of patients in the combination group compared to 89.3% in the chemotherapy-only group. Grade 3 or higher adverse events were observed in 69.8% versus 64.3% respectively. Serious adverse events were comparable between groups (11.3% vs 10.7%).

Importantly, the study found that neutropenia and thrombocytopenia were not more severe in the combination group because chemotherapy doses were reduced in the combination regimen. In the Apa+IE group, dose interruptions occurred in seven patients (13.2%), dose reductions in 16 patients (30.2%), and discontinuation in one patient (1.9%).

A notable adverse event was pneumothorax, likely due to necrosis within pulmonary lesions, which was managed through chemical or mechanical pleurodesis without treatment interruption.

Study Design and Patient Population

The trial enrolled patients aged 12-65 years with histologically confirmed locally advanced or metastatic high-grade osteosarcoma that had progressed following at least one line of prior chemotherapy. Baseline characteristics were well-balanced between groups, with approximately 54% of participants under 18 years old in both arms.

The combination group received 500 mg apatinib orally once daily with ifosfamide (1.8 g/m²/day for days 1-3) and etoposide (100 mg/m²/day for days 1-3) every three weeks. The control group received the same chemotherapy doses but on an extended schedule (days 1-5 every three weeks).

Clinical Context and Limitations

The study's median PFS results were lower than initially anticipated, which researchers attributed to several factors including the exclusion of local therapies during treatment and inclusion of a heavily pretreated population. Approximately 90% of patients had previously received ifosfamide-containing regimens, potentially weakening the efficacy of the control group.

Importantly, no overall survival benefit was observed, with median OS of 18.1 months in the combination group versus 22.9 months in the chemotherapy-only group (HR 1.48; 95% CI: 0.76-2.89; P=0.2493).

Quality of Life Outcomes

Patients in the combination group reported statistically significant improvement in global health status, with mean scores increasing from 47.12 at baseline to 56.67 by cycle 9 (P=0.042). The chemotherapy-only group did not show significant quality of life changes during treatment.

Future Directions

The researchers emphasized that these exploratory findings require confirmation in larger phase III studies. "Apatinib plus IE may offer benefit for patients with relapsed or refractory osteosarcoma, but the data are exploratory, and confirmation in larger, prospective phase III studies is needed to establish comparative efficacy and optimize patient selection," they concluded.

The study represents an important step forward in treating advanced osteosarcoma, a malignancy where 5-year post-relapse survival rates remain below 20%. The combination of anti-angiogenic therapy with traditional chemotherapy offers a promising approach for addressing both pulmonary and extrapulmonary lesions in this challenging disease.