Cabozantinib May Be a New Therapeutic Option for Ewing Sarcoma and Osteosarcoma

Cabozantinib (Cabometyx) demonstrated antitumor activity as treatment of patients with advanced Ewing sarcoma and osteosarcoma, warranting further investigation for a potential new therapeutic option for this patient population, according to findings from phase II CABONE study (NCT02243605).

Overall, 39 patients (87%) with Ewing sarcoma with a median follow-up of 31.3 months (95% CI, 12.4-35.4) and 42 patients (93%) with osteosarcoma with a median follow-up of 31.1 months (95% CI, 24.4-31.7) were assessable for efficacy. The primary end point in the Ewing sarcoma arm was best objective response within 6 months of the start of treatment, and co-primary end points in the osteosarcoma arm were 6-month objective response and 6-month non-progression assessments.

Ten patients (26%) with Ewing sarcoma had an objective response by 6 months (95% CI, 13-42), and all responses were partial responses (PRs). In the osteosarcoma arm, 5 patients (12%) had an objective response, which were all PRs (95% CI, 4-26), and 14 patients (33%) had 6-month non-progression (95% CI, 20-50).

In the Ewing sarcoma arm, 19 patients (49%) had stable disease (SD), which investigators noted were the best overall response, and 15 patients (38%) had tumor shrinkage (range, 21.6%-1.5%). Eight patients (21%) had progressive disease (PD) as the best overall response. Twenty-six patients died during the trial, and 34 had PD (n = 32) or died (n = 2).

The median progression-free survival (PFS) was 4.4 months in the Ewing sarcoma arm (95% CI, 3.7-5.6), and the median overall survival (OS) was 10.2 months (95% CI, 8.5-18.5). The proportion of patients with 6-month non-progression was 26% (95% CI, 13-42). The 6-month, 12-month, and 24-month PFS was 33% (95% CI, 19-48), 18% (95% CI, 8-33), and 5% (95% CI, <1-19), respectively. The 6-month, 12-month, and 24-month OS was 84% (95% CI, 68-93), 48% (95% CI, 31-65), and 14% (95% CI, 4-31), respectively.

Thirty-one patients in the Ewing sarcoma arm were evaluable for early metabolic response at the end of 1 cycle. Thirteen patients (42%) had partial metabolic response, 9 (29%) had stable metabolic disease, and 9 patients (29%) had progressive metabolic disease. The proportion of patients with metabolic tumor response was 42% (95% CI, 25-61).

Among those with Ewing sarcoma, the median PFS was 5.4 months (95% CI, 3.7-8.9) among those with a partial metabolic response, 4.2 months (95% CI, 1.7-9.2) among those with stable metabolic disease, and 2.7 months (95% CI, 0.9-4.4) for those with progressive metabolic disease (log-rankP=.002).

In the osteosarcoma arm, the best overall response was PR, observed in 7 patients (17%), and SD, observed in 26 patients (62%). Fourteen patients (33%) with SD had tumor shrinkage (range, 28.4%- -0.9%). An additional 8 patients had PD as the best overall response. Thirty-two patients died during the course of the trial, and 40 patients had PD (n = 31) or died (n = 9).

The median PFS in the osteosarcoma patients was 6.7 months (95% CI, 5.4-7.9), and the median OS was 10.6 months (95% CI, 7.4-12.5). The median PFS was 71% (95% CI, 55-83), 52% (95% CI, 36-66), and 9% (95% CI 55-83) at 4, 6, and 12 months, respectively. The median OS was 78% (95% CI, 62-88) at 6 months, 38% (95% CI, 23-53) at 12 months, and 23% (95% CI< 11-38) at 24 months.

A total of 31 patients were evaluable for early metabolic response by the end of 1 cycle. Twenty of those patients (65%) had partial metabolic response, 8 (26%) had stable metabolic response, and 3 (10%) had progressive metabolic response, and the median PFS was 7.2 months (95% CI, 4.7-10.9), 4.5 months (95% CI, 1.8-9.5), and 1.8 months (95% CI, 0.8-1.9), respectively.

The most common grade 3/4 adverse events (AEs) were hypophosphatasemia in 11% for Ewing sarcoma and 7% in osteosarcoma, aspartate aminotransferase increases for 4% and 7%, palmar=plantar syndrome in 7% and 4%, pneumothorax in 2% and 9%, and neutropenia in 4% and 9%, respectively.

At least 1 serious AE occurred in 61 patients (68%), and 19 patients (21%) had a dose reduction. No patients died due to treatment-related toxic events.

For the multicenter, single-arm, 2-stage trial, patients with advanced Ewing sarcoma or osteosarcoma were enrolled from 10 centers in the French Sarcoma Group. Patients had to be at least 12 years old with an ECOG performance status and documented disease progression before study entry. Patients were not excluded based on the number of prior treatments they had received.

Patients were unable to enroll to the CABONE trial if they had received cytotoxic chemotherapy or biologic agents within 3 weeks, or nitrosoureas/mitomycin C within 6 weeks of the first dose on study. They also could not have previously received cabozantinib and could not have received radiation therapy for bone metastasis within 2 weeks or any other external radiation therapy within 4 weeks of the first study dose.

Cabozantinib was administered orally once daily in 28-day cycles until progression of disease, unacceptable toxicity, the investigator&rsquo;s decision to discontinue or the participant&rsquo;s withdrawal of consent. All patients who received at least 1 dose of cabozantinib were assessed for the safety analysis, and all patients who received at least 1 complete or 2 incomplete cycles of treatment were included in the efficacy analysis.

Reference:

Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicenter, single-arm, phase 2 trial [Published Online February 17, 2020].Lancet. DOI: 10.1016/S1470-2045(19)30825-3.