Cabozantinib Prolongs Survival in Patients with Advanced Osteosarcoma and Ewing Sarcoma

Antoine Italiano, MD, PhD

Cabozantinib (Cabometyx) demonstrated the strongest response observed to date among all the multikinase inhibitors that have shown activity in bone sarcoma, according to results from the CABONE trial that were reported at the 2018 CTOS Annual Meeting.¹

“Cabozantinib has demonstrated the highest antitumor activity ever observed in single-arm studies including [patients with] osteosarcoma and Ewing sarcoma with heavily pre-treated advanced disease,” said Antoine Italiano, MD, PhD, head of the Early Phase Trials and Sarcoma Units,Institut Bergonié in Bordeaux, France, who discussed these data on behalf of the French Sarcoma Group.

The CABONE trial met all endpoints in patients with advanced non-resectable and/or metastatic bone disease. Patients with osteosarcoma demonstrated an objective response rate (ORR) of 11.9% and 33.3% lived more than 6 months without disease progression, while patients with Ewing sarcoma demonstrated an ORR of 19%.

Ewing sarcoma and osteosarcoma are the most commonly occurring bone malignancies in children and young adults. Although localized disease is effectively treated with surgery and peri-operative chemotherapy, no drugs are currently approved for the treatment of locally unresectable and metastatic disease, which carry a poor prognosis. Patients with relapsed osteosarcoma and Ewing sarcoma have median overall survivals (OS) of just 8 and 9 months, respectively.^{2,3  }

Common features of both diseases include aberrant angiogenesis and high levels ofMEToverexpression, which is associated with adverse outcomes, Italiano explained.

“Cabozantinib is an orally available, potent inhibitor of c-MET, VEGFR-2, and AXL that has shown significant antitumor activity in pre-clinical models of Ewing sarcoma and osteosarcoma,” he said. The multikinase inhibitor is already approved for the treatment of medullary thyroid cancer and advanced renal cell carcinoma. 

CABONE (NCT02243605) is one of the first trials assessing the efficacy and safety of cabozantinib in bone cancer. Each study arm contained 45 patients aged &ge;12 years with advanced, unresectable and/or metastatic osteosarcoma or Ewing sarcoma. Adults were treated with oral cabozantinib at 60 daily and patients <18 years received 40 mg/m²daily in 28-day cycles.

The osteosarcoma arm consisted of 42 assessable patients with a median age of 34 years (range, 13 to 73) and 61.9% were male. A majority of patients (57.1%) had an ECOG performance status of 1 and 92.9% patients had metastatic disease. Most of the patients had been heavily pretreated for relapsed/metastatic disease; 54.8%, 26.2%, and 19.0% of patients had received &ge;2, 2, and 1 prior chemotherapy lines, respectively, for relapsed disease.

There were 33 assessable patients remaining in the Ewing sarcoma arm with a median age of 32 years (range, 12 to 59) and 63.6% were male. Most patients (60.6%) had an ECOG performance status of 1. Of the 93.9% of patients with metastatic disease, 75.8%, 21.2%, and 3.0% of patients had received &ge;2, 2, and 1 lines of chemotherapy, respectively, for relapsed disease.

Radiological tumor assessment per RESIST v1.1 was done at baseline and every 8 weeks and centralized histological and radiological reviews were performed. The single arm 2-phase trial was designed to proceed if &ge;2 objective responses were observed under treatment. The osteosarcoma arm had a composite endpoint of 6-month non-progression or ORR and the Ewing sarcoma arm endpoint was ORR, all by centralized review.

Of the 45 patients treated in the osteosarcoma and Ewing sarcoma arms, 41 and 32 patients were assessable for efficacy; 13.3% and 20% of patients remain on treatment. Treatment in the respective arms was stopped by 86.7% and 75.5% of patients, primarily due to progressive disease in 62.3% and 57.8% of patients. Additional causes of treatment discontinuation included adverse events (AEs) in 13.3% and 11.1% of patients in the osteosarcoma and Ewing sarcoma arms, respectively, and death in 1 patient in each arm.

The remaining osteosarcoma patients showed a robust response to cabozantinib; 5 patients showed an objective response, for an ORR of 11.9%, and 41% of patients demonstrated a reduction in tumor burden. Median &nbsp;progression-free survival (PFS) was 6.2 months (95% CI, 5.4-8.2) and the median OS was 10.6 months (95% CI, 7.2-13.2).

In the Ewing sarcoma arm, 4 objective responses were observed among 21 patients included in the final analysis during trial stage 1 for an ORR of 19%. In the ongoing analysis of 33 patients, 9 responses have been observed for an ORR of 28.1%. Seventy-one percent of patients demonstrated reduced tumor burden. The median PFS was 5.2 months and the median OS was 9.8 months.

The safety analysis was done in 82 patients, with mostly grade 1/2 AEs reported. The most commonly reported AEs included fatigue (58.5%), diarrhea (54.9%), oral mucositis (47.6%), hypothyroidism (41.55%), anorexia (32.9%), and nausea (30.5%). Grade 3 AEs included pneumothorax (6.1%), fatigue (4.9%) and 3.7% of patients each reported grade 3 diarrhea, oral mucositis, palmar-plantar erythrodysesthesia, hypertension,&nbsp;and weight loss. No grade &ge;4 AEs occurred. The most commonly reported grade 3 lab abnormalities included hypophosphatemia (9.8%), and 4.9% of patients each had increased aspartate or alanine aminotransferase.

Italiano pointed out that 41% of patients in this trial experienced tumor shrinkage, compared with 10% and 15% of patients treated with sorafenib (Nexavar) plus everolimus,⁴and sorafenib monotherapy,⁵respectively, in other trials.

&ldquo;CABONE is one of the largest studies ever performed with a targeted therapy in relapsed osteosarcoma and Ewing sarcoma,&rdquo; Italiano noted.

The invited discussant Katherine Janeway, MD, director of the Pediatric Solid Tumor Program at Dana-Farber/Boston Children's Cancer and Blood Disorders Center, pointed out that another trial, SARC024, which evaluated regorafenib (Stivarga), another multikinase inhibitor, in this patient population, showed similar results.⁶

&ldquo;A clear signal of activity has been shown with multikinase inhibitors in osteosarcoma,&rdquo; Janeway said. However, she questioned whether comparisons across trials can be made at this time since the available PFS&nbsp;data show overlapping confidence intervals.

References:

1. Italiano A, Penel N, Bompas E, et al. Cabozantinib in patients with advanced osteosarcomas and Ewing sarcomas: a French Sarcoma Group (FSG)/US National Cancer Institute phase II collaborative study. Presented at: 2018 CTOS Annual Meeting; November 14-17, 2018; Rome, Italy. Paper 042.
2. McTiernan AM, Cassoni AM, Driver D, et al. Improving outcomes after relapse in Ewing's sarcoma: analysis of 114 patients from a single institution. Sarcoma. 2006;83548. doi: 10.1155/SRCM/2006/83548.
3. Leary SE, Wozniac AW, Billups, CA et al. Survival of pediatric patients after relapsed osteosarcoma: the St. Jude Children's Research Hospital experience. Cancer. 2013;119(14):2645-2653. doi: 10.1002/cncr.28111.
4. Grigniani G, Palmerini E, Ferraresi V, et al Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial. Lancet Oncol. 2015;16(1):98-107. doi: 10.1016/S1470-2045(14)71136-2.
5. Grigniani G, Palmerini E, Dileo P et al. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol. 2012;23(2):508-16. doi: 10.1093/annonc/mdr151.
6. Attia S, Bolejack V, Ganjoo KN, et al. A phase II trial of regorafenib (REGO) in patients (pts) with advanced Ewing sarcoma and related tumors (EWS) of soft tissue and bone: SARC024 trial results. J Clin Oncol. 2017;35(suppl; abstr 11005).