Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma
Open accessAbstract
PURPOSE: SARC024 is a phase II clinical trial of the multikinase inhibitor regorafenib in specific sarcoma subtypes, including advanced osteosarcoma. We hypothesized that regorafenib would improve progression-free survival (PFS) in patients with sarcoma and report the results of the osteosarcoma cohort. PATIENTS AND METHODS: This trial enrolled patients with progressive metastatic osteosarcoma with measurable disease by RECIST who had received at least one prior line of therapy. Patients were randomly assigned at a ratio of one to one to regorafenib or placebo. Crossover was allowed at time of disease progression. PFS was the primary end point of the study, which was powered to detect a difference of at least 3 months in median PFS. RESULTS: Forty-two patients from 12 centers were enrolled between September 2014 and May 2018. Median age was 37 years (range, 18 to 76 years). Patients had received an average of 2.3 prior therapy regimens. Ten patients receiving placebo crossed over to active drug at time of progression. Study enrollment was stopped early, after a data safety monitoring committee review. Median PFS was significantly improved with regorafenib versus placebo: 3.6 months (95% CI, 2.0 to 7.6 months) versus 1.7 months (95% CI, 1.2 to 1.8 months), respectively (hazard ratio, 0.42; 95% CI, 0.21 to 0.85; P = .017). In the context of the crossover design, there was no statistically significant difference in overall survival. Fourteen (64%) of 22 patients initially randomly assigned to regorafenib experienced grade 3 to 4 events attributed to treatment, including one grade 4 colonic perforation. CONCLUSION: The study met its primary end point, demonstrating activity of regorafenib in patients with progressive metastatic osteosarcoma. No new safety signals were observed. Regorafenib should be considered a treatment option for patients with relapsed metastatic osteosarcoma.
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Clinical trials involving tyrosine kinase inhibitors alone typically have median progression-free survival ranging from 4 to 6 months and are accompanied by inevitable development of secondary drug resistance.
“Additionally, clinical trials involving TKIs alone are typically with median PFS ranging from 4 to 6 months accompanied with inevitable development of secondary drug resistance1–5.”
From Apatinib plus ifosfamide and etoposide versus ifosfamide and etoposide in patients with advanced osteosarcomas (OAIE/PKUPH-sarcoma 11): a randomized phase II study (2025) · cites this paper as [2]
The Discussion (page unavailable) reports median PFS of approximately 4–6 months in several osteosarcoma trials of single-agent tyrosine kinase inhibitors, although some reported values fall outside that range. Neither the Discussion nor the Results (page unavailable) establishes that secondary drug resistance inevitably develops; the reported progression times do not establish its mechanism. (LLM, conf=0.87)
Experimental — accuracy not yet measuredProgression-free survival data for ifosfamide and etoposide in relapsed or refractory osteosarcoma were published several decades before OLIE, and the progression-free survival estimate for ifosfamide and etoposide relied on limited historical data from other clinically active agents.
“Additionally, PFS data for IE in relapsed or refractory osteosarcoma were published several decades before the OLIE study46; thus, the PFS estimate for IE relied on limited historical data from other clinically active agents,15,35,36 and IE performed better than expected relative to these assumptions.”
From Lenvatinib Plus Ifosfamide and Etoposide in Children and Young Adults With Relapsed Osteosarcoma (2024) · cites this paper as [15]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredRegorafenib demonstrated a median progression-free survival of 14.8 weeks in Ewing sarcoma, 3.6 months in osteosarcoma, and a nonprogressive rate at 3 months of 54% in chondrosarcoma, significantly better than placebo.
“demonstrating a median progression‐free survival (PFS) of 14.8 weeks in Ewing sarcoma, 10 a median PFS of 3.6 months in osteosarcoma, 11 and a nonprogressive rate at 3 months of 54%, significantly better than results with placebo in chondrosarcoma. 12”
From Nivolumab and sunitinib in patients with advanced bone sarcomas: A multicenter, single‐arm, phase 2 trial (2025) · cites this paper as [11]
Previous studies have demonstrated that multi-targeted tyrosine kinase inhibitors can induce varying degrees of objective responses and prolong progression-free survival.
“Previous studies have demonstrated that multi-targeted tyrosine kinase inhibitor (TKIs) can induce varying degrees of objective responses and prolong progression-free survival (PFS)1–5.”
Bone sarcomas on average show very low tumor mutation burden: 0.79-1.96 mutations/Mbase in osteosarcoma, approximately 0.2 mutations/Mbase in Ewing sarcoma, and <5 mutations/Mbase in chondrosarcoma with some correlation with grade.
“BS on average show very low TMB: 0.79–1.96 mutations/Mbase in osteosarcoma, 11 , 17 , 18 , 19 ∼0.2 mutations/Mbas in Ewing sarcoma 19 , 20 and <5 mutations/Mbase in chondrosarcoma with some correlation with grade. 21”
From Nivolumab and sunitinib in patients with advanced bone sarcomas: A multicenter, single‐arm, phase 2 trial (2025) · cites this paper as [11]
The Introduction describes the regorafenib trial cohorts, and the Discussion reports treatment outcomes, but neither gives tumor mutation burden values. Searches for the osteosarcoma range and for mutational burden in Ewing sarcoma and chondrosarcoma found no passage addressing the claimed figures or correlation with grade. Page numbers were not available in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measured
Objective response rates to MTKIs were low at 10-15%.
“Objective response rates were low at 10-15%.”
From Osteosarcoma (2022) · cites this paper as [146]
Dose interruptions and reductions of MTKIs have been frequent across these trials secondary to common toxic effects, including hand-foot rash syndrome, gastrointestinal toxic effects and hypertension.
“Of note, dose interruptions and reductions of MTKIs have been frequent across these trials secondary to common toxic effects of this drug class, including hand-foot rash syndrome (palmar-plantar erythrodysesthesia), gastrointestinal toxic effects and hypertension 146,147,148,149,150,151 .”
From Osteosarcoma (2022) · cites this paper as [146]
Four-month progression-free survival with MTKIs ranged from 35% to 70%.
“Four-month progression-free survival (PFS) ranged from 35% to 70% 146,147,148,149,151 .”
From Osteosarcoma (2022) · cites this paper as [146]
Prospective clinical trials evaluated sorafenib, regorafenib, cabozantinib, lenvatinib and apatinib as single agents in patients with relapsed or refractory osteosarcoma, with most enrolled patients in the adult age range.
“Prospective clinical trials evaluated the MTKIs sorafenib, regorafenib, cabozantinib, lenvatinib and apatinib as single agents in patients with relapsed or refractory osteosarcoma, with most enrolled patients falling in the adult age range 146,147,148,149,150,151 (Table 2).”
From Osteosarcoma (2022) · cites this paper as [146]
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Self-citation
- Authors
- Davis, L. E., Bolejack, V., Ryan, C. W., Ganjoo, K. N., Loggers, E. T., Chawla, S., Agulnik, M., Livingston, M. B., Reed, D., Keedy, V., Rushing, D., Okuno, S., Reinke, D. K., Riedel, R. F., Attia, S., Mascarenhas, L., & Maki, R. G.
- Affiliations
- Oregon Health & Science University (US)
- Cancer Research And Biostatistics (US)
- Stanford Cancer Institute (US)
- Fred Hutch Cancer Center (US)
- Sarcoma Oncology Center (US)
- Northwestern University (US)
- Levine Cancer Institute (US)
- Moffitt Cancer Center (US)
- Vanderbilt University (US)
- Indiana University Bloomington (US)
- Mayo Clinic (US)
- Sarcoma Alliance for Research through Collaboration (US)
- Duke Medical Center (US)
- University of Southern California (US)
- Northwell Health (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2019-06-01
- Volume
- 37
- Issue
- 16
- Pages
- 1424-1431
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC7799443
- OpenAlex
- W2941090871
- Cited by
- 268
- References
- 27
- Citations by year
- 2026: 27 · 2025: 29 · 2024: 35 · 2023: 52 · 2022: 36 · 2021: 44 · 2020: 35 · 2019: 9
- FWCI
- 22.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Cancer Institute (P30CA076292, P30CA014089)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Keywords
- regorafenib, metastatic osteosarcoma, multikinase inhibitor, progression-free survival, relapsed sarcoma, crossover design, overall survival, drug safety, colonic perforation
- MeSH terms
- Progression-Free Survival, Adolescent, Adult, Aged, Antineoplastic Agents, Bone Neoplasms, Double-Blind Method, Female, Humans, Male, Middle Aged, Phenylurea Compounds, Pyridines, Osteosarcoma, Time Factors, United States, Disease Progression, Cross-Over Studies, Protein Kinase Inhibitors, Young Adult
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