Table 1.
Phase II trials with TKIs in bone sarcomas. OS: osteosarcoma; ES: Ewing sarcoma; CI: confidence interval; mPFS: median progression-free survival; OS: overall survival; PR: partial response; SD: stable disease; DCR: disease control rate (PR + SD); ORR: overall response rate; w: weeks; m: months; HR: hazard ratio; AST: aspartate aminotransferase; ALT: alanine aminotransferase; ALP: alkaline phosphatase; LDH: lactate dehydrogenase; PPS: palmar-plantar syndrome.
| Clinical Trial (Phase) | Agent | Tumor | N | Age Range (Years) | Outcomes | G3/G4 Adverse Events | |
|---|---|---|---|---|---|---|---|
| Duffaud et al. (REGOBONE) (phase II multi-cohort) | Regorafenib (vs. placebo) |
OS [75] | 38 | 21–50 | DCR: 17/26 (65%; 95% CI 47–95) (vs. 0% in placebo); mPFS: 16 w (95% CI 8.0–27.3) vs. 4 w (95% CI 3.0–5.7) | Hypertension (24%), PPS (10%), fatigue (10%), hypophosphatemia (10%), chest pain (10%) | |
| ES [76] | 41 | 16–59 | PR: 5/36 (21.7%) (vs. 0% in placebo); mPFS: 11.4 w (95% CI 4.6–22.9) vs. 3.9 w (95% CI 3.3–7.3) | Diarrhea (13%), PPS (13%), thrombocytopenia (9%), fatigue (9%), mucositis (9%), febrile neutropenia (9%) | |||
| Davis et al. (SARC024) (phase II) [77] |
Regorafenib (vs. placebo) |
OS | 42 | 18–76 | mPFS: 3.6 m (95% CI 2.0–7.6) vs. 1.7 m (95% CI 1.2–1.8) (HR 0.42; 95% CI 0.21–0.85; p = 0.017) | Hypertension (14%), rash (9%), hypophosphatemia (9%), extremity pain (9%), thrombocytopenia (9%), PPS (5%) | |
| Attia et al. (REGO) (phase II) [78] |
Regorafenib | ES | 30 | 19–65 | PR: 3/28 (10.7%); SD: 18/28 (64.3%); mPFS: 3.6 m (95% CI 2.8–3.8) | Hypophosphatemia (20%), hypertension (6.7%), ALT increase (6.7%), fatigue (3.3%), abdominal pain (3.3%), diarrhea (3.3%), hypokalemia (3.3%), oral mucositis (3.3%), neutropenia (3.3%), rash (3.3%) | |
| Italiano et al. (CABONE) (phase II) [79] |
Cabozantinib | OS/ES | 90 | 20–53 | OS (n: 42) |
PR: 5/42 (12%; 95% CI 4–26), SD: 14/42 (33%; 95% CI 20–50); mPFS: 7.2 m PR (95% CI 4.7–10.9); 4.5 m SD (95% CI 1.8–9.5); 1.8 m PD (95% CI 0.8–1.9) | Hypophosphatemia (9%), neutropenia (7%), AST increase (6%), PPS (6%), pneumothorax (6%) |
| ES (n: 39) |
PR: 10/39 (26%; 95% CI 13–42); mPFS: 4.4 m (95% CI 3.7–5.6) | ||||||
| Grignani et al. (phase II) [80] | Sorafenib | OS | 35 | 15–62 | ORR: 14% (95% CI 2–26) DCR: 49% (95% CI 31–67) mPFS: 4 m (95% CI 2–5) |
PPS (9%), anemia (6%), thrombocytopenia (6%), CK elevation (6%), leucopenia (3%), rash (3%), mucositis (3%), nausea (3%), fatigue (3%), lipase elevation (3%), pneumothorax (3%), bleeding (3%) | |
| Grignani et al. (phase II) [81] | Sorafenib + everolimus | OS | 38 | 18–64 | ORR: 10% (95% CI 0.3–21); DCR: 63% PFS at 6 m: 45% (95% CI 28–61) |
Hypophosphatemia (16%), lymphopenia (16%), PPS (13%), thrombocytopenia (11%), fatigue (5%), mucositis (5%), diarrhea (5%), anemia (5%), pneumothorax (3%) | |
| Gaspar et al. (phase I/II) [82] | Lenvatinib | OS | 31 | 9–22 | ORR: 7% (95% CI 0.8–22.1) PFS at 4 m: 29% (95% CI 14–48); mPFS: 3 m (95% CI 1.8–5.4) |
Hypertension (3%), diarrhea (3%), proteinuria (3%), decreased weight (3%), abdominal pain (3%) | |
| Gaspar et al. (phase I/II) [83] | Lenvatinib + IF/VP16 | OS | 35 | 2–25 | PFS at 4 m: 51% (95% CI 34–69); | Neutropenia (77%), thrombocytopenia (71%), anemia (54%), leukopenia (54%) | |
| Chugh et al. (phase II) [84] | Imatinib | OS/ES/ others |
185 | 14–83 | OS (n: 27) | PR: 0/27 (0%); SD: 5/27 (19%) | No G3/G4 adverse events reported |
| ES (n: 13) | PR/SD: 0/13 (0%) | ||||||
| Palmerini et al. (IMMUNO-SARC) (phase I/II) [85] |
Sunitinib + nivolumab | OS/ES/ others |
40 | 21–74 | DCR: 24/40 (60%) (1 CR, 1 PR, 22 SD) mPFS 3.7 m (95% CI 3.4–4) mOS 14.2 m (95% CI 7.1–21.3) |
Neutropenia (10%), anemia (10%), ALT/AST increase (7.5%), fatigue (5%), oral mucositis (5%), thrombocytopenia (2.5%), dysphagia (2.5%), gastric hemorrhage (2.5%), malaise (2.5%), thromboembolism (2.5%), pneumonitis (2.5%) | |
| Xie et al. (APFAO) (phase II) [86] |
Apatinib + camrelizumab | OS | 43 | 11–43 | ORR: 9/43 (20.9%) PFS at 6 m: 50.9% (95% CI 34.6–65.0) |
Wound dehiscence (14%), ALP increase (9.3%), AST/ALT increase (9.3%), blood bilirubin increase (9.3%), hypertriglyceridemia (7.0%), anorexia (7.0%), weight loss (7.0%), pneumothorax (7.0%), platelet count decrease (4.7%), diarrhea (4.7%), PPS (4.7%), limb pain (4.7%), leukopenia (4.7%), rash (4.7%), oral mucositis (4.7%), hypertension (4.7%), toothache (4.7%), nausea (4.7%), non-cardiac chest pain (4.7%), hypothyroidism (2.3%), blood LDH increase (2.3%), proteinuria (2.3%), cough (2.3%), hemorrhoidal hemorrhage (2.3%), fatigue (2.3%), peripheral neuroinflammation (2.3%) | |
| Schuetze et al. (phase II) [87] | Dasatinib | CS | 33 | 22–87 | ORR: 6/33 (18.2%); mPFS: 5.5 m | Pain (17%), dyspnea (11%), pleural effusion (6%), diarrhea (5%), anemia (3%), thrombocytopenia (2%), neutropenia (<1%), lymphopenia (<1%) | |
| Chordoma | 32 | ORR: 6/32 (18.8%); mPFS: 6.3 m | |||||
| Stacchiotti et al. (phase II) [88] | Imatinib | Chordoma | 50 | 24–86 | PR: 1/50 (2%); SD 35/50 (70%); ORR: 2% (95% CI 0–5.3); mPFS: 9.2 m |
Fluid retention (29%) | |
| Stacchiotti et al. (phase II) [89] | Imatinib + everolimus | Chordoma | 40 | 49–70 | PR: 9/40 (20.9%); SD 24/40 (55.8%) mPFS: 11.5 m (95% CI 4.6–17.6) |
Infection (16%), fatigue (9%), anemia (2%), leukopenia (2%), febrile neutropenia (2%), thrombocytopenia (2%), cardiac ischemia (2%) | |
| Stacchiotti et al. (phase II) [90] | Lapatinib | Chordoma (EGFR) |
18 | 35–75 | PR: 6/18 (33.3%); SD: 7/18 (38.9%) mPFS: 6 m (95% CI 3–8) |
Anemia (5.6%), rash (5.6%), thromboembolism (5.6%) | |