Table 1.
Summary of already published clinical trials that evaluate target therapies in sarcomas, classified regarding the mechanism of action.
| Mechanism of action | Drugs | Trial (reference) | Study population | Benefits | Common severetoxicities | |
|---|---|---|---|---|---|---|
| Apoptosis | PARP inhibitors | Olaparib | Phase II (127) | Recurrent/metastatic adult ES (failure to prior CH), n = 12 patients | NO responses SD: 4 patients, TTP: 5.7 weeks | No significant toxicities |
| Heat shock protein inhibitors | Retaspimycin (Hsp-90 INH) | Phase I (128) | Metastatic and/or unresectable STS, n = 54 patients | PR: 2 patients (proof of clinical activity) | Grade 3–4: Fatigue Nausea and vomiting Headache Artharalgia |
|
| Proteaseome inhibitor | Bortezomib | Phase II (129) | Metastatic OS, ES, RMS, and STS with no prior treatment for advanced disease, n = 25 patients | Lack of benefit (trial prematurely closed) | Grade 3–4: Neuropathy Asthenia Myalgias |
|
| MDM2 inhibitor | RG7112 | Proof of mechanism study (130) | WDLS or DDLS with MDM2 amplification receive RG7112 prior to surgery, n = 20 patients | SD: 14 patients, IHQ: activation of p53 pathway | Grade 3–4 Neutropenia Thrombocytopenia |
|
| Phase I (131) | Phase I trial with extension cohort for sarcoma patients, n = 30 (sarcoma patients) | Metabolic responses (PET-CT) IHQ: activation of p53 (MDM2-independent) | Grade 3–4 Cytopenias | |||
| PI3K-AKT-mTOR pathway inhibitors | Ridaforolimus (mTOR INH) | Phase II (132) | Pre-treated advanced bone and STS, n = 212 patients | RR: 1.9%, clinical benefit: 28.8% | Grade 3–4 Fatigue Stomatitis Hypertriglyceridemia Anemia Thrombocytopenia |
|
| Phase III (133) | Advanced bone and STS with clinical benefit to previous CH were randomized to maintenance Ridaforolimus or Placebo, n = 711 patients | Improvement in PFS (17.7 weeks with Ridaforolimus vs. 14.6 weeks with Placebo, HR: 0.72, p: 0.001) | Similar to previous study | |||
| Everolimus (mTOR INH) | Phase II (134) | Pre-treated advanced bone and STS, n = 41 patients | Poor clinical activity | Grade 3–4 Hyperglicemia Stomatitis Pain Asthenia |
||
| Anti-angiogenic therapy | Sorafenib (VEGFR2, VEGFR3, PDGFR, and c-Kit INH) | Phase II (135) | Pre-treated advanced STS, n = 101 patients | RR: 14.5%, SD: 32.9% (leiomyosarcoma better PFS) | Grade 3–4 Fatigue Diarrhea Hand–foot Syndrome Nausea and vomiting |
|
| Pazopanib (VEGFR-1, VEGFR-2, VEGFR-3, PDGFR, and c-Kit INH) | Phase III (136) | Pre-treated non-adipocytic STS randomized to PAZOPANIB vs. PLACEBO, n = 369 patients | Improvement in PFS (4.6 months with PAZOPANIB vs. 1.6 months with Placebo, HR: 0.31, p < 0.0001) | Grade 3–4 Asthenia Hypertension Anorexia Alteration of transaminases |
||
| Mitotic catastrophe | CDK inhibitors | Palbociclib (CDK4 and CDK6 INH) | Phase II (137) | WDLS or DDLS with CDK4 amplification and pRb expression | 66% of patients free of PD at 12 weeks | Grade 3–4 Anemia Neutropenia Thrombocytopenia |
CH: chemotherapy, DDLS: dedifferentiated liposarcoma, HR: hazard ratio, INH: inhibitor, MPNST: malignant peripheral nerve sheath tumor, PFS: progression-free survival, RR: response rate, SD: stabilization disease, STS: soft-tissues sarcoma, TTP: time to progression, WDLS: well-differentiated liposarcoma.