Pursuing Precision: Receptor Tyrosine Kinase Inhibitors for Treatment of Pediatric Solid Tumors
Abstract
:Simple Summary
Abstract
1. Introduction
2. Key Clinical Trials of RTK Inhibitors to Treat Pediatric Solid Tumors
2.1. Targeting Oncogenesis in Tumors with Mutations, Fusions, or Amplifications
2.2. Targeting Angiogenesis and Non-Mutated RTKs
2.3. Targeting Tumor Microenvironment
3. Intrinsic and Acquired Resistance
4. Toxicity, Dosing, and Pharmacokinetic Considerations
5. Predictive Biomarkers and Clinical Trial Design
6. Discussion and Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Agent | Key Targets Inhibited | Relevant Tumors | Key Toxicities (Grade 3–4) | Comments |
---|---|---|---|---|
Larotrectinib [24,25] | TRKA, TRB, TRKC (IC50 5–11 nM) | Infantile fibrosarcoma, salivary gland tumor, mesoblastic nephroma, lymphoma, solid tumors | Transaminitis, anemia, neutropenia | 75–92% ORR; USFDA approved for pediatric solid tumors harboring NTRK gene fusions |
Crizotinib [26,27,28,29] | ALK (IC50 24 nM) c-MET (IC50 5–20 nM) | ALCL, IMT, NBL | Neutropenia, diarrhea | >80% ORR for ALCL or IMT; 9% ORR for NBL; USFDA approved for relapsed ALK+ ALCL ages 1–21 years |
Entrectinib [30,31,32] | ALK (IC50 12 nM) TRKA-C (IC50 1–5 nM) ROS1 (IC50 7 nM) | NBL, salivary gland tumor, sarcoma, thyroid cancer | Fatigue, weight gain, transaminitis, myelosuppression, hyperuricemia | 57% ORR; USFDA approved for patients age ≥ 12 years with metastatic/unresectable solid tumors harboring NTRK gene fusions |
Selpercatinib [33,34] | RET (IC50 4 ± 2 nM) | Thyroid cancer, malignant peripheral nerve sheath tumors, sarcomas | Hypertension, diarrhea, transaminitis, prolonged QT interval on electrocardiogram | 69–79% ORR; 64–92% PFS at 1 year; USFDA approved for RET-mutant thyroid cancers in patients age ≥12 years |
Cabozantinib [35,36] | VEGFR2 (IC50 0.035 nM) c-MET (IC50 1.3 nM) KIT (IC50 4.6 nM) RET (IC50 5.2 nM) | Ewing sarcoma, osteosarcoma | Hypophosphatemia, transaminitis, HFSR, pneumothorax, neutropenia | Osteosarcoma: 17% ORR, with PFS 52% at 6 months Ewing sarcoma: 26% ORR; with PFS 33% at 6 months |
Regorafenib [37,38,39,40,41] | VEGFR1/2 (IC50 4.2-13 nM) KIT (IC50 7 nM) RET (IC50 1.5 nM) PDGFRβ (IC50 22 nM) | Ewing sarcoma, osteosarcoma | Fatigue, chest pain, hypophosphatemia, HFSR, hypertension, alkaline phosphatase, myelosuppression, diarrhea, mucositis, hypertension | Osteosarcoma: ORR 8-14%, with 44–62% PFS at 4 months Ewing sarcoma: ORR 10–22%; 56% PFS at 8 weeks, 26% PFS at 6 months |
Lenvatinib [42,43] | VEGFR2 (IC50 4 nM) RET (IC50 6.4 nM) PDGFRα (IC50 29 nM) FGFR2 (IC50 27 nM) | Osteosarcoma | Back pain, dyspnea | ORR 7%, with 33.3% PFS at 4 months |
Sorafenib [44,45,46] | VEGFR2 (IC50 4 nM) RET (IC50 0.4 nM) PDGFRα (IC50 18 nM) | Osteosarcoma | HFSR, thrombocytopenia, anemia, creatine kinase elevation | 14% ORR; 46% PFS at 4 months; Six-month PFS increased from 29% to 45% with the addition of everolimus |
Apatinib [47,48] | VEGFR2 (IC50 1 nM) RET (IC50 13 nM) | Osteosarcoma | Pneumothorax, wound dehiscence, proteinuria, diarrhea HFSR | ORR 43%, with 57% PFS at 4 months; |
Pazopanib [49,50,51] | VEGFR1 (IC50 10 nM) | NRSTS given in combination with ifosfamide and doxorubicin | Myelosuppression, febrile neutropenia, sepsis, emesis, wound dehiscence | 58% of patients treated with pazopanib had pathological response ≥90% vs. 22% with chemo alone |
Agent | Disease | Study Population and Additional Details | ClinicalTrials.gov Identifier |
---|---|---|---|
Crizotinib | ALK-altered neuroblastoma | Newly diagnosed, high-risk patients; given with standard therapy | NCT03126916 |
Ensartinib | ALK- or ROS1-altered solid tumors, histiocytic disorders | Recurrent/refractory advanced disease; investigating biomarkers | NCT03213652 |
Entrectinib | NTRK1/2/3 or ROS1 fusion-positive solid tumors | Recurrent/refractory disease | NCT02650401 |
Erdafitinib | FGFR-mutated solid tumors, NHL, histiocytic disorders | Recurrent/refractory advanced disease | NCT03210714 |
Larotrectinib | NTRK fusion-positive solid tumors, NHL, histiocytic disorders | Recurrent or refractory advanced disease | NCT03213704 |
Lenvatinib | Phase I: all solid tumors Phase II: Ewing sarcoma, rhabdomyosarcoma | Recurrent/refractory disease; given with everolimus | NCT03245151 |
Lorlatinib | ALK-altered neuroblastoma | Phase I, alone or in combination with conventional chemotherapy | NCT03107988 |
Regorafenib | Multiple bone and soft tissue sarcoma types | Recurrent/refractory advanced disease | NCT02048371 |
Regorafenib | Osteosarcoma | Recurrent/refractory disease; given with nivolumab | NCT04803877 |
Repotrectinib | Solid tumors with ALK, ROS1, or NTRK1/2/3 alterations | Recurrent/refratcory disease | NCT04094610 |
Selpercatinib | RET-altered solid tumors, lymphomas, histiocytic disorders | Recurrent/refractory advanced disease | NCT04320888 |
Sorafenib | Hepatocellular carcinoma | Newly diagnosed advanced disease; given with chemotherapy | NCT03017326 |
Ceritinib | ALK-altered neuroblastoma | Recurrent/refractory disease; given with ribociclib | NCT02780128 |
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Bellantoni, A.J.; Wagner, L.M. Pursuing Precision: Receptor Tyrosine Kinase Inhibitors for Treatment of Pediatric Solid Tumors. Cancers 2021, 13, 3531. https://doi.org/10.3390/cancers13143531
Bellantoni AJ, Wagner LM. Pursuing Precision: Receptor Tyrosine Kinase Inhibitors for Treatment of Pediatric Solid Tumors. Cancers. 2021; 13(14):3531. https://doi.org/10.3390/cancers13143531
Chicago/Turabian StyleBellantoni, Andrew J., and Lars M. Wagner. 2021. "Pursuing Precision: Receptor Tyrosine Kinase Inhibitors for Treatment of Pediatric Solid Tumors" Cancers 13, no. 14: 3531. https://doi.org/10.3390/cancers13143531
APA StyleBellantoni, A. J., & Wagner, L. M. (2021). Pursuing Precision: Receptor Tyrosine Kinase Inhibitors for Treatment of Pediatric Solid Tumors. Cancers, 13(14), 3531. https://doi.org/10.3390/cancers13143531