RET Proto-Oncogene—Not Such an Obvious Starting Point in Cancer Therapy
Abstract
:Simple Summary
Abstract
1. Introduction
2. RET Protein and Activity
3. RET Rearrangements
4. Mutations
5. Detection of RET Alterations
6. Immunotherapy in Tumors with Genetic Changes of RET Gene
7. Treatment of RET-Altered Cancers with Multiple Kinase Inhibitors
8. RET-Specific Inhibitors
9. Next Generation Selective RET Inhibitors
10. Resistance to RET Selective Inhibitors
11. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Drug | Selpercatinib (LOXO-292) | Pralsetinib (BLU-667) | |
---|---|---|---|
Trial | LIBRETTO-001/Multicenter, Phase 1/2 | ARROW/Multicenter, Phase 1/2 | |
Date of FDA approval/type of approval | 8 May 2020 for Adult patients with metastatic, RET fusion-positive NSCLC Adult and pediatric (≥12 years of age) patients with
| 4 September 2020 for Adult patients with metastatic RET fusion-positive NSCLC 1 December 2020 for Adult and pediatric (≥12 years of age) patients with
| |
Clinical trial results | NSCLC | RET-positive NSCLC patients [90]
| RET-positive NSCLC patients [82]
|
Thyroid cancer | RET-positive thyroid cancer patients [85]
| RET-positive thyroid cancer patients [84]
| |
Adverse events | NSCLC arm Grade 1 & 2—39%, grade 3 & 4—58% Thyroid cancer arm Grade 1& 2—32%, grade 3 & 4—66% | NSCLC arm All toxicities—93%, grade 3 & 4—48% Thyroid cancer arm Grade 1 & 2—43%, grade 3 & 4—53% | |
Most common grade 3 & 4 AEs related to treatment | NSCLC | Hypertension (9%), increased ALT (9%), increased AST (6%), diarrhea (2%), prolonged QT (2%), constipation (1%), rash (1%), vomiting (1%), pyrexia (1%), thrombocytopenia (1%) | Neutropenia (19%), hypertension (11%), anemia (10%), decreased white blood cell count (6%), lymphopenia (5%), increased ALT (3%), increased AST (3%), phosphokinase (3%). thrombocytopenia (3%), Elevated blood creatine phosphokinase (3%), pneumonia (<4%) |
Thyroid cancer | Hypertension (12%), increased ALT (11%), increased AST (8%), diarrhea (3%), prolonged QT (2%), fatigue (1%), headache (1%), weight increased (1%) | Hypertension (17%), neutropenia (14%), lymphopenia (12%), anemia (10%), decreased white blood cell count (8%), increased blood creatine phosphokinase (5%), asthenia (4%), pneumonitis (3%), diarrhoea (2%) |
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Kucharczyk, T.; Krawczyk, P.; Kowalski, D.M.; Płużański, A.; Kubiatowski, T.; Kalinka, E. RET Proto-Oncogene—Not Such an Obvious Starting Point in Cancer Therapy. Cancers 2022, 14, 5298. https://doi.org/10.3390/cancers14215298
Kucharczyk T, Krawczyk P, Kowalski DM, Płużański A, Kubiatowski T, Kalinka E. RET Proto-Oncogene—Not Such an Obvious Starting Point in Cancer Therapy. Cancers. 2022; 14(21):5298. https://doi.org/10.3390/cancers14215298
Chicago/Turabian StyleKucharczyk, Tomasz, Paweł Krawczyk, Dariusz M. Kowalski, Adam Płużański, Tomasz Kubiatowski, and Ewa Kalinka. 2022. "RET Proto-Oncogene—Not Such an Obvious Starting Point in Cancer Therapy" Cancers 14, no. 21: 5298. https://doi.org/10.3390/cancers14215298