ROS1-Rearranged Lung Adenocarcinoma: From Molecular Genetics to Target Therapy
Abstract
:Simple Summary
Abstract
1. Introduction
1.1. ROS1 Gene Rearrangements
1.2. Target Therapy of ROS1-Rearranged NSCLC
1.2.1. Crizotinib
1.2.2. Entrectinib
1.2.3. Lorlatinib
1.2.4. Taletrectinib
TKI | Clinical Trial Phase | Number of Patients | ORR (%) | DCR (%) | mPFS (mo) | mDOR (mo) | mOS (mo) | Grade ¾ Adverse Events | Reference |
---|---|---|---|---|---|---|---|---|---|
Crizotinib | PROFILE 1001 I/II | 53 | 72 | 90 | 19.3 | 24.7 | 51.4 | 36 | [23,24] |
Crizotinib | East Asian NCT01945021 II | 127 | 72 | 90 | 16 | 19.7 | 44.2 | 25 | [27,28] |
Crizotinib | Ac Sé I/II | 36 | 47 | 83 | 6 | ------- | 17 | ------- | [25] |
Crizotinib | EUCROSS II | 34 | 70 | 90 | 20 | ------- | NR | 20 | [26] |
Crizotinib Platinum (PL) | Retrospective Study | 104 56 (Cr) 46 (Pl) | 84(Cr) 57 (Pl) | 96 (CR) 100 (Pl) | 14.9 (Cr) 8.5 (Pl) | -------- | NR (Cr) NR (Pl) | -------- | [29] |
Entrectinib | ALKA-372-001 STRATRK-1 STRATRK-2 I/II | 161 | 68 | 90 | 16 | 20.5 | 47.8 | 31 | [33,34,35] |
Lorlatinib | NCT01970845 I/II | 69 21 (TN) 48 (TT) | 41 (overall) 62 (CN) 35 (CR) | --------- | 25.3 (CN) 13.8 (CR) | --------- | ---------- | 43 | [36] |
Lorlatinib | LORLATINU | 80 100% (TT) 69% (CT) 64% (BM) | 45 | 82 | 7.1 | 6.9 | 19.6 | 33 | [37] |
Taletrectinib | TRUST-I | 109 67 (TN) 42 (TT) | 92.5 (TN) 52.6 (TT) | 95.5 (TN) 81.6 (TT) | 33.2 (TN) 9.8 (TT) | NR (TN) NR (TT) | --------- --------- | 29 | [39,40] |
1.2.5. Repotrectinib
1.2.6. NVL-520
1.3. Resistance Mechanisms
1.3.1. Resistance to Crizotinib
1.3.2. Resistance to Lorlatinib
1.3.3. ROS1-Extrinsic Mechanisms
1.3.4. Intracranial Failure
1.3.5. Off-Target Activation of Signaling Pathways
1.3.6. Histological Transformation into Small Cell Lung Cancer (SCLC) of ROS1-Rearranged NSCLC
2. Limitations of the Clinical Studies Carried Out on ROS1-Rearranged LUADs
3. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Fusion Protein | Frequency in NSCLC (%) | Cellular Location |
---|---|---|
CD74-ROS1 (Cluster of differentiation 74) | 49.8 | Endoplasmic reticulum |
EZR-ROS1 (Ezrin) | 23.6 | Cytoskeleton |
SDC4-ROS1 (Syndecan) | 9.1 | Endosomes |
SLC34A2-ROS1 (Solute carrier family 34 member 2) | 5.1 | Endosomes |
TPM3-ROS1 (Tropomyosin) | 2.9 | Cytoplasm |
SLC4A4-ROS1 (Solute carrier family 4 member 4) | 1.5 | Endosomes |
Drug | TRIAL | Patient Number | ORR (with CNS Metastases) | ORR (without CNS Metastases) | DOR at 6 mo (with CNS Metastases) | DOR at 6 mo (without CNS Metastases) |
---|---|---|---|---|---|---|
Repotrectinib | TRIDENT-1 | 171 71(TN) 56(1T-CN) 26(1T-1C) 18(2T-CN) | 89(TN) 33(1T-CN) 40(1T-1C) 13(2T-CN) | 76(TN) 41(1T-CN) 44(1T-1C) 40(2T-CN) | 100(TN) 63(1T-CN) 50(1T-1C) 100(2T-CN) | 87(TN) 92(1T-CN) 71(1T-1C) 50(2T-CN) |
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Testa, U.; Castelli, G.; Pelosi, E. ROS1-Rearranged Lung Adenocarcinoma: From Molecular Genetics to Target Therapy. Onco 2023, 3, 189-204. https://doi.org/10.3390/onco3030014
Testa U, Castelli G, Pelosi E. ROS1-Rearranged Lung Adenocarcinoma: From Molecular Genetics to Target Therapy. Onco. 2023; 3(3):189-204. https://doi.org/10.3390/onco3030014
Chicago/Turabian StyleTesta, Ugo, Germana Castelli, and Elvira Pelosi. 2023. "ROS1-Rearranged Lung Adenocarcinoma: From Molecular Genetics to Target Therapy" Onco 3, no. 3: 189-204. https://doi.org/10.3390/onco3030014