Table 1.
First-line ROS1 inhibitor options.
| Drug | Target kinases | Number of patientsa | ORR | PFS (months) | Most common AEsb | Reference |
|---|---|---|---|---|---|---|
| Crizotinibc | ROS1, ALK, MET | 53 | 72% | 19.2 | Vision disorder, diarrhea, nausea, edema, vomiting, elevated transaminases, constipation, and fatigued | PROFILE 1001 Global phase I4 EUCROSS European phase II23 AcSé French phase II24 East Asia phase II25 METROS Italian phase II26 |
| 30 | 70% | 20.0 | ||||
| 36 | 47.2% | 5.5 | ||||
| 127 | 71.7% | 15.9 | ||||
| 26 | 65% | 22.8 | ||||
| Entrectinibc | ROS1, TRK, ALK | 168 | 68% | 15.7 | Dysgeusia, constipation, dizziness, diarrhea, weight gain, and fatigue | Integrated global phase I/II analysis: ALKA-372-001, STARTRK-1, and STARTRK-25,27 |
| Ceritinib | ROS1, ALK | 30 | 67% | 19.3 | Diarrhea, nausea, anorexia, vomiting, cough, abdominal pain, musculoskeletal pain, fatigue, and dyspnea | Korean phase II28 |
| Brigatinib | ROS1, ALK | 28 | 67.9% | 9.3 | Diarrhea, increased CPK, nausea, cough, and hypertension | BAROSSA Japanese phase II29 |
| Unecritinib | ROS1, ALK, MET | 111 | 80.2% | 16.5 | Elevated AST, elevated ALT, vomiting, reduced neutrophil count, reduced leukocyte count, sinus bradycardia, diarrhea, elevated CPK, nausea, neurotoxicity (dysgeusia or dizziness), constipation, elevated LDH, elevated CK-MB, ocular disorders, elevated creatine, hypoproteinemia, anemia, and peripheral edema | Chinese phase II30 |
| Lorlatinib | ROS1, ALK | 21 | 62% | 21.0 | Hypercholesterolemia, hypertriglyceridemia, edema, peripheral neuropathy, cognitive effects, and weight gain | Global phase I/II31 |
| 32 | 69% | 35.8 | Korean phase II32 | |||
| Repotrectinibc | ROS1, TRK | 71 | 79% | 35.7 | Dizziness, dysgeusia, constipation, anemia, paresthesia, dyspnea, elevated ALT, fatigue, ataxia, elevated AST, nausea, and muscular weakness | TRIDENT-1 Global phase I/II6 |
| Taletrectinib | ROS1, TRK | 106 | 90.6% | NR (33.2 months among 78 TKI-naïve patients in pooled phase I/II) |
Diarrhea, elevated AST, elevated ALT, nausea, vomiting, anemia, neutrophil count decreased, WBC count decreased, bilirubin increased, dizziness, proteinuria, weight increase, creatinine increase, and prolonged QT | TRUST-I Chinese phase II33,34 |
| 25 | 92.0% | Not reported | TRUST-II Global phase II35 | |||
| Zidesamtinib | ROS1 | Evaluation ongoing including in TKI-naïve patients | ARROS-1 Global phase I/II36 | |||
aThe number of patients in the study or subgroup relevant to the efficacy evaluation in ROS1 TKI-naïve setting is shown.
bAEs reported in ≥20% of patients are shown.
cIndicated ROS1 TKIs are approved by the FDA for the treatment of metastatic ROS1 fusion-positive NSCLC and included in the NCCN guidelines as preferred first-line options.
dAEs based on frequencies reported in the PROFILE1001 trial are shown.
Abbreviations: ORR, objective response rate; PFS, progression-free survival; AEs, adverse events; TKI, tyrosine kinase inhibitor; NR, not reached; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CPK, creatine phosphokinase; LDH, lactate dehydrogenase; WBC, white blood cell.