Table 3. Putative mechanisms of resistance to EGFR-TKI and MET-TKI combination treatments.
| ID | Age (years)/sex | Prior EGFR-TKI |
Current regimen | Drug discontinuation due to adverse effect (time) | Response (PFS) | Progression site | Mechanism of acquired resistance | MET amplification after progression (test) | Subsequent treatment (response) |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 75/M | Olmutinib | Osimertinib 80 mg QD + savolitinib 600 mg QD | None | PR (11.8 m) | Lung, bone | MET D1246H | – | Sitravatinib (PR) |
| 2 | 55/M | Afatinib | Osimertinib 80 mg QD + savolitinib 600 mg QD | None | PR (4.2 m) | Brain | EGFR C797S | Negative (FISH) | Amivantamab (PR) |
| 3 | 59/F | Osimertinib | Osimertinib 80 mg QD + crizotinib 250 mg QD | None | PR (12.0 m) | Lung, liver, bone | EGFR C797S | – | – |
| 4 | 53/M | Erlotinib | Gefitinib 250 mg QD + capmatinib 400 mg BID | None | PR (20.3 m) | Lung | EGFR T790M | – | Osimertinib (PR) |
| 5 | 58/M | Dacomitinib | Erlotinib 100 mg QD + crizotinib 250 mg BID | None | PR (8.2 m) | Brain, mediastinal lymph node | EGFR T790M | Positive (FISH) | Osimertinib (PD) |
| 6 | 58/F | Osimertinib | Afatinib 20 mg QD + crizotinib 250 mg QD | None | PR (3.9 m) | Lung, liver, brain | EGFR T790M | – | Osimertinib + crizotinib (SD) |
| 7 | 60/F | Erlotinib | Osimertinib 80 mg QD + savolitinib 300 mg QD | Both drugs (8 cycles) |
PR (7.9 m) | Lung | EGFR T790M | Negative (FISH) | Osimertinib (PR) |
| 8 | 61/M | Afatinib | Erlotinib 100 mg QD + crizotinib 250 mg BID | None | PR (2.6 m) | Bone | EGFR T790M and SQCC transformation | Positive (FISH) | Osimertinib + crizotinib (PD) |
| 9 | 55/M | Erlotinib | Osimertinib 80 mg QD + savolitinib 300 mg QD | Savolitinib (1 cycle) |
PR (3.8 m) | Lung | MAP2K1 E203K and FGFR3 amplification | – | PCb (PD) |
| 10 | 57/F | Gefitinib | Osimertinib 80 mg QD + savolitinib 600 mg QD | None | SD (18.6 m) | Lung, brain | KRAS amplification | Negative (FISH) | Afatinib (PD) |
| 11 | 41/F | Gefitinib | Osimertinib 80 mg QD + savolitinib 600 mg QD | Savolitinib (1 cycle) |
PR (2.8 m) | Pericardial effusion | EGFR wild type | Negative (FISH) | GCb (PD) |
| 12 | 60/M | Osimertinib | Osimertinib 80 mg QD + crizotinib 250 mg QD | None | SD (1.8 m) | Lung | CDK4 amplification and FGFR1 amplification | Negative (FISH) | Trametinib (PD) |
| 13 | 69/F | Erlotinib | Osimertinib 80 mg QD + savolitinib 600 mg QD | None | PR (4.1 m) | Soft tissue | CCND1 amplification | Positive (FISH) | IP (PD) |
| 14 | 58/M | Erlotinib | Osimertinib 80 mg QD + savolitinib 600 mg QD | Savolitinib (1 cycle) |
SD (2.7 m) | Pleura | RB1 R320* | Positive (NGS) | Amivantamab (PR) |
TKI, tyrosine kinase inhibitor; M, male; F, female; QD, once daily; BID, twice daily; PFS, progression-free survival; PR, partial response; SD, stable disease; m, months; SQCC, squamous cell carcinoma; FISH, fluorescence in situ hybridization; NGS, next-generation sequencing; PD, progressive disease; PCb, paclitaxel plus carboplatin; GCb, gemcitabine plus carboplatin; IP, irinotecan plus cisplatin.