Table II.
Combined therapies to overcome 3rd-generation EGFR-tyrosine kinase inhibitor resistance.
| Targeted resistance | Target | Combined strategies | Primary outcomes | Clinical trial identifier | (Refs.) |
|---|---|---|---|---|---|
| EGFR-dependent resistance | |||||
| EGFR C797S, in cis | C797S | Brigatinib + cetuximab | mPFS time of 14 months and an ORR of 60% | None | (96) |
| Osimertinib + bevacizumab + brigatinib | PR after 1 month of treatment and had fewer EGFR mutations | None | (97) | ||
| EGFR C797S, in trans | C797S | Osimertinib + erlotinib | PR after 1 month of treatment, PD after 3 months | None | (98) |
| Osimertinib + geftinib | Clinical improvement within 3 days, PD after 1 month | None | Recruiting | ||
| EGFR-independent resistance | |||||
| MET amplification | c-Met | Osimertinib + crizotinib | PR after 1 month of treatment | None | (99) |
| Osimertinib + savolitinib | Safety (DLTs and incidence of AEs) and efficacy (ORR, PFS, DCR and OS) | NCT02143466 | (100) | ||
| Nazartinib + INC280 | Safety (DLTs and MTD) and efficacy (ORR and PFS) | NCT02335944 | None | ||
| HER2 amplification | HER2 | Osimertinib + trastuzumab | Safety (intensity and incidence of AEs) and efficacy (ORR, PFS, DCR and OS) | NCT03784599 | None |
| Osimertinib + necitumumab + trastuzumab | Safety (intensity and incidence of AEs) and efficacy (ORR, PFS and OS) | NCT04285671 | None | ||
| AXL amplification | AXL | Osimertinib + DS-1205c | Safety (DLTs and incidence of AEs) and efficacy (ORR, PFS, DCR and OS) | NCT03255083 | None |
| MEK | Osimertinib + selumetinib | Safety (DLTs and incidence of AEs) and efficacy (ORR, PFS, DCR and OS) | NCT02143466 | None | |
| RAS/RAF/MEK/ERK pathway aberrant activation | |||||
| BRAF mutation | BRAF | Dabrafenib + trametinib | ORR of 63% and a DCR of 79% | None | (101) |
| BRAF | Dabrafenib + trametinib | Safety (intensity and incidence of AEs) and efficacy (ORR, PFS, DCR and OS) | NCT04452877/N CT04507919 | None | |
| mTOR | Osimertinib + sapanisertib | Safety (DLTs and incidence of AEs) and efficacy (ORR, PFS, DCR and OS) | NCT02503722 | None | |
| JAK/STAT3 | JAK | Osimertinib + itacitinib | Safety (intensity and incidence of AEs) and efficacy (ORR, PFS and OS) | NCT02917993 | None |
| Osimertinib + AZD4205 | Safety (incidence of AEs) and efficacy (ORR) | NCT03450330 | None | ||
| Histological transformation | |||||
| SCLC transformation | None | Etoposide + cisplatin | Responded well to chemotherapy | None | (102) |
| Etoposide + cisplatin | Clinical response rate of 54% and an estimated mPFS time of 3.4 months | None | (84) | ||
| Others | |||||
| CCDC6-RET fusion | RET | Osimertinib + BLU-667 | PR after 2 months of treatment with grade 1 toxicities | None | (103) |
| PLEKHA7-ALK fusion | ALK | Osimertinib + alectinib | PR and a duration of response of 6 months | None | (89) |
| CDK4, CDK6 amplification | CDK4/6 | Osimertinib + G1T38 | Safety (DLTs and incidence of AEs) and efficacy (PFS and OS) | NCT03455829 | None |
| Unknown | VEGFR | Osimertinib + apatinib | Optimal dosage, safety (intensity and incidence of AEs) and efficacy (PFS and OS) | NCT03050411 | None |
| Osimertinib+ ramucirumab | Safety (intensity and incidence of AEs) and efficacy (CR, PR, SD, PFS and OS) | NCT02411448 | None | ||
| VEGF | Osimertinib + bevacizumab | Safety (MTD and intensity and incidence of AEs) and efficacy (ORR, PFS and OS) | NCT02803203/N CT02971501 | None | |
| BCL-2 | Osimertinib + navitoclax | Safety (intensity and incidence of AEs) and efficacy (ORR) | NCT02520778 | None | |
| BIM | Osimertinib + aspirin | The mPFS time was 15.3 and 9.3 months for the combination therapy and osimertinib groups, respectively. | None | (104) |
mPFS, median progression free survival; ORR, objective response rate; PR, partial response; PD, progressive disease; DLTs, dose limiting toxicities; AEs, adverse events; DCR, disease control rate; OS, overall survival; VEGFR, vascular endothelial growth factor receptor; CR, complete response; SD, stable disease; MTD, maximum tolerated dose; BIM, B-cell lymphoma-2 (BCL-2)-like 11; MET, hepatocyte growth factor receptor; HER2, human epidermal growth factor receptor 2; AXL, anexelekto; EGFR, epidermal growth factor receptor.