Table 2.
Summary of alternative strategies for the treatment of targeted drug resistance in ALK
| Drug regimen | Study phase | Results | Clinical trials/ref. |
| KIF5B-RET inhibitor (LOXO-292) | I | Ongoing | NCT03157128 |
| Immunotherapy (PD-L1 inhibitors) | Preclinical/clinical | Upregulation of PD-L1. Demonstrated marked antitumor efficacy compared with monotherapy in preclinical ALK-positive NSCLC models. In clinical trials, combinations showed some activity but with severe adverse events | [85,88-91] |
| Targeting drug-tolerant Persister cells | IV | Local consolidative approaches used to eliminate persister cells in areas of residual disease | NCT02314364 [92] |
| Multitarget therapy | |||
| Alectinib + Bevacizumab (anti-VEGF mAb) | I/II | Upfront ALK and VEGFR inhibition re-sensitized ALK-TKI-resistant ALK-positive NSCLC cell lines. Lorlatinib plus bevacizumab achieved disease regression | NCT02521051 [93,94] |
| Ceritinib + Everolimus (mTOR inhibitor) | I/Ib | Combination of ALK and mTOR inhibition significantly reduced the proliferation of ALK-TKI-resistant cell lines | NCT02321501 [95-98] |
| Ceritinib + Trametinib (MEK inhibitor) | Preclinical/clinical | Enhanced the magnitude and duration of initial drug response in untreated ALK-positive NSCLC cell lines and overcame resistance in ALK-TKI-resistant lines | NCT03087448 NCT03202940 [99-104] |
| Crizotinib + Dacomitinib (HER2 inhibitor) | I | Excessive toxicity | NCT01121575 [96] |
| Lorlatinib + Crizotinib | I/II | Unknown | NCT04292119 [105] |
| Lorlatinib + TNO155 | I/II | Unknown | NCT04292119 [106] |
| EGFR inhibitors | Preclinical | Improved therapeutic efficacy compared with ALK-TKI monotherapy | [107-111] |
| New ALK-targeting drugs | |||
| TPX-0131 | I | Terminated (adverse change in risk-benefit ratio) | NCT04849273 |
| NVL-655 (Neladalkib) | I/II | Ongoing | NCT05384626 |
| WX-0593 | II | Ongoing (recruiting) | NCT04641754 |
| TQ-B3139 | II | Unknown | NCT04056572 |
| Combination therapy | |||
| Chemotherapy (Irinotecan) + Alectinib | / | Partial response in primary lesion and metastases | [65] |
| Immunotherapy (Nivolumab) + Ceritinib | Ib | Demonstrated activity | [91] |
| Ipilimumab (CTLA-4 inhibitor) + Nivolumab (PD-1 inhibitor) | / | Improved response rates in advanced NSCLC | [106] |
ALK: Anaplastic lymphoma kinase; PD-L1: programmed death ligand 1; NSCLC: non-small cell lung cancer; TKI: tyrosine kinase inhibitor; EGFR: epidermal growth factor receptor.