How long does it take for resistance to Lorlatinib/Lorlatinib (Borina) to develop?

Lorlatinib/ Lorlatinib ( Lorlatinib) is a third-generation ALK inhibitor that has higher selectivity and stronger mutation coverage in the treatment of ALK-positive metastatic non-small cell lung cancer. Therefore, its resistance emergence time does not have a fixed pattern, but is closely related to the patient's individual tumor genetic makeup, previous medication history, the emergence rate of drug-resistant mutations in the body, drug metabolism status, and the heterogeneity of the disease itself. Judging from the trends observed in overseas literature, the design goal of lorlatinib is to delay as much as possible the common mutation breakthroughs that occurred in the first two generations of ALK inhibitors. Therefore, many patients can maintain long-term disease control, but the occurrence of drug resistance cannot be completely avoided.

The mechanisms of resistance to lorlatinib are diverse. The core reason is that in order to escape inhibition, tumor cells will produce newALK structural mutations or combination mutations. Such changes may reduce the ability of lorlatinib to bind to the target. Other patients may experience tumor "bypass activation", that is, cancer cells no longer rely mainly on the ALK signaling pathway, but turn to other pathways to maintain survival, such as the MAPK pathway, EGFR pathway, etc. Such changes will also affect the effect of drug control. In addition, some individual differences related to drug metabolism, such as plasma protein levels and enhanced extracellular drug excretion capacity, may also indirectly lead to decreased sensitivity.

The time when drug resistance appears cannot be summarized by a unified number because the biological characteristics of tumors in different patients are not consistent. For example, patients with more complex mutational backgrounds may experience breakthrough earlier, whereas patients with partial ALK fusion types or without concomitant mutations may remain stable longer. Under the intervention of factors such as mood, lifestyle, liver and kidney metabolism, combined medication, and other factors, the drug exposure levels of different patients may also vary significantly, which will affect the rhythm of the emergence of drug resistance.

References：https://www.lorbrena.com/