Will the clinical development of 4th-generation “double mutant active” ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC?
The current treatment paradigm for advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) categorizes the six approved ALK tyrosine kinase inhibitors (TKIs) into three generations. Second-generation (2G) and third-generation (3G) ALK TKIs are all considered “single mutant active,” with varying potency against a broad range of acquired single ALK resistance mutations. Clinicians continue to debate the optimal first-line (1L) ALK TKI for ALK+ NSCLC, as well as the sequencing strategies that should follow—whether they should be guided by specific on-target ALK resistance mutations or not. Regardless of the approach, sequential use of “single mutant active” ALK TKIs inevitably leads to the development of double ALK resistance mutations in cis.
In response, fourth-generation (4G) ALK TKIs, such as TPX-0131 and NVL-655, have been developed to target these double mutant resistance profiles. We outline the key properties that 4G ALK TKIs must possess to be clinically successful. Additionally, we propose conceptual frameworks for registrational randomized clinical trials (RCTs) of these 4G ALK TKIs in first-line, second-line, and molecularly-guided third-line settings.
The eventual role of 4G ALK TKIs in treatment will depend on the outcomes of clinical trials, as well as the trial designs adopted. If approved, these 4G agents could redefine the treatment paradigm for advanced ALK+ NSCLC by shifting the focus from the generational classification of ALK TKIs to a more functionally based categorization—distinguishing between “single mutant active” and “double mutant active” TKIs. This shift could potentially replace the current practice of sequentially using 2G and 3G ALK TKIs in an apparently arbitrary manner.