Figure 4. Guidelines for selecting treatment after progression on an ALK TKI.
When patients have oligoprogression on an ALK TKI, local ablative therapies can be considered. (A) When patients have systemic relapse on crizotinib, repeat biopsies should ideally be pursued if feasible, as the detection of particular ALK resistance mutations in a small number of patients (e.g., I1171, F1174, or G1202R mutations) may impact the choice of next-generation ALK TKI. However, the absence of an ALK resistance mutation after crizotinib usually does not translate into ALK independence, and these patients should go on to be treated with a next-generation ALK inhibitor. (B) After relapse on a second- or later-generation ALK TKI, we strongly recommend repeat biopsies at the time of progression to determine the resistance mechanism. The detection of a secondary ALK resistance mutation is suggestive of continued ALK dependency of tumor cells, and therefore, sensitivity to another ALK TKI that has activity against the mutant kinase. If an ALK resistance mutation is not identified, resistance may have arisen due to bypass signaling, lineage changes, or other ALK-independent mechanisms. In these cases, the tumor cells are likely no longer ALK-dependent, and combinatorial approaches or standard chemotherapy may be more effective.