Next-Generation Agents for ALK-Positive NSCLC - Episode 2

Patterns of Progression on Crizotinib for ALK+ NSCLC

Transcript:Corey Langer, MD: The individuals who receive crizotinib can manifest in many different ways. They can have disease confined to the lungs. They can have widespread metastases including bone, liver, lung, and brain. Some individuals present with rather indolent disease. Others present with fulminant disease. So, in that regard, how folks initially present with ALK-positive disease is not too different from those with ALK oncogenic drivers. There seem to be 3 patterns of progression when disease does start to advance. There’s the more generalized systemic diffuse progression, which absolutely mandates a change in treatment either to a second-generation TKI or to chemotherapy. There are those with very indolent progression. Every CT scan, you may see a 1- to 3-mm increase in the size of indicator lesions. And, in that group, you’ll often continue with the original TKI as long as the patient remains relatively asymptomatic. And a third well-identified form of progression is those who have isolated progression. Their liver or lung disease may be responding beautifully, but they develop isolated progression in the CNS or isolated progression in the contralateral lung. And in that group, we’ve realized over the last half decade that we can selectively treat these solitary oligo-sites of metastasis with radiation or radiation/radiofrequency ablation, or some other technique, and yet still continue the original tyrosine kinase inhibitor.

From the standpoint of when to switch therapy, that’s really dictated by the pace of progression, the sites of progression, and by our therapeutic options. So, an individual who has been on crizotinib and who has symptomatic, fairly measurable progression on CT imaging, there are 2 basic choices. One includes going to a second-generation TKI, which is our preferred approach these days. There are 2 FDA approved drugs: ceritinib and alectinib. There will probably be others in the next 6 to 12 months. If that fails, then systemic chemotherapy, usually a platinum-based combination, is our standard. In those who have much more indolent progression, who are asymptomatic where tumors are increasing maybe by 1 or 2 mm with each interval scan at 3- or 4-month intervals, that’s an individual where I’m much less likely to pull the trigger. I will often continue that patient on the original TKI, in this case, crizotinib.

From the standpoint of making a therapeutic change, it’s much more common to make that change based on disease progression rather than intolerance. Again, tolerability of these agents is very much drug specific. So, crizotinib is a pretty well-tolerated agent. Probably fewer than 5% to 10% require change in therapy due to toxicities.

Resistance in individuals with ALK rearrangements is virtually inevitable. Usually within the first year of treatment, certainly by 2 years, 70% to 80% have manifested some degree of clinical resistance. When we’ve done biopsies in these individuals, we seem to see 3 different patterns. About 35% to 40% have either ALK amplification or, more commonly, new mutations including L1196M and G1269A for which second-generation and the newer third-generation TKIs seem to have quite a bit of activity. We’ll often see other escape pathways, so the development of MEK or EGFR. I’ve seen one case with the development of a BRAF mutation that had not been detected before. As we see in EGFR-mutant-positive non—small cell lung cancer, there are some early reports of transformation to small cell. And then, the third pattern, where we have no identified mechanism of resistance, we find the same ALK translocation. There doesn’t seem to be any transformation in the molecular profile of that patient. And for some of these individuals, there are case reports where just escalating the dose can potentially overcome resistance.

Transcript Edited for Clarity