Insights From: Corey J. Langer, MD, Perelman Center for Advanced Medicine; Hospital of the University of Pennsylvania; Mohammad Jahanzeb, MD, Univerity of Miami Miller School of Medicine; Shirish Gadgeel, MD, Wayne State University School of Medicine; Karmanos Cancer Institute
Mohammad Jahanzeb, MD: The question is, is there potential for rebiopsy at multiple points in time—at progressions? I think it’s not only feasible, but it’s also desirable to do that. Now we routinely recommend to patients that they be rebiopsied, and we have educated our interventional radiologists and pathologists, who, initially, used to be shocked by us sending a patient whose diagnosis is already established for a biopsy. Previously, patients with cancer used to get 1 biopsy in the natural history of their cancer. Now we are doing repeat biopsies upon progression—especially in patients with driver mutations, to see what type of resistance mutation has developed—in an era where we have multiple lines of targeted therapy available.
Corey J. Langer, MD: There’s a big concern about using the second-generation TKIs and potentially inducing resistance mutations a bit earlier, but it’s all theoretical. We haven’t actually seen this in practice. The fact is that we are seeing a doubling in progression-free survival: 16 or more months for ceritinib, compared with a historic control of 8 to 10 or 11 months with the crizotinib in frontline. A median PFS of over 20 months in the J-ALEX trial for alectinib strongly suggests that, at the very least, we are delaying the onset of resistance mutations or perhaps circumventing resistance mutations. We simply lack the data. We need to prospectively assay these individuals, get serial biopsies and serial blood samples, and really determine whether or not resistance mutations are actually occurring.
Shirish Gadgeel, MD: Each of the next-generation ALK inhibitors appears to have activity in the CNS, far superior to what has been observed with crizotinib. When we look at the outcomes of patients who are treated with crizotinib, up to 70% of the patients can develop brain metastases during the course of their illness. That percentage appears to be much lower with each of the next-generation ALK inhibitors, suggesting that these drugs are not only treating patients who have evidence of CNS metastases but also may be preventing the development of CNS metastases. That is somewhat speculative, and it’s an extrapolation of the data. But the major implication is in terms of both morbidity and, I believe, mortality. CNS metastases can be a big reason for symptoms and symptomatic deterioration.
In addition, in the past, the only treatment we had for patients with brain metastases was whole brain radiation. Now we do treat patients with stereotactic radiosurgery, but each of those modalities have side effects, including cognitive impairment. Having drugs that do not require us to use radiation on the brain is, I believe, a major advantage in that we are reducing the morbidity from those treatments, as well as from the occurrence of brain metastases. My suspicion is—and this is, at the present time, only speculative—that by controlling brain metastases, we are likely to improve survival. So, I feel the major advance with these next-generation ALK inhibitors is their ability to treat and possibly prevent CNS metastases.