ALK Inhibitor Sequencing in NSCLC

Transcript:David Spigel, MD: So, as you get more options, as in many cancers, like renal cell cancer, the question of sequencing comes up. Is it better to give A before B or B before A? And then a new drug C comes along. Where does that fit in? In the case of an ALK-rearranged lung cancer patient, we’ve had crizotinib, a fantastic drug, on the market for 4 years now. We have next-generation drugs now available, approved in the second-line space—alectinib and ceritinib right now. We have seen data that ceritinib and alectinib could have value in the first-line setting as well, although technically they are not approved strategies at this point. We expect that to happen hopefully soon. And so, the question is, how do you sequence medications? I think, right now, the approach that’s available to us is everybody gets crizotinib at diagnosis and then you make a choice of whether to get alectinib or ceritinib. I don’t know that there’s one wrong or right strategy there except that you need to get one of those drugs. Now, if one of those drugs moves into an earlier-line setting, then the sequence changes, although it’s unlikely somebody’s going to start with a drug like alectinib and then move on to crizotinib. But hopefully, we’ll have other drugs, and many of them are in development now as next options for patients. And, of course, there’s always chemotherapy.

Tony Mok, MD: We’re blessed that with a number of different TKIs in this era, we have both the first-generation and second-generation. So, it comes with the natural question of which should come first. There have been investigations to look into this question. There is the J-ALEX study, which is a randomized control study comparing alectinib with crizotinib. The report is that it demonstrated that there is actually significant improvement in the progression-free survival. However, the study sample size was small, and also, we have to wait for the study—which may likely come up next year—to decide whether alectinib is actually superior to crizotinib. But then, when you have this sequencing question, you come to the other question that if someone was given the second-generation TKI in the first-line, would crizotinib work? So far, there have been very few reports in this regard, as well as the chances that it may not work that way. So, people may actually come for the logical induction, asking, “Why don’t we give crizotinib first and then follow with a second-generation? Which is the optimal sequence?” It remains debatable.

Alice Shaw, MD, PhD: There are now data from a number of different groups reporting on different resistance mechanisms that emerge to second-generation inhibitors, like ceritinib, alectinib, and brigatinib. And we see that in about one-half of cases of patients who have relapsed on a second-generation inhibitor, they have developed a new ALK-resistant mutation. The spectrum and the type of ALK-resistant mutation that develops very much depend on the second-generation inhibitor that was used. Each of these drugs has a distinct chemical structure, and this leads to selection of different resistance mutations, depending on what the ALK inhibitor was. This is very important information because some second-generation inhibitors are active against certain mutations while others are not.

And so, as an example, for alectinib-treated patients, a common mutation that emerges is I1171. It can be I1171N, I1171T, or I1171S, and this mutation is very resistant to alectinib, but very sensitive to ceritinib. This would be an example where understanding the resistance mechanism that emerged on one second-generation inhibitor, alectinib, would actually guide us toward choosing yet another second-generation inhibitor, ceritinib.

I would say, similarly, if we had a patient who relapsed on alectinib and now we found the G12O2R mutation—which is actually quite common after a failure on a second-generation inhibitor—that would be a reason not to pick ceritinib, because it’s not going to be active against G12O2R, and instead to pick a third-generation inhibitor like lorlatinib, which has demonstrated activity. In fact, knowing the mutation status and the sensitivity, resistance profiles of each of these drugs is really important for tailoring subsequent therapies for ALK-positive patients.

Most ALK-positive patients either have a never-smoking history or maybe a minimal smoking history. We know that ALK rearrangements and ROS1 rearrangements are, typically, not smoking-related cancers. And so, what we’ve seen over the years, from anecdotal institutional experience and, more importantly, from the large trials of immunotherapies, is that never-smoking patients or patients with likely minimal mutation burden really have the lowest chance of responding to immunotherapies, specifically checkpoint inhibitors, like pembrolizumab and nivolumab.

In our own institutional experience, we have never had an ALK-positive patient actually respond to a single-agent checkpoint inhibitor, like nivolumab or pembrolizumab. And when we’ve looked further at these patients’ tumors, what we found is that for patients who had ALK-positive lung cancer and had received, for example, prior crizotinib or any prior ALK inhibitors, while some of those tumors may have expressed the marker, PD-L1, there really were no tumors that had any sign of both PD-L1 and inflammation. So, these are really what we call “noninflamed” tumors. The immune system just does not seem to recognize these tumors. And I think that is the underlying reason for why we really don’t see responses when ALK-positive patients are treated with immunotherapy.

So, I would say right now, in terms of how we approach patients with advanced ALK-positive or ROS1-positive lung cancer, we, of course, like to use our most active therapies first. That would include the targeted therapies, the first-, second-, and third-generation inhibitors that we have. That would include chemotherapy, particularly pemetrexed-based chemotherapy. And while immunotherapy is technically an option for patients who have received prior standard therapies, we tend to use immunotherapy much less commonly in these subgroups of patients.

Transcript Edited for Clarity