Sequencing Switches, Intriguing Combos Being Debated in ALK+ NSCLC

Joel Neal, MD

Recent regulatory approvals of second-generation ALK inhibitors for the frontline treatment of patients with ALK-positive non—small cell lung cancer (NSCLC) have helped advance the field; however, it is leading to more sequencing questions from researchers on what to now administer in the second-line setting. In May 2017, the FDA approved ceritinib (Zykadia) as a first-line treatment of patients with ALK-positive, metastatic NSCLC—a follow-up to its April 2014 approval of second-line treatment for patients who progressed on crizotinib (Xalkori), the frontline standard of care.

Most recently, alectinib (Alecensa) was granted a priority review by the FDA for frontline ALK-positive NSCLC, based in part on findings from the phase III ALEX trial presented at the 2017 ASCO Annual Meeting. Results showed that alectinib reduced the risk of disease progression or death by 53% versus crizotinib (HR, 0.47; 95% CI, 0.34-0.65; P <.0001).

“There are now 4 ALK inhibitors that are FDA approved and the second-generation ALK inhibitors are moving toward the frontline setting; so, what do we do with the first-line choice, second-line choice, and the third-line choice?” asked Joel Neal, MD, in an interview during the 2017 OncLive^® State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer. “This is a field in flux. The old system was crizotinib (first), one of the second-generation inhibitors FDA approved in the second-line setting, maybe now distinguished by side effect profile. But, it’s going to become that the second-generation inhibitors will be first and we'll have to see what to do in the second-line setting.”

OncLive: It’s been a busy year for the field of ALK-positive NSCLC. What did you reflect on?

Neal an assistant professor of medicine and oncology at Stanford Medicine, discussed the latest therapeutic changes to the ALK-positive NSCLC armamentarium. He also explored current sequencing questions as second-line inhibitors are poised to move to the upfront setting, and also some early combination studies that could flip the field around yet again.Neal: ALK-positive lung cancer is about 4% of NSCLCs. We have, historically, identified ALK-positive lung cancer by a variety of testing methods: fluorescence in situ hybridization, immunohistochemistry, and next-generation sequencing is sometimes used. Once the ALK-positive tumors are identified, then we ask, what drug can we use? There are 4 FDA-approved targeted therapies for ALK-positive NSCLC.

Is it safe to say that alectinib will become the frontline standard of care?

The 2 approved in the frontline setting are crizotinib, which has been around for a while, and ceritinib that just got approval in the first-line setting for ALK-positive lung cancer. But, 1 of the new developments that we saw at the 2017 ASCO Annual Meeting was about alectinib. Alectinib was [explored] in a head-to-head clinical trial versus crizotinib, the old standard of care, first-line drug in ALK-positive NSCLC. We saw that, while crizotinib performed as expected with a median PFS of 10 to 11 months, alectinib gave a PFS of 25.7 months, which was more than double what crizotinib did. In the first-line setting, that is 1 of the most exciting developments and some pretty compelling data to say that alectinib is moving forward. Its [current] approval is technically for patients who are refractory to crizotinib or intolerant of crizotinib, although I have heard stories about people saying that, after 1 week, they were intolerant to crizotinib and moving along and moving to alectinib. My personal preference is the data are compelling with alectinib, but whether its ceritinib or alectinib in the second-line setting versus after crizotinib, or using ceritinib or alectinib in the first-line setting, I hope that the PFS are additive. I don’t think there is something about starting with alectinib or ceritinib that is going to outperform the sequential treatment.

However, 1 of the big differences is that that the second-generation drugs seem to penetrate the brain a lot better. Patients with ALK-positive NSCLC get a lot of brain metastases. We saw in the ALEX trial that more than half on ceritinib within 2 years developed brain metastases, and only about 10% on alectinib developed brain metastases. Being on a stable dose of a tolerated therapy without developing new brain metastases that need to be managed is a good thing for patients. They don’t have to worry for an average of 2 years.

How does brigatinib (Alunbrig) factor into this evolving paradigm?

Regarding ceritinib versus alectinib, that is more down to a side effect profile. Crizotinib has known side effects of a little bit of gastrointestinal (GI) toxicity, nausea, and some peripheral edema. Ceritinib has more GI side effects, diarrhea, stomach cramping, and there is more emerging data with food—a lower dose with food that may be…more well tolerated. But, alectinib has a different side effect profile, less GI side effects, some fatigue, and some myalgia that patients report as the major side effects.Brigatinib hasn’t really been studied in the first-line setting; we haven’t seen the data there yet versus crizotinib, although studies are being done. If a patient progresses after crizotinib, now we have 3 second-generation ALK inhibitors to choose form. We have ceritinib that has been around longest, alectinib that was approved in the not-too-distant past, and then brigatinib that was just approved. There is some difference in the resistance mutations that these drugs work against although, by and large, most of these drugs work for most patients with crizotinib-refractory ALK-positive NSCLC.

Lorlatinib has also shown some fairly encouraging data. What is the latest with this drug?

Are there combination regimens being explored in the ALK-positive space?

Brigatinib has a different side effect profile, so that is 1 of the distinguishing factors; it is generally well tolerated. There is a little bit more elevated bilirubin and patients can have some pulmonary side effects when just starting the drug if they don’t dose-escalate. The side effect profile and the dosing is a little different. It is a once-a-day drug instead of alectinib, which is 4 pills twice a day. Ceritinib is approved at 5 pills once a day; sometimes, we do adjust those doses. What distinguishes brigatinib the most, at least from the data we’ve seen, is the side effect profile. Certainly, different patients may be able to tolerate different side effects.At the 2017 ASCO Annual Meeting, findings showed us that lorlatinib, after failure of crizotinib, 2 prior ALK inhibitors, or even 3 prior ALK inhibitors, still had good response rates. Most patients’ tumors shrank on clinical trials with lorlatinib in 4 different cohorts, depending on prior treatment. Lorlatinib does have some cognitive side effects and mood effects which, for each patient, may be different in terms of their manifestation but that looks like a distinguishing side effect of lorlatinib. Although it looks like it is exciting and moving forward, we are moving second-generation ALK inhibitors into the frontline setting. We are going to need to bring something in the second-line setting, and lorlatinib is one of the candidates there. There are different types of combination regimens in terms of general strategies. The 3 basic fundamental treatments for all of NSCLC are chemotherapy, targeted therapy, and immunotherapy. When you have a targeted therapy as the anchor for a combination trial, you can certainly add chemotherapy or add another targeted therapy to try to overcome acquired resistance or add immunotherapy plus a targeted therapy.

The most scientific appeal is to keep things in a similar category together as opposed to mixing all of these categories. Historically, we tend to shift major categories. What we have seen in the EGFR field is adding chemotherapy to EGFR tyrosine kinase inhibitors (TKIs) after progression on an EGFR TKI isn’t better than just moving to chemotherapy alone. In fact, there are data to suggest that it may be worse because chemotherapy works on dividing cells and TKIs stop cells from dividing, so they may be competing in terms of mechanisms.

In terms of adding immunotherapy to TKIs, there were some safety data more from the EGFR realm that suggest that adding EGFR TKIs and immunotherapy may increase the risk of pneumonitis, which is a bad thing. More safety data in clinical trials need to be done. Combining TKIs with TKIs has more side effects.

What does the future of ALK-positive NSCLC look like to you?

We need to start identifying more specific pathways of resistance because resistance to ALK can happen not only with point mutations, but also with big bypass tracks. One of the other bypass tracks is EGFR, so it’s even conceivable that, for a few patients, EGFR inhibitors plus ALK inhibitors together might be better than ALK inhibitors alone. There are many trials in this realm, but none of them, I’m aware of, are merging toward a clear standard of care. We are seeing more and more data from trials, such as the first-line ceritinib trial and first-line alectinib trial, demonstrating that some patients will have long-term disease control when the average is 2 years; there are patients who are 3 or 4 years out with disease control. We are monitoring them to make sure that that the tumor is under control and keeping them on the targeted therapy.

Of course, we would like to cure it or prevent it in the first place, but long-term disease control on a tolerable therapy is pretty good. We are stretching out that length of time, so not just the 9 to 12 months that we saw on crizotinib, but now 2 years and more. Perhaps if lorlatinib moves to the frontline setting, it will get even a little bit longer. Keeping patients on a well-tolerated therapy is always a good thing. Will we combine [agents], substitute immunotherapy, or use other immune manipulation techniques like cellular therapies to somehow target and destroy every tumor with ALK in it? All of those things are potential 5 or 10 years from now.

But, as of right now, if we can maximize the benefit on the first-line ALK inhibitor, patients will enjoy a good quality of life.

Shaw AT, Peters S, Mok T, et al. Alectinib versus crizotinib in treatment-naive advanced ALK-positive non—small cell lung cancer (NSCLC): primary results of the global phase III ALEX study. J Clin Oncol. 2017;35 (suppl; abstr LBA9008).