Weighing Treatment Strategies in ALK+ NSCLC

Alice T. Shaw, MD, PhD, provides an overlay of current treatment strategies in ALK-positive NSCLC and highlights research on the horizon.

Alice T. Shaw, MD, PhD

The global phase III ALEX trial presented some of the most compelling data the field of ALK-positive non—small cell lung cancer (NSCLC) has ever seen, enabling a second-generation TKI to be pursued in the frontline setting, said Alice T. Shaw, MD, PhD. These data also opened the door for a more active investigation of sequencing and combination strategies that are contingent upon anticipated resistance mechanisms.

“Alectinib (Alecensa) has become a new standard of care for patients with newly diagnosed ALK-positive lung cancer,” said Shaw, director of Thoracic Oncology and Paula O’Keefe Endowed Chair in Thoracic Oncology at Massachusetts General Hospital.

According to the most recent analysis of the ALEX trial, the use of frontline alectinib in previously untreated patients led to a 57% reduction in the risk of progression or death compared with the first-generation TKI crizotinib (Xalkori).1

More recently, the results of the phase III ALTA-1L trial comparing the use of brigatinib (Alunbrig) with crizotinib were reported. While the hazard ratios for progression-free survival (PFS) for alectinib (0.43) and brigatinib (0.49)2 when compared with crizotinib may be comparable, more mature data are needed before brigatinib can be considered a valid frontline alternative to alectinib, said Shaw.

In terms of sequencing, there is great focus on determining how to best sequence TKIs, as greater exposure to next-generation ALK inhibitors is leading to a greater percentage of patients with resulting ALK independence.

“In this setting, when you have both the ALK rearrangement and now you have a bypass pathway, you need a combination of therapies to be able to overcome that,” said Shaw. “We are also very interested in developing ALK-based combination therapies to overcome resistance mediated by bypass pathways, and also, to maybe prevent those bypass pathways from developing.”

In an interview during the 2019 OncLive® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Shaw, who is also a professor of medicine at Harvard Medical School, provided an overlay of current treatment strategies in ALK-positive NSCLC and highlighted research on the horizon.

OncLive: Could you describe the management of ALK-positive NSCLC and the trials to support these approaches?

Shaw: ALK rearrangement defines a subset of patients who are really sensitive to small molecular TKIs of ALK. These targeted therapies have really transformed the course of disease for patients with ALK-positive lung cancer. ALK rearrangements are often found in patients without a smoking history. These are often younger patients, and most of them have adenocarcinoma histologies. There are some characteristic clinical pathologic features associated with ALK rearrangements. However, the truth is that any patient with NSCLC could harbor an ALK rearrangement, which is why we recommend that all patients with advanced lung cancer to undergo testing for oncogenic drivers.

There are 5 ALK inhibitors FDA approved in the United States for patients with advanced ALK-positive lung cancer. The first ALK inhibitor that was developed was crizotinib; this is a multitargeted ALK/ROS/MET TKI but was first developed as an ALK inhibitor. That [agent] was the standard of care for newly diagnosed patients with ALK-positive lung cancer.

However, randomized trials such as J-ALEX and the global ALEX trial [did a head-to-head comparison] of alectinib with crizotinib. Alectinib is a second-generation ALK TKI that is more potent than crizotinib. We were looking to see whether or not patients would benefit more from treatment with a more potent, and also, more brain penetrable, ALK TKI such as alectinib.

We reported the data from the global ALEX trial about 2 years ago. These were really impressive data, because it showed that alectinib was significantly superior to crizotinib in terms of prolonging PFS. When we reported the data from the primary analysis of the global ALEX study, the median PFS with alectinib had not been reached but was between 10 and 11 months with crizotinib, as expected. The hazard ratio came in at about 0.5, which translated to about a 50% reduction in the risk of progression or death.

At the time of the primary analysis, we also noted high response rates with alectinib, including in the central nervous system (CNS), as well as a significant delay in the time to CNS progression. This really highlighted the potent intracranial activity of alectinib. For patients with ALK-positive lung cancer, brain metastases are a very common problem, so the CNS activity of alectinib is very important in the clinic. In addition to the global ALEX study, there have been 2 other randomized studies comparing alectinib with crizotinib; they both show that alectinib is superior to crizotinib. All of those data strongly support the use of alectinib as first-line therapy.

We also have a study that compared another second-generation ALK inhibitor, brigatinib, with crizotinib; this was studied in the global ALTA-1L study and was published in the New England Journal of Medicine. This [trial] was somewhat similar to the global ALEX study, although there were some differences in design. It's also important to note that the ALTA-1L study is still at an earlier stage of analysis than the global ALEX study is. The data that we've seen are from the first planned interim analysis, so it's not the final PFS analysis.

At this interim analysis, investigators showed that brigatinib was also superior to crizotinib as frontline therapy for or patients with ALK-positive lung cancer. The hazard ratio for progression or death came in at about 0.50, which is very similar to what we saw in the global ALEX study. We're waiting for that trial to mature further, but it's very likely that brigatinib will also become a standard first-line option for patients with advanced ALK-positive lung cancer.

Pending those data, in what scenario might you choose brigatinib over alectinib as frontline therapy?

At this point, the data really strongly support alectinib. With brigatinib, we have very promising data from the ALTA-1L study, but the [data] are early, so we’ll need to wait for more mature results. From a safety standpoint, there are definite advantages to alectinib over brigatinib. Overall, alectinib is a very well-tolerated drug with mostly grade 1 or mild adverse events (AEs). In general, brigatinib is also very well tolerated; however, it does have a real risk of early pulmonary toxicity, which is seen in about 5% of patients.

Overall, we see a higher incidence of pulmonary events; even though it’s a rare AE, it can be life threatening. We take that early pulmonary toxicity very seriously. There’s more data behind alectinib, and also, from a safety standpoint, it appears to be safer. As such, for now, most oncologists do favor using alectinib as the first-line therapy for their patients with ALK-positive lung cancer.

Could sequencing strategies be based on anticipated resistance mechanisms?

The optimal sequencing of ALK inhibitors is still under investigation. We do know that when patients fail on a second-generation inhibitor, such as alectinib or brigatinib, more than half of patients will have acquired a secondary ALK resistance mutation; it's an alteration within the ALK tyrosine kinase domain that interferes with drug binding. The cancers that have acquired an ALK resistance mutation are still dependent on or driven by ALK. If there is another ALK inhibitor that can be active against that mutation, that drug may be very clinically effective.

In the setting of resistance to second-generation inhibitors, we’ve seen that a more potent drug like lorlatinib (Lorbrena), which was developed to cover all of the known ALK resistance mutations, can be very effective. Lorlatinib has been shown to be particularly active in patients whose tumors have become resistant due to one of these acquired ALK resistance mutations.

We strongly advocate for some form of repeat biopsy when a patient is failing on a second-generation ALK inhibitor. We often do tumor biopsies, but liquid biopsies or circulating tumor DNA analysis can also be very helpful in identifying an underlying ALK resistance mutation. That information may then point us towards using a drug like lorlatinib, or, in some cases, depending on the exact ALK resistance mutation that's identified, you could carefully choose another second-generation inhibitor—such as ceritinib (Zykadia) or brigatinib. I only do that in cases where I know what the resistance mutation is and I know that it should be sensitive to another second-generation drug.

Where should research be focused moving forward?

ALK independence, or what we call off-target mechanisms of resistance, refers to activation of other signaling pathways that bypass ALK altogether. Hopefully in the next few months we will be launching one of the first combination studies of lorlatinib, where we are combining lorlatinib with a second targeted therapy to try and overcome resistance. There will be 3 different combinations explored in this pilot study: lorlatinib and crizotinib—specifically targeting MET as a bypass pathway—lorlatinib and a MEK inhibitor because MAP kinase reactivation can drive resistance, and lorlatinib and a SHIP2 inhibitor. We hope that the SHIP2 inhibitor may be able to inhibit some of the relevant bypass pathways in ALK resistance.

Are there any other ongoing trials to be aware of?

The combination study of lorlatinib and other ALK inhibitors will be very important because bypass pathways are emerging as a very important mechanism of resistance. That is a really large unmet need. Hopefully, there will be other ALK-targeted strategies in the future; these may include a fourth-generation ALK inhibitor. Now that we've been studying resistance to lorlatinib for the last 5 years, we've identified a whole array of different compound ALK resistance mutations; these can be double or triple ALK mutations that cause a very high level of resistance to the 5 available ALK TKIs.

Now that we have identified these different compound resistance mutations, our hope is that we may be able to design fourth-generation drugs to overcome at least a subset of these very resistant compound mutations. The other thought is perhaps we could develop a totally different type of ALK inhibitor—an allosteric ALK inhibitor—which is targeting a different area of ALK to inhibit it but not through binding to the tyrosine kinase domain. There may be more ALK-targeted strategies that really focus on ALK but in different ways.


  1. Camidge DR, Peters S, Mok T, et al. Updated efficacy and safety data from the global phase III ALEX study of alectinib (ALC) vs crizotinib (CZ) in untreated advanced ALK+ NSCLC. J Clin Oncol. 2018;35(suppl 15, abstr 9043). doi: 10.1200/JCO.2018.36.15_suppl.9043.
  2. Camidge DR, Kim HR, Ahn M-J, et al. Brigatinib versus crizotinib in ALK-positive non¬—small cell lung cancer. N Engl J Med. 2018;379(21):2027-2039. doi: 10.1056/NEJMoa1810171.