Leveraging the Growing Arsenal of ALK and ROS1 Inhibitors in NSCLC

Nathan A. Pennell, MD, PhD, discusses the actionability of advanced ALK-positive and ROS1-positive non–small cell lung cancer and the drugs that have emerged in the frontline and second-line settings.

Nathan A. Pennell, MD, PhD

Given the number of effective targeted treatments that are available to patients with advanced ALK- and ROS1-positive non—small cell lung cancer (NSCLC), there is no reason to forego genomic testing in lieu of alternative therapy, said Nathan A. Pennell, MD, PhD.

“It's very easy to see someone with NSCLC and just give them chemotherapy and immunotherapy without worrying about testing. However, we don't know that these patients do as well with chemotherapy and immunotherapy [as patients without driver mutations],” said Pennell. “You may be, in some ways, condemning the patient to a much shorter survival than you would be if you tested them.”

If testing reveals an ALK alteration, alectinib (Alecensa) is generally recommended as frontline therapy due to its superior progression-free survival (PFS) and central nervous system (CNS) activity compared with crizotinib (Xalkori).1 However, brigatinib (Alunbrig) has also emerged as a potential option in the frontline setting after demonstrating favorable responses over crizotinib in the phase III ALTA-1L trial.2

Furthermore, the third-generation TKI lorlatinib (Lorbrena) has been positioned as an optimal second-line therapy for patients who progress on crizotinib or a second-generation inhibitor. The drug has also shown high objective responses in the frontline setting.3

Due to the similarity between the ALK and ROS tyrosine kinase domains, crizotinib has also been shown to induce high objective responses in previously untreated patients with ROS1 positivity.4

In addition to crizotinib, entrectinib (Rozlytrek) has also joined the frontline space. In August 2019, the FDA approved entrectinib for the treatment of patients with newly diagnosed metastatic ROS1-positive NSCLC, as well as for the treatment of adult and pediatric patients ≥12 years of age with solid tumors that harbor an NTRK fusion. Updated results of a pooled analysis of the STARTRK-2, STARTRK-1, and ALKA-372-001 trials showed that treatment with entrectinib led to frequent and durable responses in patients with ROS1-positive and NTRK-positive NSCLC.5

In an interview during the 2019 OncLive® State of the Science Summit™ on Non—Small Cell Lung Cancer, Pennell, director of the Lung Cancer Medical Oncology Program at the Cleveland Clinic Taussig Cancer Institute, discussed the actionability of advanced ALK-positive and ROS1-positive NSCLC and the drugs that have emerged in the frontline and second-line settings.

OncLive®: Could you discuss the targeted treatments available to patients with ALK- and ROS1-positive NSCLC?

Pennell: ALK- and ROS1-positive NSCLC are relatively rare subgroups of patients with what is generally lung adenocarcinoma. Together, patients with these alterations make up about 6% of all lung adenocarcinomas, which translates to more than 1 in 15 patients. However, these alterations as not as rare as you think. Every patient with nonsquamous NSCLC has to be tested for all of the actionable molecular markers, including ALK and ROS1, because if you don't look, you won't find them. The outcomes [with targeted therapy] are astonishingly good in these patients.

ALK was the second actionable mutation to emerge in NSCLC after EGFR. ALK is present in about 4% of patients with lung cancer. Crizotinib was the first drug to receive regulatory approval in 2011 to treat these patients; it showed a wonderful objective response rate (ORR), PFS, and a favorable safety profile.

However, the agent has recently been overtaken by the second-generation ALK inhibitors, particularly alectinib, which was initially approved for patients who progressed on crizotinib. In the global ALEX trial, previously untreated patients who received alectinib experienced a significant improvement in PFS compared with those who received crizotinib. Moreover, alectinib showed much better control of brain metastases than crizotinib. Better CNS activity is a known class effect of the second-generation drugs. As such, alectinib has become the standard in the United States for the first-line treatment of patients with ALK-positive NSCLC.

Brigatinib is another emerging drug in this space. The agent was compared in a frontline trial with crizotinib and showed [similar data] to what we've seen with alectinib. It also appears to be very well tolerated.

Could you expand on the data that have been reported with brigatinib?

Brigatinib is a second-generation ALK inhibitor that was developed along with alectinib and ceritinib (Zykadia) for patients who progressed on crizotinib. It showed an ORR of 50% to 60% and a PFS of approximately 1 year. Moreover, it has been found to be very tolerable.

From an efficacy standpoint, there is not a lot to distinguish between alectinib and brigatinib. Notably, the developer of brigatinib is sponsoring a head-to-head trial against alectinib in patients who have progressed on crizotinib. For now, both drugs are great choices if they're available. Right now, alectinib is the only drug that is approved in the first-line setting in the United States. But, if brigatinib is approved, it will be a viable choice as well.

Could you discuss the drugs that are available to patients who progress?

For patients who progress on [these] ALK inhibitors, we have the third-generation ALK inhibitor lorlatinib, which has demonstrated an ORR of approximately 32% in patients who have received a second-generation ALK inhibitor. Treatment with lorlatinib also has led to a much higher response rate in patients who received crizotinib and an even higher ORR in patients with newly diagnosed disease. It's a very exciting drug.

The one thing to note about lorlatinib is that it has a unique toxicity profile that differs from any of the other TKIs we have dealt with. Most patients get hypercholesterolemia and have to go on statin therapy. Patients can also experience cognitive adverse events, including mood and personality changes. While that's not super common, it's concerning enough that it has become something to consider when you’re deciding whether to treat a patient with the agent.

The other alternative for patients who progress on a frontline ALK inhibitor is chemotherapy. It's a traditional treatment for NSCLC. Now we have some evidence that chemotherapy plus immunotherapy may be active in patients with EGFR- and ALK-positive disease, so that's also an option for these patients. I would also want to encourage patients who progress to consider enrolling in a clinical trial. The median survival for these patients is now many years, and we want to keep pushing the envelope.

Are there any ongoing trials in the second-line ALK-positive NSCLC setting?

The ALK Master Protocol/NRG Intergroup trial is a very important study that is already open. In the trial, patients who progressed on any ALK inhibitor will get a biopsy and a blood-based plasma test to look for mechanisms of acquired resistance. Based on the results of the test, they're assigned to one of 5 or 6 different arms of different ALK inhibitors or combinations with ALK inhibitors or other targeted agents. I strongly encourage patients with progressive ALK-positive disease to be referred for that study.

Could you speak to the drugs that are showing activity in ROS1-positive NSCLC?

Crizotinib is the standard treatment for these patients. The ALK and ROS tyrosine kinase domains are almost identical, so the drugs tend to work pretty similarly. However, in the ROS1 space, we’re seeing an ORR of 70% to 80% and a median PFS of 19.3 months with crizotinib. A recent update showed a 51.4-month median OS with crizotinib in these patients.

We have a new drug in the ROS1 space called entrectinib; it also targets NTRK fusions, which are extremely rare in lung cancer. However, patients can do very well [on targeted therapy] if they’re identified. In patients with ROS1 positivity, entrectinib seemed to work identically to crizotinib in terms of ORR and PFS. The agent also seems to be active in the CNS, so it’s a very appealing option in this space. However, once patients progress, we really don't have any data for subsequent treatment. Therefore, chemotherapy alone or perhaps with immunotherapy would be an appropriate choice in that case.

Is genomic testing underutilized in NSCLC?

It’s a vastly underappreciated problem. We know that around 70% to 80% of patients in the United States are being tested for EGFR mutations, but the vast majority of patients are still getting single-gene tests. Providers are ordering an EGFR test, then an ALK test, and then a ROS1 test. We know that beyond the first couple of tests, there's a dramatic drop-off in the availability of tissue with which to do this testing. Beyond EGFR, we're probably talking about less than half of patients who are getting tested.

A publication from the University of Colorado reported that the median survival of patients with ALK-positive disease at their institution was between 7 and 8 years. I have a patient who is 11 years out with metastatic ALK-positive NSCLC who is living a very normal life. These are the kinds of outcomes that patients are going to miss out on. Everyone should talk to their pathologist about getting reflex testing at the time of diagnosis. I strongly believe that we should be doing broad next-generation sequencing—based testing rather than single-gene tests. It doesn't cost that much more to test for every actionable gene than it does to test for a single actionable gene. By the time you get beyond three tests, it's already significantly more expensive. There is no excuse not to test every patient for actionable alterations in 2019.


  1. Peters S, Camidge R, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non—small-cell lung cancer. N Eng J Med. 2017;377:829-838. doi: 10.1056/NEJMoa1704795.
  2. Califano R, Hochmair MJ, Gridelli C, et al. Brigatinib (BRG) vs crizotinib (CRZ) in the phase 3 ALTA-1L trial. Ann Oncol. 2019;30(suppl_2):ii38-ii68. doi: 10.1093/annonc/mdz063.
  3. Solomon BJ, Shaw A, Ignatius Ou S-H, et al. Phase 2 Study of lorlatinib in patients with advanced ALK+/ROS1+ non-small-cell lung cancer. Presented at: the IASLC 18th World Conference on Lung Cancer; October 15-18; Yokohama, Japan. Abstract 8573.
  4. Shaw AT, Ou S-HI, Bang Y-J, et al. Crizotinib in ROS1-rearranged non—small-cell lung cancer. N Engl J Med. 2014;371:1963-1971. doi:10.1056/NEJMoa1406766.
  5. De Braud FG, Siena S, Barlesi F, et al. Entrectinib in locally advanced/metastatic ROS1 and NTRK fusion-positive non-small cell lung cancer (NSCLC): updated integrated analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Ann Oncol. 2019;30(suppl_5). doi: doi.org/10.1093/annonc/mdz260.010.