Rapid Advances in ALK+ and ROS1+ NSCLC Bring Forth New Challenges

Conor E. Steuer, MD

The treatment of patients with non—small cell lung cancer (NSCLC) who have oncogenic rearrangements, such as ALK or ROS1, has rapidly advanced in recent years with the rise of second- and third-generation inhibitors, said Conor E. Steuer, MD. However, with that progress, sequencing questions have emerged as well as the challenge of acquired resistance.

“Both ALK and ROS1 [alterations] represent some of the great advancements in NSCLC treatment over the past decade or so, as they are now two of the FDA-recommended genomic alterations to test for as well as treat,” added Steuer. “The field is rapidly moving, starting with the FDA approval of crizotinib (Xalkori) to third-generation agents that are now approved.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Steuer, assistant professor in the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, discussed emerging agents in the treatment of patients with ALK- or ROS1-positive NSCLC and the sequencing challenges that have resulted in the space.

OncLive: What recent advances have been made in ALK- and ROS1-positive NSCLC?

Steuer: ALK is a fusion protein that is formed in combination with EML4 and is found in about 3% to 7% of patients. Some of the questions that are arising are, "How do you choose between these agents?” There are also questions in terms of sequencing. Patients with ALK-positive disease have a tendency to develop brain metastases, which is a very concerning symptom.

What's the best way to approach this with newer agents that have good central nervous system (CNS) penetration? ROS1 is less common than ALK; it’s found in about 1% of patients. Currently, there is 1 FDA-approved agent—crizotinib. However, many other agents have shown excellent efficacy and new data [with these agents were] just presented at the 2019 ASCO Annual Meeting. Another question that will arise again has to do with resistance mutations is, “how do we best overcome them and give the best options to our patients?”

In terms of sequencing, what factors do you take into consideration?

If I can get 10 months out of crizotinib, then another 10 to 15 months out of alectinib (Alecensa) in the second-line setting, and then maybe use lorlatinib (Lorbrena), [I’m wondering whether I] should do that? Or, should I just use alectinib and maybe get an increased progression-free survival (PFS) and then [use a] third-generation agent? How do I best use [the agents that are available]?

My general feeling is that you should use your best drugs upfront, because unfortunately, a large number of patients do not make it to second-line therapy. Especially in ALK-positive disease, CNS metastases tend to be a big deal, and the second- and third-generation agents have a lot more activity in the brain. As such, we would really like to use those agents for those patients upfront.

How do these agents compare with each other in terms of efficacy?

[In terms of] the second-generation agents, alectinib has shown efficacy over crizotinib and brigatinib (Alunbrig) has [over crizotinib] as well. Ceritinib (Zykadia) has only been compared with chemotherapy; we don't have data on that agent versus crizotinib at this point.

Will researchers stop using crizotinib as a comparator arm in future trials now that several agents have been shown to be more effective?

That’s a good question. If you have access to these drugs, like in the United States, it's a different question than if you're in other countries that don't have the same access that we do. If you're developing a new drug for ALK-positive NSCLC, I believe that [the comparator arm] has to at least be one of the second-generation agents. Otherwise, in 3 to 5 years, whenever you get your results, they'll be dated, and people won't know how to interpret them. At this point, in order to conduct an effective study, [the investigational agent] will need to be compared with a second-generation agent.

Are there any emerging agents that have shown some promise in this area?

To my knowledge, lorlatinib is the newest third-generation inhibitor. What is [on the horizon] are the drugs that are developed for other [oncogenic rearrangements]. TRK inhibitors, such as entrectinib (Rozlytrek), [might be useful in patients with ALK or ROS1 rearrangements]. What remains to be seen is how those agents fit into the paradigm, because they're all coming out with data for the different genomic targets.

What other agents are showing activity in ROS1-positive disease?

Crizotinib has shown activity, and lorlatinib has certainly shown a lot of exciting activity. Because ALK and ROS1 [alterations] are so similar, a lot of these agents have activity against both. One important point to remember, however, is that alectinib did not have any activity in patients with ROS1-positive disease. Therefore, when you're thinking about what to give those patients, don't consider alectinib.

Of course, some of the TKIs are exciting. Repotrectinib (TPX-0005) was just presented at the 2019 ASCO Annual Meeting and showed very exciting activity, including in patients who had resistance mutations to other drugs, including the G2032R [resistance] mutation; this is kind of the gatekeeper of mutations. That's exciting. With ALK and ROS1, it's almost less exciting to see what the new [next]-generation agent is than it is to see if there are new agents that can overcome the resistance mechanisms and extend PFS. [This area] is starting to mimic the world of EGFR with osimertinib (Tagrisso).

Are there any combination strategies under investigation?

There is a lot of excitement on the immunotherapy end. Unfortunately, toxicity is a big concern when combining immunotherapy agents with TKIs. Therefore, at this point, I'm not sure of any combinations that have proven effective. I know in the EGFR-positive space, VEGF inhibitors combined with TKIs are showing promise, but I believe more work needs to be done in this field for the treatment of these patients.