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Frontline Setting for ALK+ NSCLC Set to Undergo Shift

Gina Columbus @ginacolumbusonc
Published: Wednesday, Apr 05, 2017

Leena Gandhi, MD, PhD

Leena Gandhi, MD, PhD

Currently available as a second-line therapy for patients with ALK-positive non–small cell lung cancer (NSCLC), alectinib’s (Alecensa) frontline potential is being explored in the ongoing phase III ALEX study (NCT02075840), which could transform first-line treatment for these patients.

-positive NSCLC, as well as novel agents emerging in the field.

OncLive: Can you provide an overview of where we are with sequencing ALK inhibitors for this patient population?

Gandhi: That's a great question. It is actually very up in the air right now because we are in the midst of ongoing trials that may establish a new first-line standard of care. This is with the alectinib versus crizotinib trials that have been reported out from Japan, and it’s still ongoing out in the United States. Alectinib is now a standard of care for first-line therapy in Japan and I suspect it will become so here as well—once the ALEX study reads out.

The second-line setting, therefore, also gets completely mixed up once that changes because everything will have to shift around. There are newer drugs that are not yet approved and will probably play a very important role in that space, as well. 

What other recent advances have we seen with these ALK inhibitors?

The exciting things that we are still waiting to see are how good are the drugs brigatinib and lorlatinib, and what will they replace? They have the potential to become a first-line standard themselves, but there are also really important roles to be played for the second-line setting.

These are patients who, fortunately, live a long time and do develop resistance, so we really need an arsenal of drugs for sequential use over time. Having those types of drugs, which really have potency against a whole broader set of mutations, will be important to have for when resistance develops to first-line drugs. Therefore, I hope they will get used more in the second-line setting, and that we will learn more about how broadly they can cover different resistance mutations and resistance settings. We are yet to see how long they will last. They all look very promising. 

What other agents are being explored in ongoing clinical trials?

The ongoing trial that I mentioned was ALEX, which was the US study of alectinib versus crizotinib. However, there are other ongoing trials specifically for lorlatinib, which is also being tested versus crizotinib now. That will be a hard thing to tease out because it won’t be a relevant comparison by the time it reads out.

I suspect that alectinib will be used in the first-line setting more and more, depending on the outcome of ALEX. However, it will be important to see how lorlatinib performs in terms of PFS and preventing CNS metastases.

What are the main points community oncologists need to be aware of for their ALK-positive patients?

It is really important to think about ALK inhibitors as having uses in different settings. Specifically, we often in the world of oncology tend to use drugs very empirically. With ALK inhibitors, people might think about using them at random; but, in fact, we know a lot about how these drugs work—and they work in very specific settings.

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