Frontline Setting for ALK+ NSCLC Set to Undergo Shift

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.

This study is comparing alectinib with crizotinib (Xalkori)—a current first-line option—in the frontline setting for patients with ALK-positive NSCLC. The oncology community is anticipating reports on the data in the first half of 2017.

The FDA approved alectinib in December 2015 as a treatment for patients with metastatic ALK-positive NSCLC following progression on crizotinib, based on findings from 2 phase II clinical trials.

Recently, alectinib showed impressive results in the phase III ALUR trial, in which the ALK inhibitor significantly improved progression-free survival (PFS) versus chemotherapy in patients with ALK-positive NSCLC who had progressed following treatment with platinum-based chemotherapy and crizotinib.

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

In an interview during the 2017 OncLive^® State of the Science Summit on Advanced Non—Small Cell Lung Cancer, Leena Gandhi, MD, PhD, director of the Thoracic Medical Oncology Program at NYU Langone School of Medicine, discussed emerging developments in the first-line treatment for patients with ALK-positive NSCLC, as well as novel agents emerging in the field.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.

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

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. 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.

What other agents are being explored in ongoing clinical trials?

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. 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.

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

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.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.

You mentioned combination therapies on the horizon. Can you elaborate?

Some work better against some mutations and some work better against others. Therefore, we need to really optimize the use for individual patients. You want to be using the right drug in the right patient. The serial biopsy is a very important thing to be considering for these patients, in thinking about how to use the next-generation drugs and which of them to use next. It is hard to say about looking promising at this stage, because they’re all very early and, literally, in the design stages. However, there is an ongoing study combining the angiogenesis inhibitor bevacizumab (Avastin) with alectinib. If there is something about combining a tyrosine kinase inhibitor with an angiogenesis inhibitor—as suggested with erlotinib (Tarceva)—that may be an important study to sort of see what comes out of that.

A study that hasn’t yet started is combining MEK inhibition with alectinib, for the same idea that MEK can be an important resistant factor and this may be a way to overcome resistance.

In the next 5 to 10 years, what does the landscape of ALK-positive NSCLC look like?

I personally am conducting a study using ensartinib in combination with durvalumab, and it’s a sequencing study. When patients are treated with ensartinib, they get some benefit with the single agent; then, what does that do to the immune microenvironment? Does that tell us something about how it might be useful or not useful to combine these drugs or how to sequence them for the patients?I envision a future where patients live for many years because they have multiple options, we can use biopsies to help guide treatment, and have drugs to use in different settings. We know that with more exposure to next-generation inhibitors, patients do accumulate more mutations and may accumulate other kinds of resistance mechanisms.

There are also ongoing studies looking at combination therapies. These will be important, as well, including different TKI combinations, but also immunotherapy combinations. There are a lot of potential options out there. We rarely even use chemotherapy in ALK-rearranged patients because there are so many other targeted therapies. However, pemetrexed has very durable, long PFS compared with other chemotherapies for ALK-positive patients.

We often talk about cancer to patients with the hopes that we can turn it into a disease like diabetes—where we have many drugs to use. Although we don’t cure diabetes, we keep people well for a long time because we have so many different tools in the arsenal, and I’m hoping that will be the case for ALK-positive patients, as well.