Frontline Data, Resistance Mechanisms Guide Approaches in ALK+ NSCLC

Mary Jo Fidler, MD

The growing number of options in ALK-positive non—small cell lung cancer (NSCLC) has complicated treatment sequencing; however, Mary Jo Fidler, MD, said that emerging data on resistance mechanisms are helping physicians deliver the right drug to the right patient.

“It is going to be worthwhile to see whether we can identify the resistance mechanism to alectinib (Alecensa),” said Fidler. “For example, you can have resistance completely independent of the ALK gene wherein the ALK gene is no longer the driver.”

Of the available ALK inhibitors, alectinib solidified its role as the frontline standard of care following the results of the phase III ALEX trial, which demonstrated an overall response rate (ORR) of 79% and a 47% reduction in the risk of disease progression or death compared with crizotinib (Xalkori), the previous standard first-line agent.¹

Brigatinib, a next-generation ALK inhibitor, also bested crizotinib, in the ALTA-1L trial, results of which were presented at the 19th World Conference on Lung Cancer. In the trial, brigatinib reduced the risk of disease progression or death by 51% versus crizotinib in locally advanced or metastatic ALK-positive NSCLC.^2,3

Moreover, the FDA granted lorlatinib (Lorbrena) an accelerated approval in November 2018 for patients with ALK-positive metastatic NSCLC following progression on 1 or more ALK TKIs. The approval was based on a nonrandomized study, which demonstrated a 48% ORR with lorlatinib.⁴ The third-generation ALK inhibitor is also being compared against crizotinib in the frontline setting (NCT03052608).

It is unlikely that there will be additional head-to-head comparisons of these available ALK inhibitors, said Fidler, adding that physicians will have to incorporate the growing body of knowledge on resistance mechanisms and patient tolerability into their selection criteria.

OncLive: How would you summarize the advances that have been made in the treatment of patients with ALK-positive lung cancer?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Non—Small Cell Lung Cancer, Fidler, associate professor of Rush University Medical Center, discussed the latest developments in the treatment of patients with ALK-positive lung cancer.Fidler: There have been quite a few developments over the last few years. We have more treatment options, which is great. There is more confusion for what to start with first and there is more information emerging about why these drugs may stop working for patients.

We have recently presented data on the use of brigatinib in the first-line setting for ALK-positive disease. We have emerging data now with lorlatinib for patients, some of whom have received alectinib and brigatinib. There are quite a few drugs out there for these patients. Now, we're trying to sort out the different resistance mechanisms and the pros and cons of starting with a given agent.

Where does lorlatinib fit in the treatment paradigm?

Pending the results of this trial, how do you see that data impacting the treatment paradigm?

We have longer-term follow-up on alectinib in the first-line setting. The median PFS for alectinib is about 35 months, which is fantastic for a single agent in this setting. We also have further data with alectinib on the treatment of those with brain metastases.We're waiting for the frontline trial of lorlatinib versus crizotinib. That's not going to read out for a little while though. Right now, it fits in as a salvage option for ALK-positive patients. There are some resistance mutations that we know [lorlatinib] may not work for, but there are certainly resistance mutations that it does work for. It could be an option for patients even if they have previously received 2 or 3 different ALK inhibitors.It's hard to know. We won't have long-term follow-up data on that frontline trial for a while. Its comparator is crizotinib instead of one of the second-generation agents. [Lorlatinib is likely] to beat crizotinib because crizotinib isn't as good of an ALK inhibitor as the ones that were designed later.

Can you discuss the difficulty of sequencing?

What is known about the mechanisms of resistance to ALK inhibitors?

What is the significance of molecular testing in directing treatment decisions?

It's possible we will see a signal in patients with brain metastases. Some of the phase I/II data with lorlatinib in the CNS is excellent, so that may be a niche that will be carved out for lorlatinib. I don't think we'll have meaningful frontline PFS data for quite a few years to come, mostly because these patients are expected to do very well on [lorlatinib].It's a good confusion to have because we have a lot of drugs that work. Compared with the EGFR story, where we have a clear frontrunner in the frontline setting based on toxicity profile and activity, ALK does not have a clear frontrunner. Second- and third-generation drugs are generally very well tolerated and they all seem to work. I don't think we'll ever get the answer of which one works the best; it may be which one a patient tolerates best. There may be some differences in CNS activity, but given how well these drugs work, a head-to-head comparison is going to be difficult to come by.A resistance mutation can develop to crizotinib. It doesn't develop that often, but some of the second-generation drugs that are available can target that resistance mutation. There's not a huge role for looking at mechanisms of resistance to crizotinib at this time. However, when you have patients exposed to next-generation drugs, such as alectinib, brigatinib, and ceritinib (Zykadia), then you start seeing more resistance mutations. Some of these drugs will target these mutations differently.It's becoming more important to have a molecular diagnosis. We now have data for patients who did not have EGFR or ALK mutations, and it showed great outcomes with a combination of chemotherapy and immunotherapy. It's important to [test for] mutational markers, especially before exposing patients to immunotherapy as there are data showing potential adverse events if patients are exposed to immunotherapy before targeted agents.

That is another reason to get the right drug to the right person. For example, alectinib shows a median PFS of almost 3 years. It's hard to imagine a frontline treatment that's not TKI-based achieving those outcomes. Plus, these driver mutations are typically less responsive to immunotherapy in the first place. Getting the right drug to the right patient is really important.

References

1. Genentech. FDA approves Genentech’s Alecensa (alectinib) as first-line treatment for people with specific type of lung cancer. Published November 6, 2017. http://bit.ly/2zmLda7. Accessed November 2, 2018.
2. Camidge R, Kim HR, Ahn M, et al. Brigatinib vs crizotinib in patients with ALK inhibitor-naïve advanced ALK+ NSCLC: first report of a phase 3 trial (ALTA-1L). In: Proceedings from the IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract PL02.03.
3. Camidge R, Kim HR, Ahn M, et al. Brigatinib versus crizotinib in ALK-positive non—small-cell lung cancer [published online September 25, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1810171.
4. FDA Approves Pfizer’s Lorlatinib (Lorbrena) for Previously-Treated ALK-Positive Metastatic NSCLC. Published November 2, 2018. https://bit.ly/2yPoswj. Accessed November 2, 2018