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Frontline Data, Resistance Mechanisms Guide Approaches in ALK+ NSCLC

Caroline Seymour
Published: Tuesday, Nov 27, 2018

Mary Jo Fidler, MD

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.

In an interview during the 2018 OncLive® State of the Science SummitTM 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.

OncLive: How would you summarize the advances that have been made 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.

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.

Where does lorlatinib fit in the treatment paradigm?

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.

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

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.

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