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Liu Looks Beyond Resistance in ALK-Translocated NSCLC

Caroline Seymour
Published: Friday, Jul 06, 2018

Stephen Liu, MD

Stephen Liu, MD

Responses to targeted therapies, though effective for patients with ALK translocations, are generally fleeting, said Stephen Liu, MD, adding that the research that was done to address resistance to treatment with crizotinib (Xalkori) now needs to be replicated following alectinib (Alecensa).

Although alectinib is the new standard of care in the frontline setting of ALK-positive non–small cell lung cancer, newer agents such as brigatinib (Alunbrig), lorlatinib, and ensartinib could potentially shift the landscape. As frontline treatment evolves, so does the picture of resistance, said Liu, an associate professor of medicine, Division of Hematology and Oncology, Georgetown University Medical Center.

“It’s a moving target, so to speak,” he added.

In an interview during the 2018 OncLive® State of the Science Summit™ on Non–Small Cell Lung Cancer, Liu addressed the use of available therapies and the methods of overcoming acquired resistance in patients with ALK-positive NSCLC.

OncLive: What do we know about the treatment of ALK-translocated NSCLC?

Liu: Patients with ALK-positive NSCLC harbor ALK rearrangements. There are a couple of different [treatment] options in the frontline setting. We have 3 FDA-approved drugs in the United States: alectinib, crizotinib, and ceritinib (Zykadia). Based on the ALEX trial findings, alectinib makes a compelling case to be the de facto standard of care. It wasn't compared directly with ceritinib, but it became the gold standard in the frontline setting based on the magnitude of benefit and tolerability.

That is bound to change, and if we do our job right, it should change. We expect frontline results from first-line brigatinib, lorlatinib, and ensartinib studies. Hopefully, those numbers will continue to improve. What we're faced with now is acquired resistance.

Acquired resistance remains the biggest challenge in the clinic. While we expect responses from most patients with targeted agents, we also know that those responses are transient. Eventually, tumors evolve and become resistant to the treatments that were initially working. We need newer studies and agents to help further care after resistance.

We have 3 approved drugs in the second-line setting. However, those are based on post-crizotinib data. Now that alectinib [has been] moved to the frontline setting, what to use after alectinib becomes our biggest question in the clinic. We have a little bit of evidence [to suggest] activity with ceritinib after alectinib based on the ASCEND-9 study. It's a small study based in Japan with a response rate of 25%.

The newer investigational drugs, such as ensartinib and lorlatinib, have shown pretty robust responses despite multiple lines of therapy. As we move those drugs further up, resistance will change. If we look at resistance after crizotinib, we expect solvent-front mutations in about one-quarter of patients. If you start with alectinib or ceritinib, those mutations [will manifest] in about half of patients. Every time we change the frontline treatment, the resistance picture changes as well.

What are the data surrounding these agents?

Brigatinib was the most recently FDA-approved agent in the second-line setting post-crizotinib. It maintains activity in vitro in the presence of a lot of resistance mutations, so [there is a case to be made to] use it in the salvage setting after other tyrosine kinase inhibitors (TKIs). However, most of that evidence is preclinical. It hasn't been validated in the clinic. Those efforts are ongoing.

Ensartinib and lorlatinib maintain activity in the presence of many solvent-front mutations. They have very high central nervous system penetration and a favorable toxicity profile. Those are requirements for the newer drugs. Ensartinib has shown response rates of about 80% in TKI-naïve patients. Response rates after crizotinib are pretty similar at about 72%. Ensartinib has shown activity in heavily pretreated patients, following at least 2 prior TKIs. These patients have genomically complex tumors, but experience response rates approaching 25%.

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